Clinical trial NCT01852292
Conditions: Head and Neck Squamous Cell Carcinoma
Keywords: platinum pre-treated recurrent or metastatic Head and neck squamous cell carcinoma recurrent metastatic BKM120
Sponsor: Novartis Pharmaceuticals
Start date: 2013-10-01; Completion date: 2017-03-30
Enrollment: 157 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase II Study of efficacy and safety of buparlisib (BKM120) plus paclitaxel versus placebo plus paclitaxel in recurrent or metastatic Head and Neck cancer previously pre-treated with a platinum therapy.The primary endpoint was PFS and the key secondary endpoint was Overall Survival.

Detailed description:

Arms: arm 1: Patients who were randomized to this arm on a 1:1 randomization, took buparlisib 100 mg daily and paclitaxel 80 mg/m\^2 weekly. arm 2: Patients who were randomized to this arm on a 1:1 randomization, took buparlisib matching placebo 100 mg daily and paclitaxel 80 mg/m\^2 weekly.
Interventions: intervention 1: Buparlisib intervention 2: Buparlisib matching Placebo intervention 3: Paclitaxel
Intervention descriptions: intervention 1: Buparlisib comes in gelatin capsules and is taken orally at a dose of 100 mg/day. intervention 2: Buparlisib matching placebo comes in gelatin capsules and is taken orally at a dose of 100 mg/day. intervention 3: Paclitaxel is an intravenous infusion that is given once every week in 80 mg/m\^2.

Protocol documents:
Prot_001.pdf: 
Clinical Development 
Buparlisib (BKM120) 
Protocol CBKM120H2201 / NCT01852292 
Phase II multicenter randomized, double blind, placebo 
controlled study assessing the efficacy of buparlisib 
(BKM120) plus paclitaxel vs. placebo plus paclitaxel in 
patients with platinum pre-treated recurrent or metastatic 
head and neck squamous cell carcinoma. 
Authors 
Document type 
Amended Protocol Version 
EUDRACT number 
2013-000744-26 
Version number 
V03 Clean 
Development phase 
II 
Document status 
Final 
Release date 
30-Aug-2016
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 appendices ................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 12 
Protocol summary: ............................................................................................................. 14 
Amendment 3 (30-Aug-2016) ........................................................................................... 18 
Amendment 2 .................................................................................................................... 22 
Amendment 1 (Dec 2013) ................................................................................................. 24 
1 
Background ........................................................................................................................ 27 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 27 
1.1.1 
Epidemiology and current treatment options ........................................ 27 
1.1.2 
The PI3K Pathway ................................................................................ 29 
1.1.3 
PI3K pathway in squamous head and neck cancer ............................... 31 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 32 
1.2.1 
Overview of Buparlisib/BKM120 ......................................................... 32 
1.2.2 
Paclitaxel and potential for interaction ................................................. 40 
2 
Rationale ............................................................................................................................ 41 
2.1 
Study rationale and purpose ................................................................................... 41 
2.2 
Rationale for the study design ............................................................................... 42 
2.3 
Rationale for dose and regimen selection .............................................................. 42 
2.4 
Rationale for choice of combination drugs ............................................................ 43 
3 
Objectives and endpoints ................................................................................................... 44 
4 
Study design ...................................................................................................................... 46 
4.1 
Description of study design ................................................................................... 46 
4.1.1 
Treatment Phase .................................................................................... 46 
4.1.2 
Follow – up Phase ................................................................................. 46 
4.2 
Timing of interim analyses and design adaptations ............................................... 48 
4.3 
Primary statistical analysis .................................................................................... 48 
4.4 
Definition of the end of the study .......................................................................... 48 
4.5 
Early study termination .......................................................................................... 48 
5 
Patient population .............................................................................................................. 48 
5.1 
Inclusion criteria .................................................................................................... 48 
5.2 
Exclusion criteria ................................................................................................... 49 
6 
Treatment ........................................................................................................................... 53 


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6.1 
Study treatment ...................................................................................................... 53 
6.1.1 
Dosing regimen ..................................................................................... 53 
6.1.2 
Supportive treatment ............................................................................. 56 
6.1.3 
Guidelines for continuation of treatment .............................................. 57 
6.1.4 
Treatment duration ................................................................................ 57 
6.1.5 
Definition of treatment cycle ................................................................ 57 
6.2 
Dose modifications ................................................................................................ 58 
6.2.1 
Dose modification and dose delay ........................................................ 58 
6.2.2 
Treatment interruption and treatment discontinuation .......................... 58 
6.3 
Concomitant medications ...................................................................................... 73 
6.3.1 
Permitted concomitant therapy ............................................................. 73 
6.3.2 
Prohibited concomitant therapy ............................................................ 74 
6.4 
Patient numbering, treatment assignment and randomization ............................... 76 
6.4.1 
Patient numbering ................................................................................. 76 
6.4.2 
Treatment assignment and randomization ............................................ 77 
6.4.3 
Treatment blinding ................................................................................ 77 
6.5 
Study drug supply .................................................................................................. 78 
6.5.1 
Study drug preparation and dispensation .............................................. 78 
6.5.2 
Study drug packaging and labeling ....................................................... 78 
6.5.3 
Drug supply and storage ........................................................................ 79 
6.5.4 
Study drug compliance and accountability ........................................... 79 
6.5.5 
Disposal and destruction ....................................................................... 80 
7 
Visit schedule and assessments ......................................................................................... 80 
7.1 
Study flow and visit schedule ................................................................................ 80 
7.1.1 
Molecular pre-screening ........................................................................ 90 
7.1.2 
Screening ............................................................................................... 90 
7.1.3 
Treatment period ................................................................................... 92 
7.1.4 
End of treatment visit ............................................................................ 93 
7.1.5 
Follow up period ................................................................................... 95 
7.2 
Assessment types ................................................................................................... 96 
7.2.1 
Efficacy assessments ............................................................................. 96 
7.2.2 
Safety and tolerability assessments ..................................................... 100 
7.2.3 
Biomarkers .......................................................................................... 108 
7.2.4 
Patient reported outcomes ................................................................... 112 
7.2.5 
Pharmacokinetics ................................................................................ 114 
7.2.6 
Other assessments ............................................................................... 118 
8 
Safety monitoring and reporting ...................................................................................... 118 


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8.1 
Adverse events ..................................................................................................... 118 
8.1.1 
Definitions and reporting .................................................................... 118 
8.1.2 
Laboratory test abnormalities .............................................................. 119 
8.2 
Serious adverse events ......................................................................................... 120 
8.2.1 
Definitions ........................................................................................... 120 
8.2.2 
Reporting ............................................................................................. 120 
8.3 
Emergency unblinding of treatment assignment ................................................. 121 
8.4 
Pregnancies .......................................................................................................... 122 
8.5 
Warnings and precautions .................................................................................... 122 
8.6 
Data Monitoring Committee ................................................................................ 122 
8.7 
Steering Committee ............................................................................................. 123 
9 
Data Collection and Management ................................................................................... 123 
9.1 
Data confidentiality ............................................................................................. 123 
9.2 
Site monitoring .................................................................................................... 124 
9.3 
Data collection ..................................................................................................... 124 
9.4 
Database management and quality control .......................................................... 125 
10 Statistical methods and data analysis .............................................................................. 125 
10.1 
Analysis sets ........................................................................................................ 126 
10.1.1 
Full Analysis Set ................................................................................. 126 
10.1.2 
Safety Set ............................................................................................ 126 
10.1.3 
Per-Protocol Set .................................................................................. 126 
10.1.4 
Pharmacokinetic analysis sets ............................................................. 126 
10.2 
Patient demographics/other baseline characteristics ........................................... 126 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ..................... 126 
10.4 
Primary objective ................................................................................................. 127 
10.4.1 
Variable ............................................................................................... 127 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 127 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 127 
10.5 
Secondary objectives ........................................................................................... 128 
10.5.1 
Key secondary objective ..................................................................... 128 
10.5.2 
Other secondary efficacy objectives ................................................... 129 
10.5.3 
Safety objectives ................................................................................. 129 
10.5.4 
Pharmacokinetics ................................................................................ 131 
 
 132 
10.5.6 
Patient-reported outcomes ................................................................... 134 
 
 135 
10.7 
Interim analysis .................................................................................................... 135 


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10.8 
Sample size calculation ........................................................................................ 135 
10.9 
Operating characteristics of key secondary variables .......................................... 136 
11 Ethical considerations and administrative procedures .................................................... 137 
11.1 
Regulatory and ethical compliance ...................................................................... 137 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 137 
11.3 
Informed consent procedures ............................................................................... 138 
11.4 
Discontinuation of the study ................................................................................ 138 
11.5 
Publication of study protocol and results............................................................. 138 
11.6 
Study documentation, record keeping and retention of documents ..................... 138 
11.7 
Confidentiality of study documents and patient records ..................................... 139 
11.8 
Audits and inspections ......................................................................................... 139 
11.9 
Financial disclosures ............................................................................................ 139 
12 Protocol adherence .......................................................................................................... 140 
12.1 
Amendments to the protocol ................................................................................ 140 
13 References (available upon request) ................................................................................ 141 
14 Appendices ...................................................................................................................... 146 
14.1 
Appendix 1: Gilbert syndrome ............................................................................ 146 
14.2 
Appendix 2: List of prohibited CYP3A inhibitors and inducers ......................... 151 
14.3 
Appendix 3: List of CYP450 substrates to be used with caution ........................ 152 
14.4 
Appendix 4: Prohibited QT prolonging drugs with risk of Torsades de Pointes . 153 
14.5 
Appendix 5: List of QT prolonging drugs to be used with caution ..................... 154 
14.6 
Appendix 6: Guidelines for response, duration of overall response, TTF, TTP, 
progression-free survival and overall survival (based on RECIST 1.1) .............. 156 
14.7 
Appendix 7: Patient Self-Reported Mood Questionnaires .................................. 180 
14.7.1 
Scoring the PHQ-9 and GAD-7 .......................................................... 181 
14.8 
Appendix 8: Health Related Quality of Life Questionnaires ............................... 184 
14.9 
Appendix 9 ........................................................................................................... 188 
 


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List of appendices 
Appendix 1: Gilbert syndrome 
Appendix 2: List of prohibited CYP3A inhibitors and inducers 
Appendix 3: List of CYP450 substrates to be used with caution 
Appendix 4: Prohibited QT prolonging drugs with risk of Torsades de Pointes 
Appendix 5: List of QT prolonging drugs to be used with caution 
Appendix 6: Guidelines for response, duration of overall response, TTF, TTP, progression-
free survival and overall survival (based on RECIST 1.1) 
Appendix 7: Patient Self-Reported Mood Questionnaires 
Appendix 8: Health Related Quality of Life Questionnaires 
Appendix 9: Statistical Analysis 
List of figures 
Figure 1-1 
Schematic representation of the PI3K pathway .................................... 31 
Figure 1-2 
Effect of BKM120 on a variety of HNSCC cell lines ........................... 35 
Figure 1-3 
Treatment of a xenograft model of HNSCC (Fadu) with BKM120 ..... 36 
Figure 4-1 
Study design .......................................................................................... 47 
Figure 6-1 
Combined paclitaxel and buparlisib/placebo dosing scheme................ 56 
Figure 7-1 
On-treatment patients Follow-up after unblinding (from protocol 
amendment v.03) ................................................................................... 92 
Figure 14-1 
EORTC QLQ-C30 (version 3) ............................................................ 184 
Figure 14-2 
EORTC QLQ-HN35 (version 1.0) ...................................................... 186 
List of tables 
Table 1-1 
Key randomized phase III trials as first-line treatment in recurrent 
or metastatic HNSCC ............................................................................ 28 
Table 1-2 
Overview of key studies in recurrent HNSCC after platinum based 
treatment ................................................................................................ 29 
Table 1-3 
Disease control in individual patients with tumors of squamous 
histology treated with buparlisib ........................................................... 40 
Table 3-1 
Objectives and related endpoints .......................................................... 44 
Table 6-1 
Dose and treatment schedule ................................................................. 53 
Table 6-2 
Dose reduction steps for Buparlisib/placebo......................................... 59 
Table 6-3 
Criteria for interruption and re-initiation of buparlisib/placebo ........... 60 
Table 6-4 
Management of Pneumonitis ................................................................. 68 
Table 6-5 
Packaging and labeling ......................................................................... 78 
Table 7-1a 
Visit evaluation schedule ...................................................................... 82 


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Table 7-1b 
Visit evaluation schedule for patients receiving paclitaxel alone 
after unblinding ..................................................................................... 88 
Table 7-1c 
Visit evaluation schedule for patients receiving buparlisib +/- 
paclitaxel after unblinding ..................................................................... 89 
Table 7-2 
Imaging collection plan ......................................................................... 99 
Table 7-3 
ECOG performance status ................................................................... 101 
Table 7-4 
Local Clinical laboratory parameters collection plan ......................... 101 
Table 7-5 
Local ECG collection plan .................................................................. 105 
Table 7-6 
Patient self-reported mood questionnaire collection plan ................... 107 
Table 7-7 
Classification of severity based on depression and/or anxiety 
questionnaire scores ............................................................................ 108 
Table 7-8 
Biomarker sample collection plan ....................................................... 109 
Table 7-9 
Summary of tissue biomarkers ............................................................ 110 
Table 7-10 
New biopsies collection: division, priority, disposition ...................... 111 
Table 7-11 
Summary of biomarkers in blood ........................................................ 112 
Table 7-12 
Patient health-related QOL questionnaire collection plan .................. 114 
Table 7-13 
Non-compartmental PK parameters .................................................... 116 
Table 7-14 
Pharmacokinetic log table for patients with full PK sampling (16 
patients) ............................................................................................... 116 
Table 7-15 
Pharmacokinetic log table for patients with sparse PK sampling (40 
patients) ............................................................................................... 117 
Table 7-16 
Pharmacokinetic log table for patients with trough samples 
collection (all remaining randomized patients) ................................... 117 
Table 10-1 
Study Operating Characteristics .......................................................... 136 
Table 10-2 
Study Operating Characteristics to meet Proof of Concepts for OS ... 137 
Table 14-1 
List of prohibited CYP3A inhibitors and inducers ............................. 151 
Table 14-2 
List of CYP450 substrates to be used with caution*........................... 152 
Table 14-3 
List of prohibited QT prolonging drugs .............................................. 153 
Table 14-4 
List of QT prolonging drugs to be used with caution ......................... 154 
Table 14-5 
PHQ-9 Depression Scale ..................................................................... 180 
Table 14-6 
GAD-7 Anxiety Scale ......................................................................... 181 


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List of abbreviations 
AE 
Adverse Event 
AKT 
Protein Kinase B 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AUC 
Area Under the Curve 
BAL 
Bronchoalveolar lavage  
BUN 
Blood Urea Nitrogen  
CBC 
Cells Blood Count 
CERT 
Center for Education and Research on Therapeutics 
CI 
Confidence Interval 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System  
CPK 
Creatine Phosphokinase 
CR 
Complete response 
CrCl 
Creatinine Clearance 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P 
DCR 
Disease Control Rate 
DHEA 
Dehydroepiandrosterone 
DILI 
Drug-induced liver injury 
DLCO 
Carbon monoxyde diffusing capacity 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
DS&E 
Drug Safety and Epidemiology 
DSM- IV 
Diagnosic and Statistical Manual of Mental Disorders, 4th Edition 


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EBV 
Epstein-Barr Virus 
EC 
Ethic Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG P.S. 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EGFR 
Epidermal growth factor receptor 
EIAED 
Enzyme-inducing anti-epileptic drug  
EORTC 
The European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
ESMO 
European society for medical oncology 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose-Positron Emission Tomography 
FGF 
Fibroblast growth factor  
FPG 
Fasting plasma glucose 
FU/F up 
Follow-Up 
GAD-7 
General Anxiety Disorder Assessment 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor  
GGT 
Gamma-glutamyltranspeptidase 
GI 
Gastrointestinal 
GM-CSF 
Granulocyte macrophage colony-stimulating factor  
HbA1c 
Glycosylated Hemoglobin 
HBsAg 
Hepatitis B surface Antigen 
HBV 
Hepatitis B Virus 
hCG 
human chorionic gonadotrophin  
HCV 
Hepatitis C Virus 
HDL 
High density lipoprotein 
HDPE 
High Density Polyethylene 
HIV 
Human immunodeficiency virus 
H&N 
Head and Neck 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HPV 
Human papillomavirus 


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HR 
Hazard Ratio 
HSV 
Herpes Simplex Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like growth factor 1 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System 
and Interactive Web Response System 
IUD 
intrauterine device  
IUS 
intrauterine system 
i.v./IV 
intravenous(ly) 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LFT 
Liver Function Tests 
LLN 
Lower Limit of Normal 
LMWH 
Low molecular weight heparin  
LVEF 
Left Ventricular Ejection Fraction  
MAP 
Master Analysis Plan documents project standards in the statistical methods which 
will be used within the individual clinical trial RAP documentation 
MedDRA 
Medical Dictionary for Regulatory Activities 
mOS 
Median overall survival 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
mTOR 
Mammalian target of rapamycin 
MUGA 
Multiple Gated acquisition scan 
NA 
North America 
NaF PET 
Sodium Floride Positron Emission Tomography 
NCI CTC 
National Cancer Institute Common Terminology Criteria 
NCCN 
National Comprehensive Cancer Network 
ORR 
Overall Response Rate 
OS 
Overall Survival 


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PD 
Progressive disease 
PD 
Pharmacodynamics 
PFS 
Progression Free Survival 
PHQ-9 
Patient Health Questionnaire 
PI3K 
Phosphatidylinositol 3-kinase 
PIK3CA 
Gene which encode the p110alpha catalytic subunit 
PK 
Pharmacokinetics 
PLT 
Platelets 
p.o. 
per os/by mouth/orally 
PHI 
Protected Health Information 
PR 
Partial response 
PT 
Prothrombin time 
PTEN 
Phosphatase and tensin homolog 
aPTT 
Activated Partial Prothrombin time 
QLQ 
Quality of Life Questionnaire 
QTcF 
Q-T interval in the ECG (corrected according to the formula of Fridericia) 
Rb 
retinoblastoma 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended phase two dose 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SD 
Stable disease 
TBL 
Total bilirubin 
TdP 
Torsades de Pointes  
TTP 
Time to Progression 
TTR 
Time to Response 
TSC1/TSC2 
TSC1 and TSC2 are the tumor-suppressor genes mutated in the tumor syndrome 
TSC (tuberous sclerosis complex). 
UDPGA 
Uridine 5'-diphospho-glucuronic acid  
UGT 
uridine diphosphate glucuronyltransferase 
UNK 
Unknown 
UNL 
Upper Limit of Normal 
WBC 
White Blood Cell  
WHO 
World Health Organization 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.)  
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved 
indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which 
is linked to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Patient Number (Patient No.)  
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, baseline, titration, washout, 
etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; 
at this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed 
for progression and/or survival 
Randomization number 
A unique treatment identification code assigned to each randomized 
patient, corresponding to a specific treatment arm assignment 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the 
size of the tumor, whether lymph nodes contain cancer, and whether 
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Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; 
study treatment in this case refers to the investigational and non-
investigational treatments in combination 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature 
patient withdrawal 
Supportive treatment 
Refers to any treatment required by the exposure to a study treatment, 
e.g. premedication of vitamin supplementation and corticosteroid for 
pemetrexed disodium 
Treatment group 
A treatment group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. Cohorts are not expanded, new 
cohorts are enrolled 
Variable 
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints 


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Protocol summary:  
Protocol number 
CBKM120H2201 
Title 
Double blind, placebo controlled study assessing the efficacy of buparlisib 
(BKM120) plus paclitaxel vs. placebo plus paclitaxel in patients with 
platinum pre-treated recurrent or metastatic head and neck squamous cell 
carcinoma (HNSCC). 
Brief title 
Study of efficacy and safety of buparlisib (BKM120) plus paclitaxel vs. 
placebo plus paclitaxel in recurrent or metastatic Head and Neck cancer 
previously pre-treated with a platinum therapy. 
Sponsor and Clinical 
Phase 
Novartis  
Phase 2 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to assess the treatment effect of buparlisib in 
combination with weekly paclitaxel vs. buparlisib-matching placebo plus 
weekly paclitaxel on median PFS in patients with recurrent or metastatic 
HNSCC cancer that has progressed after platinum based regimen. 
 
 
 
 
Primary Objective(s)  
• 
To estimate the efficacy of buparlisib in combination with paclitaxel on 
PFS according to local radiological assessment and RECIST 1.1 in 
patients with recurrent or metastatic HNSCC cancer 
Key Secondary 
Objective 
• 
To assess the efficacy of the combination with paclitaxel in this patient 
population in terms of overall survival 
Other Secondary 
Objectives 
• 
To assess the safety and tolerability of buparlisib in combination with 
paclitaxel in this patient population as assessed by Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03  
• 
To evaluate additional efficacy parameters: Overall Response Rate 
(ORR); Time to Response (TTR); Disease Control Rate (DCR); 
Duration of Response (DoR) 
• 
To characterize the pharmacokinetics of buparlisib given in 
combination with paclitaxel 
• 
To assess the effect of buparlisib in combination with paclitaxel on 
patient’s symptoms and health-related quality of life (HRQoL) 
 
Study design 
A multi-center, randomized, double-blind, placebo-controlled phase II trial 
Patients will be randomized to receive either buparlisib 100 mg daily in 
combination with weekly paclitaxel or buparlisib-matching placebo daily in 


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combination with weekly paclitaxel and will be stratified according to the 
number of prior lines of treatment (1 vs 2) and the region of the 
investigator site (North America versus Rest of the World).  
Population 
Approximately 150 randomized patients, both females & males with 
histologically/cytologically-confirmed HNSCC, recurrent or metastatic 
disease progressing after platinum based first line treatment. 
Key Inclusion criteria 
• 
Patient has histologically/cytologically-confirmed HNSCC. 
• 
Patient has archival or new tumor tissue for the analysis of PI3K-
related biomarkers.  One tumor block (preferred) or a minimum of 12 
(15 recommended) unstained slides to be provided. Enrollment in the 
study is contingent on confirmation of an adequate amount of tumor 
tissue. 
• 
Patients with recurrent or metastatic disease after failure to platinum-
based chemotherapy (defined as progression while on or after 
platinum-based chemotherapy given in the recurrent/metastatic 
setting). Pretreatment with cetuximab (as part of chemoradiation, 
included in first-line regimen or as maintenance, or used as single-
agent as second-line therapy) is allowed 
• 
Measurable disease as determined by per RECIST criteria v1.1. If the 
only site of measurable disease is a previously irradiated lesion, 
documented progression of disease and a 4 week period since 
radiotherapy completion is required 
• 
Adequate bone marrow function and organ function 
• 
ECOG Performance Status ≤ 1 
Key Exclusion criteria 
• 
Patient has received previous treatment with any AKT, mTOR 
inhibitors or PI3K pathway inhibitors; 
• 
Patient treated with more than one prior chemotherapy regimen for 
recurrent/metastatic disease (i.e. chemotherapy, chemotherapy in 
association with a biologic/targeted agent,) 
• 
Patient has symptomatic CNS metastases. Patients with 
asymptomatic CNS metastases may participate in this trial. The 
patient must have completed any prior local treatment for CNS 
metastases ≥ 28 days prior to the start of study treatment (including 
radiotherapy and/or surgery) and must have stable low dose of 
corticosteroid therapy; 
• 
Patient has not recovered to ≤ grade 1 (except alopecia) from related 
side effects of any prior antineoplastic therapy 
• 
Patient has any of the following cardiac abnormalities: 
• 
symptomatic congestive heart failure,  
• 
history of documented congestive heart failure (New York 
Heart Association functional classification III-IV), 
documented cardiomyopathy,  
• 
Left Ventricular Ejection Fraction (LVEF) <50% as 
determined by Multiple Gated acquisition (MUGA) scan or 
echocardiogram (ECHO) 
• 
myocardial infarction ≤ 6 months prior to enrolment,  
• 
unstable angina pectoris,  
• 
serious uncontrolled cardiac arrhythmia,  


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• 
symptomatic pericarditis,  
• 
QTcF > 480 msec on the screening ECG (using the QTcF formula) 
• 
currently receiving treatment with medication that has a known risk 
to prolong the QT interval or inducing Torsades de Pointes, and 
the treatment cannot be discontinued or switched to a different 
medication prior to starting study drug. A list of prohibited drugs 
will be provided in the final protocol 
Investigational and 
reference therapy 
• 
buparlisib (BKM120) plus paclitaxel  
• 
Placebo plus paclitaxel  
Efficacy assessments 
Tumor assessment done 4 weeks after study treatment start and every 6 
weeks afterwards; 
• 
CT/MRI of primary tumor  
• 
Chest and abdomen CT scan 
• 
Pelvis CT scan if clinically indicated 
• 
Whole body bone scan if clinically indicated to be performed according 
to institutional guidelines (if already performed within 6 weeks prior to 
start of treatment, this scan can be considered as the screening scan). 
• 
Localized CT, MRI or X-rays of all skeletal lesions identified on the 
screening bone scan, which are not visible on the chest, abdomen or 
pelvis CT (or MRI) must be taken at screening and at each 
subsequent tumor assessment. 
• 
Brain CT or MRI if clinically indicated 
• 
From protocol amendment v03, tumor assessment done as per local 
clinical practices. 
Safety assessments 
• 
Monitored by  
• 
ECOG Performance status 
• 
Vital signs 
• 
Physical examination 
• 
Weight 
• 
Pulmonary function testing 
• 
Hematology 
• 
Biochemistry 
• 
Creatinine clearance determination 
• 
Coagulation 
• 
Lipid profile 
• 
Fasting plasma glucose, C-peptide 
• 
HbA1c 
• 
Adverse events 
• 
Prior/concomitant medications 
• 
PHQ-9 
• 
GAD-7 
• 
Serious and non-serious Adverse Events (AE) collection 


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Data analysis 
• 
The primary analysis will be performed when approximately 120 PFS 
events have been observed. 
• 
For the key secondary analysis, the analysis of Overall Survival will be 
performed when approximately 112 deaths have been recorded. 
The primary and the key secondary analyses will be based on the point 
estimate and posterior distribution of the respective hazard ratios 
estimated via a stratified Cox Proportional hazards model.  
All secondary analyses will be reported for the adequate population (i.e. 
FAS, Safety Set) by treatment groups. 
 
Buparlisib, BKM120, paclitaxel, platinum pre-treated recurrent or 
metastatic head and neck squamous cell carcinoma (HNSCC). 


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Amendment 3 (30-Aug-2016) 
Amendment rationale  
Enrolment in study CBKM120H2201 was completed on 7 April 2015, with a total of 158 
patients randomized. At the time of this amendment, all protocol planned analyses (Final PFS 
and Final OS) have been completed. No further analyses are planned except for safety updates 
after the Last Patient Last Visit (LPLV). As of 18 August 2016, six patients are still on study 
treatment.  
The main purposes of this protocol amendment are to: 
• Provide a clarification on the measures to follow when a patient exhibits suicidal ideation 
regardless of the response to question 9 of the PHQ-9 questionnaire (as has been 
described in the BKM120 Investigator’s Brochure Ed. 8.0).  
Rationale: Patient Health Questionnaire-9 (PHQ-9) is used to increase the sensitivity of 
identifying potential depression and suicidal thoughts via positive response to “ question 9” . 
However, it has not been consistently predictive for suicidal ideation or attempt in buparlisib 
trials, as some patients who exhibited suicidal ideation or attempt, reported as an adverse 
event, either had a negative response to question 9 or did not answer it. Hence, measures to be 
followed for any adverse event of suicidal ideation regardless of the response to question 9 or 
the total score of PHQ-9 have been specified in the Investigator’s Brochure Ed. 9.0/dated 29 
April 2016. 
A prospective suicidality assessment in clinical trials with buparlisib is important and i s  
facilitated using question 9 of the PHQ-9 questionnaire. A timely interview with the 
patient after the questionnaire completion is recommended. Patients with a positive responses 
to question 9 (as indicated by selecting “1”, “2” or “3”), or otherwise exhibiting any suicidal 
ideation must immediately interrupt the buparlisib/placebo treatment and must be assessed by 
a Psychiatrist. This is regardless of the response or lack of to question 9 or total PHQ-9 score 
or CTCAE grading of the suicidal ideation. 
• Unblind patients’ treatment considering that all planned analyses have been completed. 
The study will be closed after LPLV 
• Reduce assessment schedule for patients still on study treatment. Tumor assessment will 
be performed per local clinical practices and safety evaluation will be done per revised 
visit schedule.  
• For patients who are still on study treatment and are considered benefiting from study 
drug (s), study treatment will continue to be provided on or off this study. Treatment for 
these patients can also be managed according to local clinical practices per investigator 
discretion. Where feasible and available, patients may be transitioned to commercial 
paclitaxel. 
Additional changes 
Update to the guidelines for buparlisib/placebo administration related to food intake. 


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Rationale: A clinical pharmacology study [CBKM120C2108] investigating the food effect of 
both a low fat low calorie meal (LFLC) or a high fat, high calorie meal (HFHC) on the 
pharmacokinetics of buparlisib in healthy volunteers showed that intake of food 
concomitantly with buparlisib led to a delayed and reduced Cmax without a meaningful 
impact on exposure (AUCinf) compared to fasting administration (BKM120 Investigator’s 
Brochure Ed. 8.0). Based on these findings, buparlisib can be administered with or without 
food and accordingly the guidelines had been updated.  
Changes to the protocol 
Changes to the protocol summary section: Tumor assessments in the randomized treatment 
phase and post-treatment follow-up phase updated 
Update to the section on buparlisib dosing, regardless of food intake: 
Buparlisib/Placebo can be taken with or without food; 
Changes in the section on management and follow-up of mood alteration: 
Clarification on measures to be followed (interruption of buparlisib/placebo and psychiatric 
consultation) for any patient who presents with suicide ideation of any grade  
Changes to the study assessments: 
• The inclusion of a statement that regardless of grade or response to question number 9 in 
PHQ-9 questionnaire, any patient who presents with suicide ideation must be referred for 
a psychiatric consultation. 
• Adding a statement to require the investigator to assess the patient for suicidal ideation 
regardless of the answer to question 9 of PHQ- 9 or if the patient did not respond to 
question 9 in PHQ-9 questionnaire. 
• For patients still on study treatment, assessment frequency will be reduced. Tumor 
assessment will be performed per local clinical practices and safety evaluation will be 
done per revised visit schedule. New Table 7-1b and Table 7-1c have been added to 
describe the assessments. Table 7-1 has been renamed 7-1a.  
• Collection of EORTC QLQ-C30 and EORTC QLQ-HN35 questionnaires to be 
discontinued for patients still on study treatment 
The following sections have been changed in the amended protocol: 
• Section 4.1.1 Treatment phase: updated to clarify patient monitoring after unblinding. 
• Section 4.1.2 Follow-up phase: implementation of the reduced assessments schedule and 
Figure 4-1 updated; 
• Section 4.4 Definition of the end of the study: updated.  
• Section 6.1.1 Dosing regimen: removal of the requirement that buparlisib/placebo be 
taken with regard to food intake  
• Section 6.1.4 Treatment duration: disease progression to be evaluated as per standard of 
care instead of RECIST 1.1 
• Section 6.2.2 Table 6-3 Criteria for interruption and re-initiation of buparlisib/placebo 
treatment - Mood alteration (Depression, anxiety): for grade 1 and 2 the inclusion of a 


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statement that any patient who presents with suicide ideation must be referred for a 
psychiatric consultation  
• Section 6.2.2.3.6 Guidelines for the treatment of study drug induced psychiatric disorders: 
Statement that any patient who presents with suicide ideation must interrupt 
buparlisib/placebo and be referred for a psychiatric consultation regardless of grade or 
response to question 9 in the PHQ-9 questionnaire 
• Section 6.4.3 Treatment blinding: clarification on the study unblinding given the 
completion of final OS analysis 
• Section 6.5.3 Drug supply and storage: clarification for patients on paclitaxel alone to 
switch to commercial stock if feasible 
• Section 7.1 Visit schedule and assessments: renamed Table 7-1 as 7-1a and addition of 
Table 7-1b and Table 7-1c to describe the assessments performed after unblinding 
• Section 7.1.3 Treatment period: clarification for patients on study treatment after 
unblinding 
• Section 7.1.4 End of treatment visit: implementation of the reduced assessments when 
patients discontinue treatment. 
• Section 7.1.5 Follow-up period: implementation of the reduced assessments for efficacy 
and survival follow-up 
• Section 7.2.1 Efficacy assessment and Table 7-2: description of the updated assessments 
schedule  
• 
Section 7.2.2.1 Physical examination: description of the updated assessments performed. 
• 
Section 7.2.2.2 Vital signs: description of the updated assessments performed. 
• 
Section 7.2.2.3 Height and weight: description of the updated assessments performed. 
• 
Section 7.2.2.4 Performance status: description of the updated assessments performed. 
• 
Section 7.2.2.5 Table 7-4: Local clinical laboratory parameters collection plan updated 
• 
Section 7.2.2.5.1 Hematology: description of the updated assessments performed.  
• 
Section 7.2.2.5.2 Biochemistry: description of the updated assessments performed.  
• 
Section 7.2.2.5.3 Fasting clinical laboratory parameters: monitoring fasting plasma 
glucose, c-peptide, serum lipid profile, lipase and HbA1C: description of the updated 
assessments performed.  
• Section 7.2.2.5.4 Coagulation: description of the updated assessments performed  
• Section 7.2.2.5.5 Urinalysis: description of the updated assessments performed.  
• Section 7.2.2.5.7 Viral hepatitis serology and other tests for hepatotoxicity follow-up: 
description of the updated assessments performed. 
• Section 7.2.2.6 Radiological examinations: description of the updated assessments 
performed. 
• Section 7.2.2.7.2 Cardiac assessments: description of the updated assessments performed 
• Section 7.2.2.8 GAD-7 and PHQ-9 Questionnaires:  
• Adding a statement that any patient who presents with suicide ideation must interrupt 
buparlisib/placebo and be referred for a psychiatric consultation regardless of grade or 
response to question 9 in the PHQ-9 questionnaire. 


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• Adding a statement requiring assessment of suicidal ideation for any patient who does 
not answer question 9 or the whole PHQ-9. 
• Section 7.2.4.1 EORTC QLQ-C30 and QLQ-HN35: clarification on requirements. 
• Section 8.2.2 Reporting: updated 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Summary of previous amendments 


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Amendment 2 
In the current study CBKM120H2201 the enrolment was completed as of 7 April 2015, and 
overall 158 patients have been randomized in this trial. As of 26 June 2015, 28 patients are 
still on treatment. 
Amendment Rationale 
The main purpose of this protocol amendment is to provide additional guidance to 
investigators around management of liver toxicities in view of the Aggregated Safety Finding 
Report submitted by Novartis to Health Authorities in May 2015. 
Alterations in liver function tests (LFTs) have been commonly observed in clinical trials with 
buparlisib as an investigational agent. These include mostly transient increases in 
transaminase enzymes (ALT and/or AST), which often occur during the first 6 to 8 weeks of 
BKM120 (buparlisib) treatment, and rarely are associated with signs/symptoms of impaired 
liver function. Current buparlisib protocols have conservative inclusion criteria for LFTs at 
study entry with close monitoring guidelines to be followed during the treatment and stringent 
dose modification/interruption criteria. 
In March 2015, a search for potential drug-induced liver injury (DILI) cases in buparlisib 
Novartis-sponsored trials using conservative biochemical criteria (e.g. AST/ALT >3.0x ULN 
and total bilirubin (TBL) >2.0xULN at any time during the treatment period, regardless of 
causality) has been conducted. Upon medical review, most of these occurred in the context of 
disease progression in advanced cancer patients and/or were confounded by other causes. 
However, six of these DILI candidates were consistent with Hy’s law criteria (e.g. AST/ALT 
>3.0x ULN and TBL >2.0xULN in the absence of cholestasis and other explanatory causes). 
Five of these cases were in combination with fulvestrant in study CBKM120F2302, and one 
in combination with the investigational drug LDE225 (sonidegib) in study CLDE225X2114. 
All patients have recovered upon treatment discontinuation except one patient for whom the 
outcome is not available because the patient refused to return for safety follow-up. Of note, 
with the exception of the first case reported as Investigator notification (IN) in April 2014, it 
is unknown at this stage whether the remaining patients received BKM120 or placebo as the 
trial remains blinded. Updated liver safety including the identified DILI/Hy’s law candidates 
for the randomized, blinded studies CBKM120F2302 and CBKM120F2303 were further 
presented to the Data Monitoring Committee (DMC) in April 2015; the DMC noted no 
change or additional liver safety concerns and recommended continuing the respective studies 
as planned. 
An Aggregated Safety Finding Report was submitted to Health Authorities and all 
investigators participating in buparlisib studies in May 2015 informing them about the liver 
findings including a brief summary of six Hy’s law cases identified. In addition, Novartis 
decided to update the current liver-related safety measures in ongoing protocols to enhance 
patient safety. Therefore, the purpose of this protocol amendment is to provide additional 
guidance to investigators around management of liver toxicities as outlined below. 
On 11 May 2015, the DMC reviewed the safety data from 135 randomized patients, and have 
been presented a summary of the aggregated safety report of liver toxicity. The 


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recommendation was to continue with the trial as planned. The DMC also recommended that 
sites vigilantly monitor ongoing patients, in particular for AEs of special interest as 
thoroughly stated in the protocol. 
Additional changes to the protocol 
Changes to the protocol summary section:  
• Clarification provided in the data analysis to reflect the change in wording for number of 
events needed for final Progression Free Survival and final Overall Survival analyses; 
Changes to the background section: 
• Update of the clinical background section on liver toxicity to align with the protocol 
amendment rationale. 
Changes in the section on management and follow-up for selected toxicities: 
• Addition of hepatotoxicity management guidelines 
Changes to the visit schedule and assessments: 
• Clarification of laboratory parameters collection plan and viral hepatitis testing.  
Changes to the statistical section: 
• Clarification of the wording for the number of Progression-free survival events required 
for the PFS analysis and for the number of deaths to be observed for the planned final 
Overall Survival analyses. 
Changes to the protocol  
The following sections have been changed in the amended protocol: 
Section 1.2.1.2 Clinical experience: addition of the outcome from a recent medical review for 
the liver toxicity. 
Section 4.3 Primary Statistical Analysis, wording change for the number of events to be 
obtained for the primary PFS Analysis 
Section 4.4 Definition in the end of study, new wording added for a potential transition to 
another protocol for patients still on treatment at the time of the final OS analysis 
Section 6.2 - Table 6-3 (Criteria for interruption and re-initiation of BKM120/placebo 
treatment): Clarification of the management of AST or ALT side effects. 
Section 6.2.2.3.7 (Additional management and follow-up for selected toxicities): New section 
added “Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total bilirubin >2.0x 
ULN) in patients receiving BKM120/placebo” including detailed liver event follow-up 
assessments and close monitoring measures. 
Section 7.1 Study flow and visit schedule - Table 7-1 (Visit evaluation schedule): addition of 
hepatotoxicity follow-up testing/procedures. 
Section 7.1.4.1 Criteria for premature patient withdrawal updated with new wording for 
withdrawal of consent  


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Section 7.2.2.5 (Laboratory evaluations) and Table 7-4 (Clinical laboratory parameters 
collection plan): addition of hepatotoxicity follow-up testing and procedures (Note: testing not 
mandatory).  
Section 7.2.2.5.7: New section added “Viral hepatitis serology and other tests for 
hepatotoxicity follow-up”. 
Section 10 Statistical methods and data analysis, wording change for the number of events to 
be obtained for the primary PFS Analysis 
Sesction 10.4.2 Statistical hypothesis, model, and method of analysis, wording change for the 
number of events to be obtained for the primary PFS Analysis 
Section 10.5.2 Other secondary efficacy objectives, wording change for the number of events 
to be obtained for the final Overall Survival Analysis 
Section 10.5.3.2 Post-treatment period: starting at day 31 after last dose of study 
medication.Adverse events (AEs), updated with summary of deaths will include on-treatment 
and post-treatment deaths. 
Other changes have been done for editorial purpose throughout 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. 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Amendment 1 (Dec 2013) 
The main rationale of the amendment 1 was: 
• To include PK sampling collection in a subset of patients in order to characterize the 
pharmacokinetics of buparlisib given in combination with paclitaxel. The aim is to assess 
if patients treated with buparlisib are exposed to the drug within the targeted range. The 
inclusion of this assessment is based on findings that emerged from study 
[CBEZ235A2118] which investigated the use of the same combination (buparlisib and 
paclitaxel). In this combination study, it was observed that the administration of 100 mg 
buparlisib led to a 35% lower exposure compared to the administration as single agent in 
study [CBKM120X2101]. The collection of additional PK data will provide more 
information in support of this study indication (dose exposure/effect relationship in the 
targeted population) and also to obtain a more robust population PK model based on 
several indications currently in clinical development using the same regimen. Objectives 
and statistical plan are updated accordingly  


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• To reduce the amount of tumor tissue required at baseline for HPV and PI3K pathway 
determination (inclusion criterion # 4). Novartis has adopted the use of a more sensitive 
platform (Next Generation sequencing) requiring smaller amount of DNA compared to the 
one previously used (Sanger sequencing). The list of biomarkers being assessed will not 
change. 
• To allow confirmation of an adequate amount of tumor tissue for enrollment by central or 
local pathologist (following Novartis defined procedure) in order to accelerate the turn-
around time for eligibility decision making process and eventually to start the study 
treatment earlier.  
• 
To modify inclusion criteria #7 as follows:  
• 
Mild and asymptomatic transaminase elevations at baseline are a common finding in 
this patient population even in the absence of liver metastasis (e.g. related to 
concomitant medications, prior treatment/surgery, underlying disease, fatty liver, 
etc.). Therefore, the upper limit for AST/ALT in patients without liver metastasis will 
be slightly increased to allow 1.5x ULN for study inclusion. The ULN for bilirubin 
remains unchanged. Furthermore, the requirement to be above the lower limit of 
normal has been removed for AST/ALT and bilirubin since values below the normal 
range are considered not clinically relevant for the purpose of entry into this study. 
• Grade 1 and asymptomatic electrolyte alterations at baseline are a common finding in 
this patient population therefore if judge not clinically relevant by the investigator; 
patient may enter into the study. 
• To update safety management guidelines for skin toxicity (section 6.2.2.3.4): rash being a 
frequent and expected AE observed with buparlisib, more detailed guidelines for dose 
reduction/interruption and therapeutic approach are provided for an optimal management 
of skin toxicities.  
• To provide an update on clinical experience with buparlisib (section 1.2.1.2) and permitted 
concomitant therapy (section 6.3.1) according to information included in the latest 
Investigator’s Brochure 
• To provide additional clarification of study procedures during screening, baseline tumor 
evaluation requirements, and schedule of DMC meetings are included in the amendment  
Changes to the protocol 
The following sections were changed in the Amendment 1 of the protocol: 
1. Section 1.2.1.2 Clinical experience with buparlisib has been updated according to the 
latest Investigator’s Brochure 
2. Section 1.2.2. Paclitaxel and potential for interaction has been updated to introduce the PK 
sampling added to this protocol 
3. Section 2.3 Rationale for dose and regimen selections has been updated 
4. Section 3 Objectives and endpoints has been updated to include an additional secondary 
endpoint based on PK 


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5. Section 5.1 Inclusion Criteria / criterion #4 has been revised to reduce the number of 
tumor tissue to be collected at screening and allow confirmation by both central and local 
pathologists 
6. Section 5.1 Inclusion Criteria / criterion #7 has been revised to allow upper limit for 
AST/ALT in patients without liver metastasis to be slightly increased to 1.5x ULN and to 
allow patients to enter the study with grade 1 and asymptomatic electrolytes alterations if 
judge not clinically relevant by the investigator 
7. Section 5.2 Exclusion Criteria/ criterion #8 and criterion #9 have been updated to reflect 
data from the last Investigator’s Brochure 
8. Section 6.1.1.1 has been updated to provide the definition of a light breakfast, and 
additional dosing guidelines for PK sampling 
9. Section 6.2.2.1 Criteria for buparlisib /placebo dose modifications has been updated for 
skin toxicities 
10. Section 6.3.1 Concomitant Medication, this section has been updated according to the 
latest Investigator’s Brochure 
11. Section 6.5.1 Study Drug Preparation and dispensation, this section has been updated to 
clarify the use of IRT for paclitaxel dispensation 
12. Section 7.1 Study Flow and Visit Schedule has been updated to reflect PK sampling 
13. Section 7.2.1 Efficacy assessments has been revised for imaging requirement at screening 
14. Section 7.2.2 Safety and Tolerability / Laboratory Evaluation has been clarified for the 
situation when lab assessment has been done 7 days prior to study treatment start and PTT 
was corrected to aPTT 
15. Section 7.2.3 Biomarkers has been updated based on the reduction on tumor tissue and 
blood requirement; 
16. Section 7.2.5 has been amended and refers now to the PK section 
17. Section 8.6  Data Monitoring Committee, has been amended to clarify schedule of the 
safety  review by the DMC  
18. Section 9.3 Data Collection has been updated to include PK data 
19. Section 10.1 Analysis Sets has been amended to include PK analysis sets 
20. Section 10.5 Secondary Objectives has been amended to add a section for 
Pharmacokinetics  
 
 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
1.1.1 
Epidemiology and current treatment options 
Cancer of the head and neck includes all cancers arising from the upper aerodigestive tract, 
and typically refers to squamous cell carcinomas originating from mucosal surfaces which 
represent more than 90% of cases. The incidence of head and neck squamous cell carcinoma 
(HNSCC) has been gradually increasing over the last three decades. It is the fifth leading 
cause of cancer by incidence and the sixth leading cause of cancer mortality in the world 
(Parkin 2006). The most important risk factors so far identified are tobacco and alcohol which 
have a synergistic effect on the mucosal surfaces. Diet is another factor implicated in the 
etiology, especially a low consumption of fibers and vitamins (Majewski 2009). Oral hygiene 
and the state of dentition have also been linked to an increased risk of developing oro-
pharyngeal cancer.  
There has been increasing awareness of a subset of HNSCC, i.e. Human papillomavirus 
(HPV)-positive HNSCC. HPV infection contributes to the etiology of around 60% of 
oropharyngeal cancers, and HPV16 is the most frequently detected strain. HPV leads to 
tumorigenesis through the production of two oncoproteins, E6 and E7, which degrade the 
tumor suppressor proteins, p53 and retinoblastoma (Rb), respectively. These events lead to 
uncontrolled cell cycle progression and potential malignant transformation. HPV infection is 
currently the only biomarker capable of predicting response to chemotherapy in this tumor 
type, whereby HPV-positive tumors present a better response to chemotherapy, leading to 
improved locoregional control and longer overall survival (Braemer 2010). Patients with 
HPV-positive HNSCC tend to be younger and have a lower intake of tobacco and alcohol.  
Treatment modalities for HNSCC include surgery, radiation therapy, and chemotherapy. Most 
patients with HNSCC present with advanced locoregional disease. With advanced HNSCC, 
only 35% to 55% of patients survive and remain disease-free for three years, despite 
aggressive therapy. Locoregional recurrence develops in 30% to 40% of patients and distant 
metastases develop in 12% to 22% of patients (Forastiere 1998). Palliative treatment of 
recurrent/metastatic HNSCC remains largely ineffective and little progress has been made. 
More effective, targeted treatments are needed. 
Although HNSCC can be considered a chemosensitive disease as shown by high response 
rates with aggressive induction therapies (eg. combination of 5-FU, cisplatin and docetaxel), 
the results are poor at relapse (Posner 2007; Vermorken 2007). Despite the progress in the 
primary treatment by combining chemotherapy, surgery, radiation therapy, and supportive 
care, the recurrence rate ranges from 30 to 50%. Patients usually relapse locally and develop 
symptoms such as difficulties in swallowing, eating, and speaking. The median survival for 
patients with recurrent disease is six months and can reach 10 months in patients with good 
general status (Vermorken 2008). Thus, improving the clinical benefit in this population is 
important to improve patients’ quality of life. 


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Platinum-based chemotherapy has been the cornerstone of first-line treatment for metastatic 
HNSCC since the 1980s. Two randomized Phase III studies conducted as first-line treatment 
in the metastatic setting showed that platinum-based doublets produced higher response rates 
than those of single-agent therapy, even though median overall survival (mOS) was not 
extended (Forastiere 1992; Jacobs 1992). In a phase III trial in patients with 
metastatic/recurrent HNSCC, there was no significant difference in survival between cisplatin 
plus 5-FU and cisplatin plus paclitaxel, but the safety profiles of the two regimens were 
different (Gibson 2005). Therefore, the combination cisplatin/5-FU still represents the most 
commonly used chemotherapy regimen in 1st line setting.  
More recently, the addition of cetuximab to the combination of cisplatin and 5-FU for first -
line treatment has shown not only a higher response rate when compared to chemotherapy 
alone and has also resulted in a remarkable increase in OS since the introduction of cisplatin 
(Vermorken 2008) (Table 1-1).  
Table 1-1 
Key randomized phase III trials as first-line treatment in recurrent or 
metastatic HNSCC 
Reference 
No. of patients 
and 
characteristics 
Treatment  
RR (%) 
mPFS 
(months) 
mOS 
(months) 
Jacobs (1992) 
N=245  
PS 0–1 in 62%; 
mostly 
recurrent 
A. Cisplatin/5-
FU 
B. Cisplatin 
C. 5-FU 
A. 32 (21–42) 
B. 17 (9–25) 
C. 13 (6–21) 
A vs B: p= 
.035 
A vs C: p= 
.005 
A. 2.4 
B. 2.0 
C. 1.7 
p= .023 
A. 5.5 (4.0–8.8) 
B. 5.0 (4.1–
7.2) 
C. 6.1 (4.6–
7.2) 
p= .49 
Forastiere 
(1992) 
N=261 
PS 0–1 in 72%; 
recurrent (93%) 
A. Cisplatin/5-
FU 
B. 
Carboplatin/5-
FU 
C. 
Methotrexate 
A. 32  
B. 21  
C. 10 
A vs B: p< 
.001 
B vs C: p= .05 
NR 
6.6 
5.0 
5.6 
p=NS 
Vermorken 
(2008) 
(EXTREME 
trial) 
N=442 
KPS >70 
(88%); 
recurrent only 
(53%); 
metastatic with 
or without 
recurrence 
(47%) 
A.Platinum/5-
FU /cetuximab 
B.Platinum/5-
FU 
36 (29–42) 
20 (15–25) 
p= .001 
5.6 (5.0–6.0) 
3.3 (2.9–4.3) 
p= .001 
10.1 (8.6–
11.2) 
7.4 (6.4–8.3) 
p= .04 
Therefore, the combination of cetuximab with cisplatin/5-FU has become the standard first-
line treatment for patients with recurrent or metastatic HNSCC, in fit patients with a good 
general status and in patients with more aggressive or symptomatic disease (NNCN 
guidelines; Price 2012). Platinum doublets with 5-FU or taxanes are still considered as an 


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alternative first-line treatment when it is not feasible to use cetuximab in association with 
platinum (Price 2012). In case of lack of tolerance, contraindication to platinum-based 
regimens or frail patients, the use of single agents (such as paclitaxel, docetaxel, capecitabine, 
methotrexate), is still considered an alternative option in first-line treatment.  
For patients who progress after platinum-based therapy there is no standard second-line 
chemotherapy regimen. The most commonly used compounds after platinum failure are single 
agent methotrexate and taxanes (De Andrade 2012). For this group of patients, even if another 
treatment is initiated, median OS remains low (between three and seven months), thus 
highlighting the aggressiveness of this malignancy and the need for more effective therapies 
(Stewart 2009; Leon 2005). Other chemotherapeutic agents including bleomycin, oxaliplatin, 
cyclophosphamide, pemetrexed, gemcitabine and doxorubicin have been tested in the 
palliative setting, either in combination or as monotherapy.  
Among targeted therapies, single-agent cetuximab is the only one currently approved (only by 
FDA) after platinum-failure based on the results of a single arm phase II study with 103 
patients. The observed median TTP and OS were 2.3 and 5.9 months, respectively (see Table 
1-2) (Vermorken 2007).  
Only small studies have assessed the combination of cetuximab and cytotoxic agents, but 
none of these regimens is currently approved or recommended by international guidelines.    
Table 1-2 
Overview of key studies in recurrent HNSCC after platinum based 
treatment  
Study and 
Reference 
No. of patients 
and 
Characteristics 
Treatment 
RR (%) 
mTTP/mPFS 
(months) 
mOS  
(months) 
Cetuximab 
Ph II 
(Vermorken 
2007) 
N=103 
All pts platinum 
failure 
Cetuximab 
13% 
 
2.3 
5.9 
Taxanes  
Ph II (Tahara 
2011) 
N=74 
- 23% of patients 
2nd line (after 
platinum) 
- 77% of patients 1st 
line (no platinum-
compounds in 
rec/met phase) 
Paclitaxel 100 
mg/m2 weekly for 
6 out 8 weeks 
 
37% 
 
 
3.4 
 
14.0 
Ph II (Koussis 
2007) 
N=24 
All pts platinum-
failure 
Docetaxel 35 
mg/m2 weekly 
25% 
3.2 
Not 
assessed 
1.1.2 
The PI3K Pathway  
The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates diverse cellular 
functions, including cell proliferation, survival translational regulation of protein synthesis, 
glucose metabolism, cell migration, and angiogenesis (Katso 2001). PI3K signaling also 
serves a central role in the pathogenesis of numerous forms of neoplasia. At the structural 
level, the enzyme PI3K is composed of a 110-kDa catalytic subunit and an 85-kDa adaptor 


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subunit. PI3K signaling is modulated by multiple regulators, including growth factors (such as 
EGF, IGF-1, and FGF), hormones (such as estrogen and thyroid hormone), integrins, 
intracellular calcium levels, and RAS signaling. PI3K signaling is negatively regulated at the 
level of PIP3 clearance by phospholipid phosphatases, such as the phosphatase and tensin 
homologue (PTEN) protein and the inositol 5-phosphatase-2 (SHIP2) protein.  
Constitutive activation of PI3K signaling is known to be a critical step in mediating the 
transforming potential of oncogenes and tumor suppressors in many tumor types (Liu 2009). 
Resistance to a variety of therapeutic interventions, including chemotherapy, hormonal 
therapy and anti-HER2 therapies, can also be linked to constitutive activation of the PI3K 
pathway (McCubrey 2006). Moreover, preliminary data suggest that activation of the PI3K 
pathway might be a predictor of poor prognostic outcome in many cancers.  
Molecular changes leading to constitutive activation of the PI3K pathway are diverse and 
include, but are not limited to:  
a. Gain-of-function mutations of PI3K subunits (PIK3CA encoding the PI3K catalytic subunit 
p110α; genes encoding the p85 regulatory subunit) or oncogenes encoding positive 
regulators of PI3K (e.g., HER2, EGFR, RAS, Src-family proteins)  
b. Loss-of-function mutations or epigenetic alterations affecting negative regulators of PI3K 
signaling (e.g., loss of PTEN expression or function) (Chow 2006; Cully 2006)  
Together these observations suggest that the PI3K pathway could be a critical therapeutic 
target for the treatment of patients with advanced solid malignancies who often have limited 
therapeutic options beyond the regional standard of care. Hence, pan-PI3K inhibitor treatment 
with buparlisib potentially addresses an unmet medical need in such patients. A schematic 
representation of these PI3K components is shown in Figure 1-1.  


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Figure 1-1 
Schematic representation of the PI3K pathway 
 
1.1.3 
PI3K pathway in squamous head and neck cancer 
The PI3K (phosphatidylinositol 3-kinase) pathway is a signal transduction cascade that is 
central to a variety of important physiological functions, including cell cycle, cell survival, 
protein synthesis, growth, metabolism, motility and angiogenesis. Constitutive PI3K-Akt-
mTOR pathway activation, which occurs approximately in 30% of human cancers, has been 
associated with poor prognosis. In patients presenting with HNSCC, molecular alterations 
affecting both the level of expression and function of PI3K pathway constituents have been 
identified. These include gain-of-function mutations and amplifications in PIK3CA, loss of 
heterozygosity and inactivating mutations in PTEN (negative regulator of the PI3K pathway), 
as well as overexpression/activation of AKT and mTOR signaling (molecular components 
downstream of p110a but critical to overall PI3K pathway activation) (Leemans 2010; 
Molinolo 2009). 
Multiple genetic and epigenetic events may converge to promote the activation of the PI3K-
Akt-mTOR pathway in HNSCC. Copy number gain and amplification at 3q26, where the 
PI3Ka gene is located, represents a frequent (approximately 40% of cases) and early genomic 
aberration in HNSCC (Woenckhaus 2002), which may contribute, along with epigenetic 
events, to PI3K overexpression and Akt activation (Fenic 2007; Pedrero 2005). Interestingly, 
activating mutations in the PIK3CA gene can be observed in a small fraction (< 10%) of 
HNSCC tumors (Stransky 2011; Kozaki 2006; Murugan 2008) but have been seen with a 
higher frequency (20%) in HNSCC arising from a pharyngeal site (Qiu 2006; Qiu 2008). 
PTEN can display genetic alterations in 5–10% of HNSCC lesions. Remarkably, loss of 
PTEN expression can be observed in approximately 30% of HNSCCs, and may constitute an 
independent indicator of poor clinical outcome (Lee 2001; Squarize 2002).  


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Akt, another component of the PI3K pathway has been shown to be persistently activated in 
the vast majority of HNSCC cases. The activation status of Akt showed correlation with 
disease progression, with a different expression in dysplasia, carcinoma in situ and HNSCC 
(Amornphimoltham 2004). Activation of Akt represents an independent prognostic marker of 
poor clinical outcome in both tongue and oropharyngeal HNSCCs (Massarelli 2005; Yu 
2007). Akt can be activated in HNSCC due to excessive activity of EGFR, RAS mutations, 
PI3Ka gene amplification, overexpression, or activating mutations, or defective PTEN activity 
resulting from genetic alterations and/or decreased expression. These multiple convergent 
pathways, all of which can result in enhanced Akt function, may explain why activation of 
this pathway represents one of the most frequent events in HNSCC (Molinolo 2007).  
The PI3K pathway has also been shown to be activated in response to HNSCC-specific 
alterations, either as a mechanism of resistance to EGFR inhibition (Rebucci 2011) or 
associated with HPV infection (Yarbrough 2007). However, specifically with regards to HPV 
induced HNSCC, still preliminary is the role of PI3K pathway activation as predictive or 
prognostic factor.  
In HPV negative oropharyngeal SCC, a retrospective analysis has been conducted on 73 
patients primarily treated with surgery followed by postoperative radiation to assess the 
association between expression of EGFR, IGF1R, PI3KCA, TP53 and disease-free survival 
(DFS). Interestingly, in 40% of patients was observed an increased PI3KCA gene copy 
number and the results from the analysis have shown that PI3KCA amplification and 
polisomy were associated with better prognosis (HR: 3.20, p=0.003) (Perrone 2010). 
Recently, a Phase I/II clinical trial evaluated the combination of everolimus with paclitaxel 
and carboplatin as induction treatment for advanced unresectable HNSCC stage III-IV 
patients. Preliminary results have shown promising antitumor activity, supporting the role of 
mTOR pathway inhibition in head and neck cancer treatment. Among 13 evaluable patients: 
11 objective responses were observed, including one complete response (CR), 10 partial 
responses (PR) and one stable disease (SD) (Faivre Oral presentation ESMO 2012).  
This evidence supports the need for further investigation of the PI3K pathway inhibition in the 
clinical setting in an attempt to improve quality of life, symptoms, disease control and 
outcome in patients with recurrent and/or metastatic head neck cancer in whom available 
treatments have shown a limited benefit. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of Buparlisib/BKM120 
NVP-Buparlisib (BKM120) is a potent and highly specific oral pan-class I PI3K inhibitor that 
is a 2,6-dimorpholino pyrimidine derivative. This compound has been studied extensively in 
non-clinical models and is currently being evaluated in clinical trials. Class I PI3Ks are key 
components of the PI3K/AKT/mTOR signaling pathway, which regulates cell proliferation, 
growth, and apoptosis. In many tumors the PI3K signaling pathway is constitutively activated. 
This is thought to be a critical step in mediating the transforming potential and growth 
stimulating activity of various activated proto-oncogenes (ErbB2, EGFR, Ras, Src, etc) 
contributing to the onset and progression of solid tumors as well as of hematological 


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malignancies. This compound has been studied extensively in non-clinical models and is 
currently being evaluated in clinical setting. 
1.2.1.1 
Non-clinical experience 
1.2.1.1.1 Pharmacodynamics 
Buparlisib inhibits all four PI3K catalytic subunits, including the PI3Kα mutant (H1047R-, 
E542K-, and E545K-p110α) with at least 50-fold selectivity towards this target compared to 
other protein and lipid kinases. Through this inhibition, it indirectly reduces activation of the 
direct downstream effector AKT. Buparlisib does not inhibit the related kinases mTor or 
Vps34, nor does it inhibit receptors and ion channels profiled (IC50 >10 µM). 
Buparlisib demonstrates significant tumor growth inhibition in relevant tumor xenografts in 
mice and rats when administered orally, including models of renal cell cancer (RENCA, 786-
0, Caki-1), glioblastoma multiforme (U87MG), prostate cancer (PC3M), lung cancer (A549, 
NCI-H1975), ovarian cancer (A2780), colorectal cancer (HCT116, HCT-15) and melanoma 
(A2058, A375). In vivo PK/PD analyses of tumor tissues shows a good correlation between 
exposure, PI3K pathway blockade (S473P-Akt levels), and anti-tumor activity. 
1.2.1.1.2 Safety pharmacology and toxicology 
Safety pharmacology studies in rats revealed no effects on neuronal (behavior) or respiratory 
functions. Cardiac safety studies, conducted in vitro and in vivo did not indicate a prominent 
electrophysiological risk. No relevant electrophysiological effect was seen in dogs. The only 
effect considered relevant was a trend towards an increase in systolic and diastolic blood 
pressure, which was observed in two dog telemetry studies. In rats and dogs, clinical 
pathology and histopathology findings showed quantitative reductions of lymphoid and 
erythroid counts and lymphoid tissue hypoplasia. 
The pancreas was seen to be affected by treatment with buparlisib, particularly in dogs, where 
acinar cell toxicity was seen in the exocrine part of this organ. At higher doses in the 2-week 
dose-range-finding study in rats, there were histopathological findings in both the endocrine 
as well as the exocrine pancreas. 
Male sexual organs and associated tissues were found to be targets of toxicity in both rats and 
dogs. Changes included minimal to slight germ cell depletion, formation of spermatic giant 
cells and abnormal spermatids, and cellular debris in epididymal tubules. Testicular toxicity 
did not fully reverse after the 4-week treatment-free period in rats (highest dose), although a 
clear trend towards recovery was seen. In individual female rats, minimal to slight cyst 
formation occurred in the Graafian follicles. In dogs, there was no effect on female sexual 
organs.  
Glucose homeostasis was affected in various species (mice, rats, dogs), as expected from the 
mode of action of buparlisib. However, these effects were minimal in both rats and dogs at the 
doses used in the 4-week studies. 
Other safety considerations include: 
• 
After up to 2 weeks of treatment with up to 2.5 mg/kg/day of buparlisib, alterations in 
the levels of multiple brain neurotransmitters were seen in rats. 


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• No evidence for a direct DNA interaction was found in an Ames test and two chromosome 
aberration tests in vitro with buparlisib. However, evidence of a genotoxic potential with 
buparlisib has been seen in vitro and in vivo and is likely due to an aneugenic effect.  
• No phototoxic potential or any effect on wound healing has been identified with buparlisib 
in pre-clinical studies. 
In conclusion, the majority of the observed effects were related to the pharmacological 
activity of buparlisib as an inhibitor of PI3K, such as a potential influence on glucose 
homeostasis and the risk of increased blood pressure.   
Please refer to the Investigator’s Brochure for additional information on the preclinical testing 
of buparlisib. 
1.2.1.1.3 Pharmacodynamic biomarkers 
Preclinical in vivo studies with in mouse xenograft models indicate that detectable inhibition 
of AKT phosphorylation, which is an accurate readout of PI3K activity, as well as further 
suppression of downstream signaling (e.g., decrease of phosphorylation of S6) was obtained 
soon after buparlisib administration. PI3K is known to serve a pivotal role in the regulation of 
glucose homeostasis, and preclinical studies in which oral glucose and intraperitoneal insulin 
tolerance tests were performed have suggested post-treatment induction of insulin 
insensitivity/resistance. Therefore, throughout the trial the circulating levels of several 
markers for glucose metabolism (e.g., glucose, C-peptide) will be assessed as an additional 
measure of PI3K signaling modulation. 
1.2.1.1.4 Non-Clinical experience of BKM120 in HNSCC 
In preclinical setting it was already shown that the mTOR inhibitor rapamycin, either as single 
agent or in combination with carboplatin and paclitaxel exerts an antiproliferative effect on 
head and neck cancer cell lines. Indeed it was observed that mTOR inhibitors potentiate the 
proapoptotic effects of cytotoxic agents in HNSCC cells; this synergistic effect may 
counteract the resistance to chemotherapy (Aissat 2008). 
Treatment of a series of HNSCC cell lines using BKM120 showed response in the majority of 
the lines (Figure 1-2). Furthermore in vivo treatment of a xenograft model (FaDu) showed 
down regulation of pAKT in tumor treatment as well as significant reduction of tumor 
hypoxia in the animals treated with doses equivalent to patient’s MTD. Results from a study 
conducted in FaDu xenograft models with BKM120 have shown that inhibition of the PI3K-
Akt-mTOR pathway can elicit tumor regression, normalizes the tumor vasculature and 
induces radiosensitization (Fokas 2012). 


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Figure 1-2 
Effect of BKM120 on a variety of HNSCC cell lines 
IC50s are under 1micromolar (equivalent to dose expected in patients) in the majority of the 
cell lines indicating a potential for benefit from a pan PI3K inhibitor. 
 
 


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Figure 1-3 
Treatment of a xenograft model of HNSCC (Fadu) with BKM120 
Treatment with BKM120 elicits downregulation of pAKT in tumor tissue (left panel) while 
significantly decreasing hypoxia in the tumor (right panel) (Fokas 2012) 
 
1.2.1.1.5 Non-clinical pharmacokinetics 
Buparlisib showed favorable pharmacokinetic properties in all animal species tested. The 
absorption of [14C]-BKM120- related radioactivity was > 84% in the rat. Oral bioavailability 
was moderate to high in rats, dogs and monkeys (42-100%). The estimated steady state 
plasma volume of distribution (Vss) was moderate in all species (3.0–3.5 L/kg). Buparlisib 
penetrated the blood brain barrier in rats with a tissue-to-plasma ratio about 2. Buparlisib was 
moderately bound to plasma protein across all species examined (free fraction ~15% and 
independent of concentration in humans). 
Oxidative metabolism of buparlisib is predominantly mediated by cytochrome P450 (CYP) 
isoenzyme 3A4, the estimated fraction of the oxydative metabolism is above 0.9. 
Recombinant human CYP1A1 also has the capacity to metabolize buparlisib, however, its 
endogenous expression in the human liver is negligible, and therefore it is not expected to 
have any impact on hepatic buparlisib metabolism. Direct phase II metabolism 
(glucuronidation) via UGT1A4 is also observed in human liver microsomes supplemented 
with uridine diphosphate glucuronic acid (UDPGA). All phase I metabolites identified in 
human hepatocytes and microsomes are not unique to humans and were also detected in 
animals. Buparlisib and identified metabolites have a low potential for covalent binding to 
protein. 
Buparlisib is a weak reversible inhibitor of CYP3A4 (Ki= 13.6 μM,) and it also weakly 
inhibits the CYP2C family (2C8, 2C9 and 2C19) with IC50 values ranging from 35–65 μM. 
Buparlisib did not show time-dependent inhibition of CYP450 enzymes. With respect to 
transporter-based drug-drug interactions, buparlisib is not an inhibitor or substrate of P-
glycoprotein (P-gp), multi-drug resistance associated protein (MRP)-2, breast cancer 
resistance protein (BCRP), and organic cation transporter (OCT)2. Buparlisib can inhibit 
hMATE1 and hMATE2K in vitro at concentrations above 10 µM. Based on the observed free 
concentrations of buparlisib in plasma the impact in vivo of such inhibition is expected to be 


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very limited. It is possible that buparlisib activates the pregnane X receptor (PXR) in vivo and 
induces CYP3A4 at concentrations ≥50 µM, however, the absence of any time dependent 
changes in the pharmacokinetics of buparlisib in the relevant therapeutic dose range in 
humans, suggests that this may not be relevant in vivo. Finally, experiments showed a 
potential for buparlisib to induce UGT1A1 at concentrations between 0.5 and 100 µM. The 
mean maximum free concentration calculated at steady state to date in the study 
[CBKM120X2101] was 0.671 µM (Cmax,tot=4.20 µM). Therefore a potential induction of 
UGT1A1 cannot be formally excluded, however the clinical relevance of observed activation 
of UGT1A1 activity is unclear. 
In GLP toxicology studies, buparlisib exposure in terms of AUC0-24h and Cmax increased in 
a dose proportional manner in rat and dog. There was no noticeable drug accumulation in dog 
or male rats after 13 weeks of daily dosing. There was a slight accumulation in female rats (< 
2 fold). This gender based difference in the plasma concentrations has not been seen in the 
human Phase I study. 
1.2.1.2 
Clinical experience 
• As of 15-September-2013, a total of 1469 patients and healthy volunteers have been 
enrolled into twenty two Novartis sponsored clinical studies of buparlisib: Phase I single 
agent studies [CBKM120X2101], [CBKM120X1101], [CBKM120Z2102], 
[CBKM120C2110], [CBKM120C2104], [CBKM120C2106], [CBKM120C2111] and 
[CBKM120C2102]. 
• Phase II single agent studies [CBKM120C2201] and [CBKM120D2201]  
• Phase I combination studies [CBKM120B2101], [CBKM120X2107], [CBKM120E2101], 
[CBEZ235A2118], [CLDE225X2114], [CSTI571X2101], [CMEK162X2101], 
[CINC424A2104] and [CBEZ235D2101].  
• Phase II combination study [CBKM120F2202]  
• Phase III combination study [CBKM120F2302] and [CBKM120F2303] 
1.2.1.2.1 Human safety, tolerability data, single agent buparlisib  
Study [CBKM120X2101] was a Phase I first-in-man dose escalation study of single-agent 
oral buparlisib in patients with advanced solid tumors. This study has been completed, 83 
patients were enrolled and treated with at least one buparlisib dose. The MTD/RP2D of 
single-agent oral buparlisib was determined to be 100 mg/day. The most frequent AEs 
(≥10%), regardless of grade, causality and buparlisib dose, were nausea (45.8%); decreased 
appetite (42.2%); asthenia (37.3%); diarrhea (36.1%); hyperglycemia (33.7%), rash (31.3%); 
constipation (30.1%); fatigue (28.9%); vomiting (26.5%); stomatitis (25.3%); abdominal pain 
(22.9%); pruritus (20.5%); anxiety (19.3%); depression or pyrexia (16.9% each); dry skin, 
dyspepsia, or somnolence (15.7% each); mood altered (14.5%); AST increased, dizziness, 
dyspnea, or transaminases increased (13.3% each); back pain, insomnia, or performance status 
decreased (12.0% each); and ALT increased, arthralgia, cough, or edema peripheral (10.8% 
each). The most common CTCAE grade 3 or 4 AEs (>2%), regardless of causality and 
buparlisib dose, were asthenia (12.0%); performance status decreased (9.6%); transaminases 
increased or hyperglycemia (8.4% each); rash (7.2%); hyperbilirubinaemia or AST increased 
(4.8% each); ALT increased, abdominal pain, fatigue, pneumonia, or diarrhea (3.6% each); 


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and affective disorder, anxiety, mood altered, glucose tolerance test abnormal, arthralgia, 
dyspnea, pruritus, or intestinal obstruction (2.4% each).  
Another single agent trial, [CBKM120X1101], was a phase I dose escalation study in 
Japanese patients with advanced solid tumors; dose levels ranged from 25 to 100 mg/day (Doi 
2011). Enrollment of 15 patients has been completed, including 9 patients at 100 mg/day. One 
DLT (G4 hepatic function abnormal) was observed in the 100 mg/day group. The most 
common G3 or G4 adverse events occurring in at least 2 patients were hepatic function 
abnormal in 6 patients, including transaminase increase in 2 patients, transaminase elevations 
typically occur during the first 6 to 8 weeks of treatment start, G3 anemia in 2 patients, and 
hypokalemia in 2 patients. The recommended Phase 2 dose (RP2D) in this population of 
Japanese patients has been determined to be 100 mg/day, which is identical to that in the 
western population.  
[CBKM120D2201] is a Phase II open label two-stage study of orally administered buparlisib 
in patients with NSCLC with an activated PI3K pathway (defined by PIK3CA mutation, 
PTEN mutation, and/or PTEN loss of protein expression). As of 15 Sep 13, 62 patients have 
been enrolled and treated with at least one buparlisib dose of 100 mg/day. The median age 
was 64.5 (39-78) years, the male/female ratio was 40/22 patients, and the distribution of 
ECOG performance status of 0/1/2 at baseline was 18/41/3 patients, respectively. The most 
frequent AEs (≥10%), regardless of grade, causality and buparlisib dose, were decreased 
appetite and diarrhea (35.5% each); asthenia and nausea (32.3% each); hyperglycemia 
(30.6%); fatigue (25.8% ); rash (24.2%); depression and pruritus (21% each); alanine 
aminotransferase increased, cough, anxiety or weight decreased (17.7% each); aspartate 
aminotransferase increased and vomiting (16.1% each); dry skin (14.5%); anaemia, 
constipation or dysgeusia (12.9% each). The most common CTCAE grade 3 or 4 AEs (seen in 
more than 2 patients) regardless of causality and buparlisib dose, were hyperglycemia 
(16.1%); asthenia (11.3%) and dyspnea, asparate aminotransferase increased, alanine 
aminotransferase increased or fatigue (8.1%). See [Investigator’s Brochure] for more details. 
1.2.1.2.2 Human safety and tolerability data, buparlisib combination therapy 
Study [CBEZ235A2118] is a Phase Ib multi-center, open-label, four-arm dose-escalation 
study of oral BEZ235 or buparlisib in combination with weekly paclitaxel in patients with 
advanced solid tumors and weekly paclitaxel/trastuzumab in patients with HER2+ metastatic 
breast cancer. As of 02-Apr 13, 53 patients had been enrolled into buparlisib + paclitaxel arm 
and treated with at least one buparlisib dose. The MTD was determined to be buparlisib 100 
mg/day in combination with weekly paclitaxel 80 mg/m2 for cycles of 28 days. The most 
frequent AEs (≥10%), regardless of grade, causality, and buparlisib dose, were diarrhea 
(62.3%); nausea (58.5%); asthenia (54.7%); decreased appetite (49.1%); fatigue (41.5%), 
anemia (39.6%), alopecia (37.7%); hyperglycemia, constipation (34% each); vomiting 
(30.2%); stomatitis (28.3%); cough (24.5%); dry skin, dyspnea or epitaxis (22.6% each); 
depression, dysgeusia, neurotoxicity or pyrexia (20.8% each); peripheral edema (18.9%), 
abdominal pain, back pain or pruritus (17% each); hypomagnesaemia, neutropenia, peripheral 
sensory neuropathy, maculo-papular rash or decreased weight (15.1% each); dyspepsia, 
nasopharyngitis, or rash (13.2% each); abdominal pain upper, aspartate aminotransferase 
increased, acneiform dermatitis, hypophosphatemia, or pain in extremity (11.3% each). The 
most common CTCAE grade 3 or 4 AEs (seen in more than 2 patients), regardless of causality 


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and buparlisib dose, were neutropenia (15.1%), hyperglycemia (11.3%), fatigue (9.4%), 
dyspnea or hypokalemia (7.5% each); diarrhea, decreased appetite, peripheral sensory 
neuropathy, or hypomagnesaemia (5.7% each); asthenia, anemia, hypophosphatemia, blood 
bilirubin increased, lymphopenia, neutrophil count decreased, presyncope, performance status 
decreased or abdominal pain (3.8% each). An ongoing trial [CBKM120XUS01T] is 
evaluating the safety and efficacy of daily buparlisib administered with every-three-week 
carboplatin dosed at an AUC=5 and paclitaxel at 175 mg/m2 in patients with solid tumors 
(
 personal communication). Among 12 patients enrolled as of the data cut-off 
date, a preliminary evaluation indicates 1/6 DLT at 50 mg buparlisib, 0/3 DLT at 80 mg 
buparlisib, and 0/3 DLT at 100 mg buparlisib. In addition, one patient treated at 100 mg 
buparlisib was removed from the study during cycle 1 due to a hypersensitivity reaction 
associated with buparlisib administration.  
A Phase Ib trial of buparlisib with docetaxel is ongoing [CBKM120XUS16T], and 8 patients 
have been enrolled as of 20 December 2012. The MTD of the treatment combination will be 
determined also in this study. 
A recent liver safety review across Novartis-sponsored trials with BKM120 identified several 
potentially drug-induced liver toxicity (DILI) cases (e.g. AST/ALT >3.0 x ULN and TBL 
>2.0 x ULN at any time during the treatment, regardless of causality. Upon medical review, 
most of these cases occurred in the context of disease progression in terminally ill, advanced 
cancer patients and/or were confounded by other causes. However, six of these DILI 
candidates were consistent with Hy’s law criteria (e.g. AST/ALT >3.0x ULN and TBL 
>2.0xULN in the absence of cholestasis and other explanatory causes) with probable causal 
relationship to study treatment. Five of these cases were enrolled in study CBKM120F2302 in 
combination with fulvestrant, and one  in combination with the investigational drug LDE225 
(sonidegib). All patients have recovered upon treatment discontinuation except one patient for 
whom no data is available since the patient refused to return for safety follow-up.  
1.2.1.2.3 Clinical pharmacokinetics 
Buparlisib has been administered from 25 mg to 150 mg daily, and the single agent RP2D is 
100 mg. When orally administered, buparlisib is rapidly and well absorbed, and the extent of 
absorption is estimated to be between 57 and 85%, with a median Tmax between 0.5 and 3 
hours after administration. Cmax and AUC appeared to be linear in the tested range, with an 
estimated slope close to 1, but the 90% CI for both AUC0-24, [0.75, 1.21], and Cmax, [0.72, 
1.16], was fairly wide, most likely due to low sample size at extreme doses. In plasma, 
buparlisib concentrations follow a bi-exponential decay, with a long terminal half-life that 
could not be well estimated given the initial sampling schedule used after daily dosing. It was 
however well estimated from the terminal half-life cohort and was found to be 48 hours.  
After repeated dosing the effective half-life (T1/2, acc), was obtained from the observed drug 
accumulation (Racc). The median T1/2, acc (T1/2 accumulation) calculated from exposure 
data on Day 28 ranged between 36 and 58 hours across all dose levels. After repeated single 
dose, steady state is reached in almost 8 days with an accumulation ratio around 3. Buparlisib 
is eliminated mainly through metabolism in a plethora of entities. After administration of a 
single dose of [14C]-buparlisib, 51% of the radioactivity was recovered in urine even though 
buparlisib only contributed to less than 2%. The rest of the radioactivity was recovered in 
feces with buparlisib represented 15% all other metabolites being below 5%. CYP3A4 was 


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found in vitro to be a major contributor to buparlisib metabolism together with direct 
glucuronidation which would contribute for less than 10%.  
For further details please refer to the [Investigator’s Brochure].  
1.2.1.2.4 Clinical activity of buparlisib in squamous cell carcinoma   
Although tumors of squamous histology from different tissue beds are biologically distinct, 
clinical data in other squamous tumor settings provides evidence to support the investigation 
of buparlisib in squamous head and neck cancer.  
These collective data summarized in Table 1-3, suggest that tumors of squamous histology 
may be sensitive to buparlisib-containing therapy. 
Furthermore, patients with tumors of squamous histology pretreated with chemotherapy 
(including taxanes) obtained confirmed tumor responses with paclitaxel-BKM120 treatment.  
(Dirix ESMO 2012). 
The ongoing [CBKM120D2201] trial of buparlisib in PI3K pathway activated NSCLC, is 
enrolling patients with squamous or non-squamous histology who have received 1 or 2 prior 
lines of therapy for metastatic disease. The analysis of efficacy is being conducted separately 
for patients with NSCLC of squamous and patients with non-squamous histology.  
Table 1-3 
Disease control in individual patients with tumors of squamous 
histology treated with buparlisib 
Clinical Trial* 
Tumor histology 
Study treatment 
Best response 
[CBEZ235A2118] 
Cervical SCC 
buparlisib/paclitaxel 
PR 
[CBEZ235A2118] 
Vulvar SCC 
buparlisib/paclitaxel 
PR 
[CBEZ235A2118] 
Penile SCC 
buparlisib/paclitaxel 
CR 
[CBKM120X1101] 
HNSCC 
buparlisib 
PR 
[CBKM120D2201] 
NSCLC squamous 
buparlisib 
PR 
[CBKM120D2201] 
NSCLC squamous 
buparlisib 
PR 
[CBKM120D2201] 
NSCLC squamous 
buparlisib 
PR (not confirmed due to drug 
interruption in setting of AE 
and subsequent death) 
Data for patients included on clinical trial CBEZ235A2118 were those only in the BKM arm of the 
study. 
* Results of individual patients from indicated clinical trial 
1.2.2 
Paclitaxel and potential for interaction 
• Paclitaxel 
Paclitaxel is administered as an intravenous infusion at different doses with different infusion 
times and administration intervals. In the current trial, paclitaxel will be administered at a 
dose of 80 mg/m2 every week as a 1-hour infusion with a cremophor EL formulation. This 
paclitaxel formulation exhibits strong linearities related partly to the high level of protein 
binding of paclitaxel and as well to the vehicle (Henningson 2003). Paclitaxel is mainly 
eliminated via metabolism, with only 5% of the administered dose recovered unchanged in the 


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feces; the urinary route only contributes to a small extent, with 14% of the administered dose 
present in the urine. The main metabolite is 6α-hydroxypaclitaxel, which appears to be mainly 
formed via CYP2C8. Another metabolism route of paclitaxel is via CYP3A4, forming 3’-p-
hydroxypaclitaxel. Both metabolites lead to 6α-3’-p-hydroxypaclitaxel.  
• Potential for interaction 
No major risk for pharmacokinetic interaction is anticipated between the two drugs. In 
addition, the interaction between buparlisib and paclitaxel has already been investigated in the 
trial [CBKM120A2118], where buparlisib was administered at doses between 40 and 120 mg 
and where paclitaxel was administered weekly at the dose of 80 mg/m2 as a 1-hour infusion 
every week. No impact of buparlisib has been observed on the pharmacokinetics of paclitaxel. 
However at the dose of 100 mg, buparlisib exposure could decrease up to 36%. This decrease 
is not observed at other doses of buparlisib or when combined with paclitaxel and 
trastuzumab. Therefore, the relation between paclitaxel and buparlisib exposure remains 
unclear. 
A pharmacokinetic assessment will be conducted in a group of patients to further evaluate 
buparlisib exposure in this specific patient population. 
2 
Rationale 
2.1 
Study rationale and purpose 
The purpose of this randomized, placebo controlled study is to assess the treatment effect of 
buparlisib in combination with weekly paclitaxel vs. buparlisib-matching placebo plus weekly 
paclitaxel on PFS in patients with recurrent or metastatic HNSCC cancer that has progressed 
after prior platinum based regimen. 
 
  
The rationale behind assessing the effectiveness of buparlisib plus weekly paclitaxel is based 
on: 
• The unmet medical need in this indication and poor outcome with rapid clinical 
deterioration observed in patients progressing after platinum based regimen in metastatic 
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• Treatment of a series of HNSCC cell lines using buparlisib showed response in the 
majority of the lines. The preclinical data in Fadu xenograft models of HNSCC treated 
with buparlisib have shown that inhibition of the PI3K-Akt-mTOR pathway can elicit 
tumor regression (see Figure 1-3). 
2.2 
Rationale for the study design 
This is a multicenter, randomized, double-blind placebo controlled phase II study. Patients 
with histologically/cytologically-confirmed HNSCC, recurrent or metastatic disease 
progressing after prior platinum-based first-line treatment will be randomized in a 1:1 ratio to 
receive in a blinded manner one of the two treatment arms: buparlisib in combination with 
paclitaxel or placebo in combination with paclitaxel.  
It is anticipated that approximately 150 subjects will be enrolled in this trial.  
For patients who progressed after platinum-based therapy, there is no standard second-line 
chemotherapy. The standard treatment of patients with incurable or metastatic head and neck 
cancer is in large part dictated by the patient’s performance status. In this setting, there is only 
one targeted therapy only approved in the US, which is cetuximab as single-agent. 
Patients will be stratified according to prior lines of systemic treatments received, (1 line vs. 2 
lines; i.e. patients that received single agent cetuximab as 2nd line) and by region (North 
America vs. Rest of the world). 
Patients will continue to receive study treatment according to randomization until disease 
progression (assessed by RECIST 1.1), unacceptable toxicity, death  or  discontinuation from 
study treatment for any other reason (e.g., withdrawal of consent, start of a new neoplastic 
therapy or at the discretion of the investigator). 
 
 
 
 
 
The study will be conducted under DMC supervision and regular safety data reviews are 
planned.  
2.3 
Rationale for dose and regimen selection 
As described in Section 1.2.1.2, buparlisib 100 mg once daily has been established as the 
MTD/RP2D in two single agent trials ([CBKM120X2101] and [CBKM120X1101]) and in 
one combination trial ([CBKM120X2107] with trastuzumab), and single agent dosing with 
100 mg daily buparlisib in patients with solid tumors is generally well tolerated. 
In study [CBEZ235A2118], one treatment arm evaluated buparlisib in combination with 
weekly paclitaxel in patients with advanced solid tumors, and the drug combination was well 
tolerated. As of 02-Apr-13, 53 patients had been enrolled into the buparlisib + paclitaxel arm 
and treated with at least one buparlisib dose. The MTD/RP2D was defined as being buparlisib 
100 mg/day of buparlisib in combination with weekly paclitaxel 80 mg/m² with each 
treatment cycle being of 28 days (Section 1.2.1.2).  


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Based on preliminary efficacy results in squamous cell tumors and the favorable safety profile 
of this combination, the same dose regimen is proposed in this study (Section 1.2.1.2 where 
the study is described). Moreover PK assessment will be conducted to ensure appropriate 
patient’s exposure to the combination buparlisib –paclitaxel (Section 7.2.5) 
A randomized, double-blind, placebo controlled, phase II study [CBKM120F2202] assessing 
buparlisib in combination with weekly paclitaxel in patients with HER2 negative inoperable 
locally advanced or metastatic breast cancer is currently ongoing. A safety review was 
performed by the DMC on June 1, 2013. The DMC confirmed that no action was needed and 
recommended that the study should proceed as planned. 
2.4 
Rationale for choice of combination drugs  
Paclitaxel is one of the agents widely used in the treatment of HNSCC (Table 1-2); either as 
single agent or in combination with other agents as recommended by international guidelines 
(NCCN 2012, Section 2.4).  
It is recognized that paclitaxel treatment failure may be related either to inherited resistance 
against the drug or/and the acquired resistance during the therapy. While the exact 
mechanism(s) underlying the development of treatment resistance towards paclitaxel remain 
largely unknown, it has been demonstrated that activation of the PI3K-Akt-mTOR pathway 
confers resistance to paclitaxel (Hu 2002), and that increase in Akt activity may be an early 
compensatory mechanism of resistance to chemotherapy (Clark 2002). It is thus believed that 
activation of the PI3K pathway plays an important role in either primary or secondary 
paclitaxel resistance (Clark 2002). Additionally, in preclinical models, concomitant inhibition 
of the PI3K pathway enhances the efficacy of paclitaxel as compared to each agent given 
separately by reducing tumor burden by 80% as opposed to 38% and 51% for agents given 
individually (Hu 2002).  
Paclitaxel has been evaluated in association with LY294002, a PI3K inhibitor, in NSCLC and 
breast cancer cell lines. It was observed that the PI3K inhibitor greatly enhanced the apoptotic 
effects of paclitaxel used at the lowest clinically relevant concentration (10 nM) that blocks 
normal cell cycle progression and induces Raf-1 and ERK1/2 activation. Increasing 
concentrations of LY294002 from suboptimal (4 µM) to complete inhibition (50 µM) of PI3K 
inhibitor combined with low-dose paclitaxel resulted in a dose-dependent enhancement of 
tumor apoptosis (apoptosis enhanced 6-fold over paclitaxel alone) (MacKeigan 2002). 
Therefore, considering the established activity of paclitaxel in recurrent/metastatic HNSCC, 
the relevance of PI3K pathway inhibition in this tumor type as a potential therapeutic target 
and for overcoming resistance to paclitaxel and also due to the preliminary encouraging 
clinical activity observed with buparlisib as single agent and in combination with paclitaxel in 
patients with squamous cell carcinomas, the regimen buparlisib/paclitaxel deserves to be 
investigated in the setting of recurrent/metastatic HNSCC. 


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3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below 
 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
 
To estimate the efficacy of buparlisib in 
combination with paclitaxel 
PFS according to local radiological assessment 
and RECIST 1.1 
Refer to Section 10.4 
Key Secondary 
 
 
To assess the efficacy of the combination with 
paclitaxel in this patient population in terms of 
overall survival  
Overall Survival  
Refer to Section 10.5.1 
Secondary 
 
 
To assess the safety and tolerability of buparlisib 
in combination with paclitaxel in this patient 
population 
Frequency and severity of adverse events 
Other safety data as considered appropriate 
Refer to Section 10.5.3 
To evaluate additional efficacy parameters 
Overall Response Rate (ORR) 
Time to Response (TTR) 
Disease Control Rate (DCR) 
Duration of Response (DoR) 
Refer to Section 10.5.2 
To characterize the pharmacokinetics of 
buparlisib given in combination with paclitaxel 
PK parameters including Cmax, AUCtau 
Refer to Section 10.5.4 
To assess the effect of buparlisib in combination 
with paclitaxel on patient’s symptoms and health-
related quality of life (HRQoL) 
Change from baseline in the global health 
status/QOL and pain scale scores of the EORTC 
QLQ-C30 and QLQ-HN35, respectively 
Time to definitive 10% deterioration in the global 
health status/QOL and pain scale scores of the 
Refer to Section 10.5.6 


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4 
Study design  
4.1 
Description of study design 
This is a multi-center, randomized, double-blind, placebo-controlled phase II trial to evaluate 
the efficacy and safety of 100 mg daily of buparlisib in combination with weekly paclitaxel 
compared to buparlisib-matching placebo in combination with weekly paclitaxel in patients 
with histologically/ cytologically confirmed HNSCC, recurrent or metastatic disease 
progressing after prior platinum based treatment.  
Approximately 150 patients will be randomized in a 1:1 ratio. 
Patients will be stratified according to number of prior lines of treatment (1 vs. 2) and the 
region of investigator’s site (North America vs. Rest of the World). 
 
 
 
4.1.1 
Treatment Phase 
Patients will continue to receive study treatment according to randomization until disease 
progression (assessed by RECIST 1.1), 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). Efficacy and safety monitoring will 
continue as per visit schedule (Table 7-1a). Tumor assessments will be performed 4 weeks 
after study treatment start and afterwards every 6 weeks until radiological progression. 
After unblinding, patients who are still benefiting from study drug (s) will continue to be 
provided study treatment as long they benefit if considered in their best interest. Safety 
monitoring will continue as per updated visit schedule (Table 7-1b or Table 7-1c). 
Tumor assessments will be performed as per local clinical practices. Imaging assessments will 
no longer be sent to central vendor. 
4.1.2 
Follow – up Phase 
After discontinuation of treatment, patients will be followed according to Section 7.1.5 
All patients, regardless of reason for treatment discontinuation will be followed for safety for 
30 days after the last dose of study treatment. 
All patients who discontinue from study treatment due to disease progression must have their 
progression clearly documented according to the criteria specified in RECIST v1.1. If a 
patient did not discontinue study treatment due to disease progression, death, start of new anti-
neoplastic therapies, lost to follow-up, or withdrawal of consent to efficacy follow-up, then 
tumor assessments should continue to be performed every 6 weeks until the start of new anti-
cancer therapy, disease progression, death, lost to follow-up or withdrawn consent to efficacy 
follow-up. 


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In addition, all new anticancer therapies given after the last dose of the study treatment, until 
disease progression, death, lost to follow-up, or withdrawal of consent will be recorded in the 
electronic Case Report Forms (eCRFs). 
All patients will be followed for survival status every 3 months or earlier if needed, regardless 
of treatment discontinuation reason (except if consent is withdrawn or patient is lost to follow-
up). 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.  
From protocol amendment v.03, regardless of reason for study treatment discontinuation, 
tumor assessments will be performed as per local practices in the follow-up phase and scans 
will neither be collected nor sent to BIRC for review. 
Patients continuing to receive study treatment, will be followed up for safety up to 30 days 
after last dose of study treatment.  
Patients in efficacy and survival follow up at the time of this protocol amendment, will come 
off study and be followed-up per local clinical practices. 
For details on required assessments, please refer to Table 7-1b and Table 7-1c. 
Figure 4-1 
Study design 
 
 
1 From protocol amendment v.03, regardless of EOT reason, patients will only be followedup for 30 days after last dose of 
study treatment. These patients will not continue in Efficacy and Survival follow-up phases. 
1 


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4.2 
Timing of interim analyses and design adaptations 
There is no planned efficacy interim analysis. Safety data will be reviewed every 6 months or 
more frequently if needed by a Data Monitoring Committee (DMC).  
4.3 
Primary statistical analysis 
The primary statistical analysis will be based on data from all patients up to the time at which 
approximately 120 PFS events have been observed. The first CSR will be based on the 
primary analysis of the data and the final CSR will be based on additional data (e.g. survival 
and safety data) that were not summarized in the first CSR for patients who were still 
receiving treatment, patients in follow-up phase or patients in survival follow-up phase after 
the last patient last visit has occurred. The duration of OS follow-up should be up until 
approximately 112 patient deaths have occurred.  
4.4 
Definition of the end of the study 
The End of Study is defined as the time point when data collection will stop and the final 
analysis of the study will occur.   
• End of Study will be declared when the study is terminated early or at the latest 
occurrence  of: All patients have completed the safety follow-up period (30 days after 
treatment discontinuation) or 
• Approximately 112 deaths have been observed. 
4.5 
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 similar to that for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial. 
5 
Patient population 
The targeted patient population is patients with histologically/cytologically-confirmed 
HNSCC, recurrent or metastatic disease progressing after platinum based first-line treatment. 
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study. 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Patient is ≥ 18 years old; 
2. Written informed consent obtained before any trial related activities and according to local 
guidelines. 


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3. Patient has histologically/cytologically-confirmed HNSCC. 
4. Patient has archival or new tumor tissue for the analysis of PI3K-related biomarkers.  One 
tumor block (preferred) or a minimum of 12 (15 recommended) unstained slides to be 
provided. Enrollment in the study is contingent on confirmation of an adequate amount of 
tumor tissue. 
5. Patients with recurrent or metastatic disease after failure to platinum-based chemotherapy 
(defined as progression while on or after platinum-based chemotherapy given in the 
recurrent/metastatic setting). Pretreatment with cetuximab (as part of chemoradiation, 
first-line therapy or maintenance, or as single agent second line regimen) is allowed 
6. Measurable disease as determined by per RECIST criteria v1.1. If the only site of 
measurable disease is a previously irradiated lesion, documented progression of disease 
and a 4 week period since radiotherapy completion is required 
7. Adequate bone marrow function and organ function as shown by: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
• Hemoglobin ≥ 9 g/dl (which may be reached by transfusion) 
• Platelets ≥ 100 x 109/L (which may be reached by transfusion) 
• INR ≤ 1.5 
• Potassium, calcium (corrected for serum albumin) and magnesium within normal 
limits (WNL) or ≤ grade 1 severity according to NCI-CTCAE version 4.03 if judged 
clinically not significant by the investigator   
• Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 1.5xULN 
(or < 3.0 x ULN if liver metastases are present)  
• Total serum bilirubin below or equal upper limit of normal range (or ≤ 1.5 x ULN if 
liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin below 
or within normal range in patients with well documented Gilbert’s Syndrome, which 
is defined as presence of episodes of unconjugated hyperbilirubinemia with normal 
results from CBC count (including normal reticulocyte count and blood smear), 
normal liver function test results, and absence of other contributing disease processes 
at the time of diagnosis (see Appendix in the final protocol) 
• Serum creatinine ≤ 1.5 x ULN or calculated or directly measured CrCl ≥ 50% LLN 
(Lower Limit of Normal) 
• Fasting plasma glucose (FPG) ≤ 120mg/dL or ≤ 6.7 mmol/L 
• HbA1c ≤ 8% 
8. ECOG Performance Status ≤ 1 
9. Patient is able to swallow and retain oral medication 
Note: patients able to swallow oral medication but mostly self-nourished through gastric or 
jejunal feeding tube are eligible 
5.2 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 


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1. Patient has received previous treatment with any AKT, mTOR inhibitors or PI3K pathway 
inhibitors; 
2. Patient received treatment with a taxane as part prior treatment for metastatic disease 
3. Patient treated with more than one prior chemotherapy regimen for recurrent/metastatic 
disease (i.e. chemotherapy, chemotherapy in association with a biologic/targeted agent,) 
Notes:  
• Patients treated with adjuvant/neoadjuvant chemotherapy and/or concomitant 
chemoradiotherapy regimen that may have included biologic/targeted agent are 
eligible. 
• Cetuximab single agent used in metastatic setting is allowed. 
4. Patient has symptomatic CNS metastases. Patients with asymptomatic CNS metastases 
may participate in this trial. The patient must have completed any prior local treatment for 
CNS metastases ≥ 28 days prior to the start of study treatment (including radiotherapy 
and/or surgery) and must have stable low dose of corticosteroid therapy; 
5. Patient who has received wide field radiotherapy ≤ 4 weeks or limited field radiation for 
palliation ≤ 2 weeks prior to starting study drug or who have not recovered to grade 1 or 
better from related side effects of such therapy (except alopecia)  
6. Patient has not recovered to grade 1 or better (except alopecia) from related side effects of 
any prior antineoplastic therapy  
7. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects 
8. Patient is currently receiving increasing or chronic treatment (> 5 days) with 
corticosteroids or another immunosuppressive agent  
• The following uses of corticosteroids are permitted: single doses; standard 
premedication for paclitaxel; topical applications (e.g., rash), inhaled sprays (e.g., 
obstructive airways diseases), eye drops or local injections (e.g., intra-articular) 
9. Patient is being treated at start of study treatment with any of the following drugs:   
• Drugs known to be strong inhibitors or inducers of isoenzyme CYP3A4 including 
herbal medications (list of prohibited CYP3A4 inhibitors and inducers are provided in 
Appendix 2 and Appendix 3) 
• Drugs with a known risk to induce Torsades de Pointes (list of prohibited QT 
prolonging drugs provided in Appendix 5) 
Note: The patient must have discontinued strong inducers for at least one week and must 
have discontinued strong inhibitors before the treatment is initiated. Switching to a 
different medication prior to starting study treatment is allowed. 
10. Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for 
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin 
(LMWH), or fondaparinux is allowed; 
11. Patient has a known hypersensitivity and/or contra indication to paclitaxel, standard pre-
treatment for paclitaxel or other products containing Cremophor; 


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12. Patients who have other concurrent severe and/or uncontrolled medical conditions that 
would, in the investigator’s judgment, contraindicate patient participation in the clinical 
study (eg. active or uncontrolled severe infection, chronic active hepatitis, 
immunocompromised, acute or chronic pancreatitis, uncontrolled high blood pressure, 
interstitial lung disease, etc.) 
13. Patient has a known history of HIV infection (testing not mandatory) infection 
14. Patient has any of the following cardiac abnormalities: 
• symptomatic congestive heart failure,  
• history of documented congestive heart failure (New York Heart Association 
functional classification III-IV), documented cardiomyopathy,  
• Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple 
Gated acquisition (MUGA) scan or echocardiogram (ECHO) 
• myocardial infarction ≤ 6 months prior to enrolment,  
• unstable angina pectoris,  
• serious uncontrolled cardiac arrhythmia,  
• symptomatic pericarditis,  
• QTcF > 480 msec on the screening ECG (using the QTcF formula) 
• currently receiving treatment with medication that has a known risk to prolong the QT 
interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or 
switched to a different medication prior to starting study drug. A list of prohibited 
drugs will be provided in the final protocol; 
15. Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); 
16. Patient has a score ≥ 12 on the PHQ-9 questionnaire; 
17. Patient selects a response of “1, 2 or 3” to question number 9 on the PHQ-9 questionnaire 
regarding potential for suicidal thoughts or ideation (independent of the total score of the 
PHQ-9); 
18. Patient has a GAD-7 mood scale score ≥ 15; 
19. Patient has a medically documented history of or active major depressive episode, bipolar 
disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal 
attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others); ), or 
patients with active severe personality disorders (defined according to DSM- IV) are not 
eligible.  Note: for patients with psychotropic treatments ongoing at baseline, the dose and 
the schedule should not be modified within the previous 6 weeks prior to start of study 
drug.  
20. Patient has ≥ CTCAE grade 3 anxiety; 
21. Patient has other prior or concurrent malignancy (except for the following: adequately 
treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, 
early gastric or GI cancer resected completely by endoscopy procedures or any other 
cancer from which the patient has been disease free for ≥ 3 years); 


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22. Patient has a history of non-compliance to medical regimen or inability to grant consent; 
23. Patient is concurrently using other approved or investigational antineoplastic agent. 
24. Pregnant or nursing (lactating) women Patients with elevated hCG at baseline that is 
judged to be related to the tumor are eligible if hCG levels do not show the expected 
doubling when repeated 5-7 days later, or pregnancy has been ruled out by vaginal 
ultrasound; 
25. Patient who does not apply highly effective contraception during the study and through the 
duration as defined below after the final dose of study treatment:  
• Men should use an effective method of contraception and not father a child during the 
trial and up to six months after treatment and are recommended to seek advice on 
conservation of sperm prior to treatment with paclitaxel as per product label. 
• Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, must use highly effective contraception during the study and 
through at least 4 weeks after the final dose of study treatment or as specified in the 
local prescription guidelines for paclitaxel (e.g. for 6 months after final dose of 
paclitaxel according to the PI/SmPC from France and United Kingdom).  
• Highly effective contraception is defined as either:  
1. 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].  
2. 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  
3. Male partner sterilization (with the appropriate post-vasectomy documentation of 
the absence of sperm in the ejaculate). [For female study subjects, the 
vasectomized male partner should be the sole partner for that patient]  
4. Use a combination of the following (both a+b):  
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)  
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository.   
Note: Hormonal contraception methods (e.g. oral, injected, implanted) are not 
allowed as buparlisib decreases the effectiveness of hormonal contraceptives.  
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) at least six weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of child bearing potential. 


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6 
Treatment 
6.1 
Study treatment 
The study drugs to be used in the course of this trial are the following: buparlisib or placebo 
and paclitaxel. As this is a double blind study, the investigator and patient, as well as the 
clinical team, will be blinded (i.e. will not know if the patient is receiving buparlisib or 
buparlisib-matching placebo).  
Study treatment is defined as buparlisib once daily plus weekly paclitaxel or buparlisib-
matching placebo plus weekly paclitaxel depending on the randomization arm (described in 
Section 6.1.1 Dosing regimen and Section 6.2 Dose modifications). 
Study treatment consists of either a combination regimen (paclitaxel and buparlisib/placebo) 
or a monotherapy regimen if one of the study drugs (paclitaxel or buparlisib/placebo) is 
permanently discontinued. 
Novartis Drug Supply Management or its designee will provide buparlisib and buparlisib-
matching placebo as 10-mg, and 50-mg hard gelatin capsules as individual patient supply, 
packaged in bottles. Buparlisib will be dosed on a flat scale of mg/day and not be adjusted to 
body weight or body surface area. 
Paclitaxel is a commercially available product. If available, generic paclitaxel may be used as 
part of study treatment, when possible. Paclitaxel will be prescribed by the investigator and 
obtained as outlined in the investigator Clinical Trial Agreement. Medication labels will 
comply with the legal requirements of each country and be printed in the local language. The 
labels will supply no information about the patient. 
6.1.1 
Dosing regimen 
Patients will be randomized to receive either: 
• Buparlisib plus weekly paclitaxel 
• Buparlisib-matching placebo plus weekly paclitaxel 
Buparlisib or buparlisib-matching placebo will be administered orally once daily on a 
continuous dosing schedule starting on day 1 in combination with once weekly paclitaxel at a 
dose of 80 mg/m2 i.v. (days 1, 8, 15 and 22) in a 28-day cycle. Buparlisib/placebo will be 
given before paclitaxel and any associated premedication, as described in Section 6.1.1.1. 
Weekly paclitaxel at 80 mg/m2 plus buparlisib-matching placebo at a continuous dosing 
schedule will be used for the control arm. Patients will be treated until disease progression, 
unacceptable toxicity, death or discontinuation from study treatment due to any other reason.  
Permitted dose modifications are presented in Section 6.2.2.2. 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form 
and route of 
administration 
Dose2 
Frequency and/or 
Regimen 
Buparlisib 
Oral gelatin capsules 
100 mg  
(2x 50mg capsules1) 
Once daily 


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Study treatments 
Pharmaceutical form 
and route of 
administration 
Dose2 
Frequency and/or 
Regimen 
Paclitaxel 
Intravenous infusion 
80 mg/m2  
Once every week 
Buparlisib-matching 
Placebo 
Oral gelatin capsules 
Matching placebo 100 mg  
(2x placebo to 50 mg 
capsules1) 
Once daily 
1. In case of patient supply difficulties, any combination of buparlisib/placebo (according to patient assignment) 50 
mg or 10 mg capsules may be taken to consume a dose of 100 mg/day (or dose reduction level). 
2. Dose reduction levels for buparlisib/placebo will be administered according to Table 6-2.  For example, 
buparlisib/placebo 80 mg should preferentially be administered as 1x 50mg capsule, and 3x10 mg capsules or 
the equivalent in placebo capsules. 
A complete treatment cycle is defined as 28 days of once daily continuous treatment with 
buparlisib/placebo with once weekly paclitaxel. 
6.1.1.1 
Buparlisib/placebo dosing 
Buparlisib/placebo will be administered on a continuous once daily dosing schedule. There 
will be no breaks between dosing cycles. 
The following general guidelines should be followed for buparlisib/placebo administration:   
• Patients should be instructed to take the dose of buparlisib/placebo once daily in the 
morning, at approximately the same time each day  
• Buparlisib/placebo can be taken with or without food. 
• Buparlisib/placebo should be taken with a glass of water. Patients should swallow the 
capsules as a whole and not chew them. 
• During the study, the patient should record if the dose was taken or not in the 
buparlisib/placebo patient diary.  
• Premedication for paclitaxel (e.g. H2 antagonists) or other stomach acid reduction 
treatments (e.g. proton pump inhibitors, antacids) should be taken at least 1 hour after 
buparlisib/placebo administration, if indicated. 
• 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 during a 
treatment cycle must be noted in the adverse events section of the eCRF.  
• If the patient forgets to take his/her dose until 18:00 (6:00 PM), then the dose should be 
withheld that day and buparlisib/placebo should be restarted the following day. 
• Patients must avoid consumption of Seville orange (and juice), grapefruit or grapefruit 
juice, grapefruit hybrids, pummelos, starfruits and cranberry juice  from 7 days prior to the 
first dose of study drug and during the entire study treatment period due to potential 
CYP3A interaction.  Regular orange (Citrus X sinensis) juice is allowed.  
• Patients must avoid concomitant intake of strong CYP3A inhibitors and inducers. Detailed 
information on potential drug interactions and a list of prohibited concomitant CYP3A 
interfering medications is provided in Table 14-1 in Appendix 2. 


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6.1.1.1.1 Additional dosing guidelines for pharmacokinetic sampling 
On days with pharmacokinetic sampling (e.g., Cycle 1 Day 15 and Day 22), the following 
additional guidelines should be followed:  
• The patient should take his/her dose in the clinic. The patient does not have to fast 
overnight, unless they are also having a fasting plasma glucose and c-peptide sample taken 
(See Section 6.1.1.1.2). 
• The pre-dose sample should be drawn just before buparlisib/placebo dosing. The sampling 
time of the pre-dose PK sample and the dosing time of buparlisib/placebo must be 
precisely recorded in the eCRF. Furthermore, the dosing time of buparlisib/placebo on the 
previous day must be precisely recorded in the eCRF and in the buparlisib/placebo patient 
diary. If vomiting occurs, the exact time of the first vomiting episode within the first 4 
hours post-dosing on that day must be noted. 
6.1.1.1.2 Additional dosing guidelines for fasting glucose and/or c-peptide sampling 
• On days with a pre-dose fasting (overnight) glucose and/or c-peptide sample (e.g. Day 1 
of each cycle for both, Day 15 of cycle 1 and 2 for fasting plasma glucose), the patient 
must be fasting overnight for at least 10 hours prior to the blood collection for fasting 
glucose and C-peptide, but can freely drink water. After this blood sample, the patient 
should take his/her dose of buparlisib/placebo in the clinic (Section 6.1.1.1). If a 
pharmacokinetic sample is also being drawn, then the additional guidelines described in 
Section 6.1.1.1.1 must be followed as well. 
6.1.1.2 
Paclitaxel preparation and dosing 
Paclitaxel is supplied as multi-dose vials for injection. Paclitaxel must be diluted using 0.9% 
Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% 
Sodium Chloride Injection, USP, or 5% Dextrose in Ringer’s Injection to a final concentration 
of 0.3 to 1.2 mg/mL. 
Paclitaxel will be administered every week as a 1-hour (± 15 minutes) IV infusion after 
standard premedication on Day 1 of every cycle.  
Following the initial administration of therapy, patients should be observed for any 
hypersensitivity reaction for at least 1 additional hour. 


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Figure 6-1 
Combined paclitaxel and buparlisib/placebo dosing scheme  
 
*On days with fasting plasma glucose and/or c-peptide monitoring, breakfast should not be eaten until 
after the blood sampling has been completed (Section 6.1.1.1) 
**in accordance to local clinical practice 
***premedication for paclitaxel (stomach acid reduction treatments such as H2 antagonists, proton 
pump inhibitors, antacids) should be taken at least 1 hour after buparlisib/placebo administration, if 
indicated. 
Patients should be observed for any hypersensitivity reaction for at least one hour after the 
end of the first paclitaxel infusion. 
6.1.2 
Supportive treatment 
6.1.2.1 
Paclitaxel pre-medication 
Prior to administration of paclitaxel, patients should be pre-medicated according to the 
standard institutional practice or the product label in order to prevent severe hypersensitivity 
reactions. Anti-hypersensitivity therapy may be administered prior to the ECG of each 
cycle. 
The following is a suggested anti-hypersensitivity therapy guideline. Any one or more of the 
following may be used to prevent hypersensitivity reactions and can be modified in 
accordance to local practice: 
• Dexamethasone: 20 mg PO to be administered approximately 12 and 6 hours prior to 
the start of paclitaxel administration. 
• Diphenhydramine (or equivalent): 50 mg IV to be administered approximately 30-60 
minutes prior to the start of paclitaxel administration. 
AND: 
• Ranitidine: 50 mg IV to be administered approximately 30-60 minutes prior to the start 
of paclitaxel administration. Of note, there are no clinically significant interactions 
foreseeable at the level of the isozymes CYP1A2, and CYP3A4 in the therapeutic 
use of ranitidine. (Martinez 1999) 
OR: 
 
 
 
  -1h                            0h                         +1h       +1.5h      +2h           +2.5h                                                                                 
Light 
breakfast* 
Buparlisib or 
placebo 
administration 
Paclitaxel 
infusion 
Paclitaxel pre-medication 
(dexamethasone, diphenhydramine, 
ranitidine or cimetidine)** 
Paclita-
xel pre-
med.*** 


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• Cimetidine: 300 mg IV to be administered approximately 30-60 minutes prior to the 
start of paclitaxel administration. Note: Cimetidine is a CYP3A4 and CYP1A2 
inhibitor, and therefore administration of cimetidine as a single dose should only be 
considered if no alternative can be found. 
If hypersensitivity occurs during the administration of paclitaxel, the following treatment 
guidelines may be followed: 
• For mild symptoms (e.g., mile flushing, rash, pruritus) it is possible to complete the 
infusion under close supervision 
• For moderate symptoms (e.g., moderate rash, flushing, mild dyspnea, chest discomfort, 
mild hypotension), 
1. Stop the paclitaxel infusion and give diphenhydramine 25-50 mg IV and 
methylprednisolone 125 mg IV. 
2. Once symptoms have resolved, resume paclitaxel infusion at a rate of 10% of original 
rate for 15 minutes, then at 25% of original rate for 15 minutes. If no further 
symptoms develop, continue at original rate until infusion is complete. 
• For severe symptoms (e.g., one or more of: respiratory distress requiring treatment, 
generalized urticaria, angioedema, hypotension requiring therapy), 
1. Stop the paclitaxel infusion and give diphenhydramine and methylprednisone as 
above. Use epinephrine or bronchodilators, if indicated. 
2. Do not rechallenge the patient with paclitaxel. 
6.1.3 
Guidelines for continuation of treatment 
For guidelines for continuation of treatment, refer to Section 6.2 Dosing modifications. 
Patients who discontinue one of the study drugs for any reason other than disease progression 
may continue the other study drug as part of the trial therapy at the investigators discretion 
and should follow the protocol safety and efficacy assessments as scheduled. After 
discontinuing study treatment, further treatment is left to the physician’s discretion. No cross 
over to the buparlisib arm will be allowed. 
6.1.4 
Treatment duration 
Treatment will be continued until disease progression (radiologically confirmed according to 
RECIST v1.1) or until discontinuation due to any other reason (see Section 6.2.1). 
After unblinding, treatment will be continued until disease progression (radiologically 
confirmed according to local clinical practices) or until discontinuation due to any other 
reason. 
6.1.5 
Definition of treatment cycle 
A complete treatment cycle is defined as 28 calendar days during which buparlisib/placebo is 
given once daily and paclitaxel is given once weekly. 
The last day of a complete treatment cycle is day 28. Day 1 of the next cycle starts on day 29. 


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6.2 
Dose modifications 
6.2.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. Any changes in 
buparlisib/placebo or paclitaxel administration must be recorded on the eCRF. In addition, for 
paclitaxel infusion, site personnel must record the infusion start and stop date and times, the 
volume of drug infused, the actual dose given and the intended dose in the patient’s medical 
records. 
Buparlisib/placebo dose modification guidelines are described in Section 6.2.2.1 and the 
paclitaxel recommendations for dose modification are described in Section 6.2.2.2. 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 (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 buparlisib/placebo or paclitaxel is interrupted for reasons other than 
toxicity, then treatment with the respective study drug may be resumed at the same dose. The 
same provision applies if the patient experienced an unacceptable toxicity not specifically 
described in Table 6-3 and Table 6-4 provided that this toxicity resolved to ≤ CTCAE grade 1, 
unless otherwise specified. 
6.2.2 
Treatment interruption and treatment discontinuation 
During the treatment phase following cytotoxic therapy administration, patients requiring a 
buparlisib/placebo dose delay of > 28 days must be permanently discontinued from study 
drug. Grade 4 adverse events will lead to permanent discontinuation, irrespective of recovery 
time, unless otherwise specified. In addition, in most instances, patients that experience a 
treatment interruption because of an adverse event will decrease the dose of study drug after 
their recovery (see specific tables for dose adjustment guidelines). Furthermore, patients 
requiring > 3 dose reductions for buparlisib/placebo will be permanently discontinued from 
study drug. Any need for dose reduction of buparlisib/placebo below 80 mg/day will require 
discontinuation from this study drug.  
If one or more study drugs are held due to toxicity, scheduled visits and all assessments 
should continue to be performed (with the exception of the dosing of the held study drug), as 
described in Table 7-1a, Table 7-1b and Table 7-1c.  
If treatment with buparlisib or matching placebo is permanently discontinued the patient may 
continue to receive paclitaxel on the study at the discretion of the investigator until disease 
progression, unacceptable toxicity, death or discontinuation from study treatment due to any 
other reason (see the criteria for patient withdrawal in Section 7.1.4.1). 
Patients who discontinue paclitaxel may continue to receive buparlisib or matching placebo  
at the discretion of the investigator until disease progression, unacceptable toxicity, death or 
discontinuation from study treatment due to any other reason (see the criteria for patient 


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withdrawal in Section 7.1.4.1). The patients will not need to return to the investigational site 
for days 8 and days 22 of all cycles following paclitaxel discontinuation. 
Patients who permanently discontinue all study drugs should have weekly follow-up for 30 
days after discontinuation of all study treatment or resolution of the AE to ≤ grade 1, 
whichever occurs first, that includes all study assessments appropriate to monitor the event.   
6.2.2.1 
Criteria for buparlisib/placebo dose modifications 
A maximum of 3 dose reductions of buparlisib/placebo will be allowed according to the dose 
levels described in Table 6-2. For patients already receiving buparlisib/placebo at the Dose 
level – 3 (80 mg/day 5 days out of 7) no further dose reductions are allowed; in that case the 
patient will be discontinued from treatment with buparlisib/placebo. Dose reduction should be 
based on the worst preceding toxicity. A change from continuous schedule to intermittent (5 
days out of 7) must be preceded by 2 days without buparlisib/placebo treatment. 
Table 6-2 
Dose reduction steps for Buparlisib/placebo 
Buparlisib/placebo dose levels and dose reductions* 
 
Starting dose level  
100 mg/day continuously 
Dose level – 1 
80 mg/day continuously 
Dose level – 2 
100 mg/day 5 days out of 7 
Dose level – 3 
80 mg/day 5 days out of 7** 
*Dose reduction should be based on the worst preceding toxicity 
**Dose reduction below 80 mg/day 5 days out of 7 is not allowed. If a dose reduction below dose level 
–3 is required, the patient should be permanently discontinued from buparlisib/placebo. 
Guidelines for dose modification and dose interruption of buparlisib/placebo are described in 
Table 6-3.  
When toxicities requiring study treatment dose adjustment are potentially attributable to either 
buparlisib or paclitaxel, the first dose adjustment should be made for buparlisib according to 
Table 6-3. At this time, the paclitaxel dose also may be adjusted consistent with Section 
6.2.2.2 according to the investigator’s clinical judgment. If there is a second occurrence of the 
same adverse event after dose adjustment of buparlisib, or there is persistence of the adverse 
event beyond 7 days, then an adjustment of the paclitaxel dose should be made where relevant 
according to Section 6.2.2.2. 
For hematologic toxicities, the first dose adjustment should be made with paclitaxel according 
to Section 6.2.2.2. At this time, the buparlisib dose also may be adjusted consistent with Table 
6-3 and according to the investigator’s clinical judgment. If there is a second occurrence of 
the same adverse event after dose adjustment of paclitaxel, or there is persistence of the 
adverse event beyond 7 days, then an adjustment of the buparlisib dose should be made where 
relevant according to Table 6-3.  
After treatment is resumed at a lower dose: 
• If the same toxicity recurs with the same severity, then the next treatment re-initiation 
must resume at a lower dose irrespective of duration. 
• If the same toxicity recurs with a worse severity, then the patient must discontinue 
treatment with buparlisib/placebo.   


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• These stipulations do not apply to hyperglycemia, as specific rules are stated in Table 6-3. 
Table 6-3 
Criteria for interruption and re-initiation of buparlisib/placebo 
These changes must be recorded on the Dosage Administration Record CRF 
Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for buparlisib/placebo 
HEMATOLOGICAL 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain  dose level  
Grade 3 (ANC < 1.0 – 0.5 x 109/L) 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Febrile neutropenia  
(ANC < 1.0 x 109/L, with a single temperature of 
≥ 38.3 °C or a sustained temperature of ≥ 38 °C 
for more than one hour ) 
Omit dose until resolved, then  1 dose level 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50-25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
RENAL 
Serum creatinine  
Grade 1 (< 2 x ULN) 
Maintain dose level  
Grade 2 (2 – 3 x ULN ) 
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 – 6.0 x ULN)  
Permanently discontinue patient from buparlisib/placebo   
Grade 4 ( > 6.0 x ULN)  
Permanently discontinue patient from buparlisib/placebo   
HEPATIC 
Bilirubin  
(*for patients with Gilbert Syndrome these dose modifications apply to changes in direct bilirubin only) 
will be fractionated if elevated 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level with LFTs* monitored as per protocol 
Grade 2 (> 1.5 - 3.0 x ULN) with ALT or AST ≤ 
3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) with ALT or AST ≤ 
3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days,  1 dose level 
If resolved in  7 days discontinue patient from 
buparlisib/placebo 
Grade 4 (> 10.0 x ULN) 
Permanently discontinue patient from buparlisib/placebo  
 
 
AST or ALT 


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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for buparlisib/placebo 
AST or ALT without bilirubin elevation > 2ULN 
Note: confounding factors and/or alternative causes for increased transaminases like concomitant medications, 
infection, hepato-biliary disorder, obstruction, liver metastasis, etc. should be excluded before dose 
interruption/reduction 
Same grade as baseline (i.e. Grade 0 or Grade 
1 (> ULN – 3.0 x ULN) if presence of liver 
metastasis) 
Maintain dose level with LFTs* monitored per protocol 
Increase from baseline Grade 0 to > 1.5 ULN or 
from baseline Grade 1 to Grade 2 
Can continue treatment at  1 dose level 
Increase of two grades from baseline (from 
baseline Grade 0 to Grade 2 or from baseline 
Grade 1 to Grade 3) 
Omit dose until resolved to Grade 1 or less, then  1 dose 
level** 
If no recovery in ≤ 28 days, discontinue permanently 
BKM120/placebo 
Grade 3 (> 5.0 - 20.0 x ULN) without total 
bilirubin elevation to > 2.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then 
 1 dose level** 
If no recovery in ≤ 28 days, discontinue permanently 
BKM120/placebo 
Grade 4 (> 20.0 x ULN) without bilirubin 
elevation to > 2.0 x ULN 
Permanently discontinue patient from BKM120/placebo 
AST or ALT and concurrent Bilirubin 
AST or ALT > 3.0 x ULN and total bilirubin > 2.0 
x ULN 
Permanently discontinue buparlisib/placebo*** 
*(LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase 
(fractionated if alkaline phosphatase is grade 2 or higher) and GGT) 
** In case of recurring Grade 3 or higher toxicity after re-challenge, patients should be permanently discontinued 
*** All patients with ALT or AST >3.0x ULN and total bilirubin > 2.0x ULN in the absence of cholestasis must 
immediately be withdrawn from BKM120/placebo and every attempt should be made to carry out the liver event 
follow-up assessments as described below in Section 6.2.2.3.7 Management of hepatotoxicity (ALT and/or AST 
>3.0x ULN and total bilirubin >2.0x ULN) in patients receiving BKM120/placebo and Section 7.2.2.5.7 Viral 
hepatitis serology and other tests for hepatotoxicity follow-up 
Hepatic toxicity monitoring (*for patients with Gilbert Syndrome: total and direct bilirubin must be monitored, 
intensified monitoring applies to changes in direct bilirubin only; the monitoring includes the following LFTs: 
albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase (fractionated if 
alkaline phosphatase is grade 2 or higher) and GGT): 
Cycle 1 and 2: every other week (if visit schedule allows a more frequent monitoring this should be considered) 
or more frequently if clinically indicated especially for patients with borderline acceptable AST/ ALT or bilirubin* 
values 
Cycle 3 and onward: monthly or more frequently if clinically indicated  
In case of any occurrence of ALT/AST or bilirubin* increase ≥ grade 2 the liver function tests must be monitored 
weekly or more frequently if clinically indicated until resolved to ≤ grade 1 In case of any occurrence of ALT/ AST 
or bilirubin* increase ≥ grade 3  the liver function tests must be monitored weekly or more frequently if clinically 
indicated until resolved to ≤ grade 1; hereafter the monitoring should be continued every other week or more 
frequently if clinically indicated until the end of treatment with study medication 
Patients who discontinued study treatment should be monitored weekly, including LFTs* or more frequently if 
clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE grade change over 4 weeks). 
ENDOCRINE/METABOLIC 
Fasting Plasma Glucose (FPG) 


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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for buparlisib/placebo 
Grade 1 (> ULN - 160 mg/dL) [> ULN - 8.9 
mmol/L] 
Maintain dose level, check FPG every week 
initiate or intensify medication with appropriate anti-diabetic 
treatment as per investigator’s discretion 
instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes 
mellitus (such as those provided by the American Diabetes 
Association) during the study 
consider use of oral anti-hyperglycemic therapy such as 
metformin (or intensify existing medications) 
check FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks 
Grade 2 (>160 - 250 mg/dL) [> 8.9 - 13.9 
mmol/L] 
If asymptomatic, maintain dose and re-check FPG within 24 
hours. If grade worsens or improves then follow specific 
grade recommendations. If FPG remains at Grade 2:  
maintain dose level and monitor FPG at least weekly until 
FPG resolves to ≤ Grade 1 
initiate or intensify medication with appropriate anti-diabetic 
treatment such as metformin; consider adding a second oral 
agent if no improvement after several days 
instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes 
mellitus (such as those provided by the American Diabetes 
Association) during the study 
If FPG does not resolve to ≤ Grade 1 within 14 days after 
institution of appropriate anti-diabetic treatment reduce  
buparlisib/placebo by 1 dose level 
Continue with anti-diabetic treatment and check FPG at least 
weekly for 8 weeks, then continue checking at least every 
2 weeks 
Grade 3 (> 250 - 500 mg/dL) [> 13.9 - 27.8 
mmol/L] 
Omit buparlisib/placebo, initiate or intensify medication with 
appropriate anti-diabetic treatment, re-check FPG within 
24 hours.  If grade worsens or improves then follow specific 
grade recommendations.  If FPG remains at Grade 3: 
administer intravenous hydration and intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances as 
clinically appropriate 
continue to omit buparlisib/placebo 
monitor FPG at least twice weekly until FPG resolves to 
≤ Grade 1  
If FPG resolves to ≤ Grade 1 in 7 days or less, then re-start 
buparlisib/placebo and  1 dose level 
If FPG remains greater than Grade 1 severity for more than 7 
days, then discontinue patient from buparlisib/placebo 
initiate or continue anti-diabetic treatment as appropriate 
instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes 
mellitus (such as those provided by the American Diabetes 
Association) during the study 
consider use of oral anti-hyperglycemic therapy such as 
metformin 
check FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks 
For non-fasting plasma glucose >250-500 mg/dL (> 13.9 - 
27.8 mmol/L) accompanied by signs/symptoms of 


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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for buparlisib/placebo 
hyperglycemia (for example, mental status changes, 
excessive thirst, polyuria), or presence of blood or urine 
ketones, omit BKM120/placebo and following guidance for 
management of Grade 3 fasting plasma glucose (FPG) 
Grade 4 (> 500 mg/dL) [≥ 27.8 mmol/L] 
Immediately omit BKM120/placebo, initiate or intensify 
medication with appropriate anti-diabetic treatment, re-check 
within 24 hours. If grade improves then follow specific grade 
recommendations.  If FPG is confirmed at Grade 4: 
administer intravenous hydration and intervention for 
electrolyte/ketoacidosis/hyperosmolar disturbances as 
clinically appropriate 
discontinue patient from BKM120/placebo 
instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes 
mellitus (such as those provided by the American Diabetes 
Association) during the study 
consider use of oral anti-hyperglycemic therapy such as 
metformin 
check FPG at least weekly for 8 weeks, then continue 
checking at least every 2 weeks if clinically indicated 
For non-fasting plasma glucose >500 mg/dL (> 27.8 mmol/L) 
accompanied by signs/symptoms of hyperglycemia (for 
example, mental status changes, excessive thirst, polyuria), 
or presence of blood or urine ketones, discontinue BKM120 
and following guidance for management of Grade 4 fasting 
plasma glucose (FPG). 
CARDIAC 
Cardiac - Left Ventricular systolic dysfunction 
Asymptomatic,  
resting ejection fraction 40-50%; 
or 10-20% drop from baseline 
Maintain dose level, and continue buparlisib with caution 
Repeat LVEF within 4 weeks or as clinically appropriate 
Symptomatic,  
responsive to intervention,  
ejection fraction 20-39% 
or > 20% drop from baseline 
Omit buparlisib/placebo until resolved* (as defined below), 
then  1 dose level 
LVEF measurement to be repeated, if not resolved* within 3 
weeks, permanently discontinue patient from buparlisib 
treatment 
*the event is considered resolved when the patient is 
asymptomatic, has a resting ejection fraction ≥ 40% and 
≤20% decrease from baseline 
Refractory or poorly controlled,  
ejection fraction < 20% 
Permanently discontinue patient from buparlisib/placebo 
Cardiac – QTc prolongation  
QTcF > 500 ms (≥ Grade 3)  
or > 60 ms change from baseline  
on at least two separate ECGs 
First Occurrence: 
omit buparlisib/placebo 
Perform an analysis of serum potassium and magnesium, 
and if below lower limit of normal, correct with supplements to 
within normal limits. Concomitant medication usage must be 
reviewed. 
Perform a repeat ECG within one hour of the first QTcF of > 
500 ms or >60ms from baseline 
If QTcF remains > 500 ms or >60ms from baseline, repeat 
ECG as clinically indicated, but at least once a day until the 
QTcF returns to < 480 ms. Seek cardiologist input. 
Once QTcF prolongation has resolved, buparlisib/placebo 


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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for buparlisib/placebo 
may be restarted at a one lower dose level 
Second Occurrence: 
Permanently discontinue patient from buparlisib/placebo 
Other Cardiac Events 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Permanently discontinue patient from buparlisib/placebo 
OTHER 
Mood alteration 
Grade 1* 
Maintain dose level 
Consider psychiatric consultation at the investigator’s 
discretion and introduce optimal management except in 
presence of suicidal ideation where dose must be interrupted 
and psychiatric consultation is required to provide optimal 
management 
Grade 2* 
 
Omit dose until resolved to ≤ Grade 1, or baseline status 
Consider psychiatric consultation at the investigator’s 
discretion and introduce optimal management except in 
presence of suicidal ideation where dose must be interrupted 
and psychiatric consultation is required to provide optimal 
management 
First event: if the condition resolved to Grade ≤ 1 or to 
baseline status, continue to co-medicate and then maintain 
dose level 
Second and further events: if the condition resolved to Grade 
≤ 1 or to baseline status, continue to co-medicate and then  
1 dose level 
Grade 3* 
Omit dose until resolved to ≤ Grade 1, or baseline status 
Psychiatric consultation is required and introduce optimal 
management 
If the condition resolved to Grade ≤ 1 or to baseline status, 
continue to co-medicate and then then  1 dose level 
Grade 4* 
Permanently discontinue patient from buparlisib/placebo 
Psychiatric consultation is required and introduce optimal 
management 
* Note: A timely interview with the patient after the questionnaire completion is recommended. For all grades, if 
question 9 on the PHQ-9 has a positive response (as indicated by selecting “1”, “2”, or “3”), and/or the patient 
presents with suicidal ideation, interrupt study drug and refer patient for psychiatric consultation regardless of 
the total questionnaire score or CTCAE grading for optimal management and to confirm if study drug should be 
interrupted or permanently discontinued. . If the patient does not respond to question 9 on the PHQ-9 or to the 
whole questionnaire, then the investigator must assess if the patient has suicidal ideation. If the investigator 
identifies suicidal ideation, then study drug must be interrupted and the patient referred for psychiatric 
consultation for assessment. 
Skin Toxicity 
Maculopapular rash  
 
Grade 1 
(macules or papules covering <10% BSA with 
or without symptoms) 
Maintain dose level. Consider to initiate recommended 
treatment* with topical steroid bid and  oral antihistamines.  
Grade 2 
(macules or papules covering 10-30% BSA with 
or without symptoms) 
Tolerable: same management as G1 
Intolerable: Start recommended treatment* with topical 
steroids bid, oral antihistamines and oral steroids.  


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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for buparlisib/placebo 
  First occurrence:  Omit dose until resolved to Grade ≤ 1 
then: 
If resolved in ≤ 2 weeks, maintain dose level. 
If resolved in more than 2 weeks,  1 dose level. 
Second occurrence:  1 dose level 
Treatment can be continued up to 2 weeks after rechallenge 
with buparlisib; consider prompt implementation in case of 
flare after interruption of recommended treatment.   
Grade 3 
(macules or papules covering >30%BSA with or 
without symptoms) 
Omit dose until resolved to CTCAE Grade ≤ 1; then  1 dose 
level. 
Start recommended treatment* with topical steroids bid, oral 
antihistamines and oral steroids. Treatment can be continued 
up to 2 weeks after rechallenge with buparlisib; consider 
prompt implementation in case of flare after interruption of 
recommended treatment  
Grade 4 
(Papules and/or pustules covering any % BSA, 
associated with symptoms or not but associated 
with extensive superinfection) 
Permanently discontinue patient from buparlisib/placebo 
 
*Recommended treatment: please refer to Section 6.2.2.3.4  
Acneiform Rash 
Grade 1 
(<10% body surface area BSA; no 
associated erythema or pruritus) 
Maintain dose level. Consider to initiate recommended 
treatment** with topical steroid moderate potency and topical 
antibiotic bid 
Grade 2 
(10 to 30% BSA and associated with erythema 
or pruritus; limited instrumental  activities of 
daily living (ADL) 
Tolerable: same management as G1 
Intolerable: 
  First occurrence:  Omit dose until resolved to Grade ≤ 1 
then: 
If resolved in ≤ 2 weeks, maintain dose level. 
If resolved in more than 2 weeks,  1 dose level. 
Start recommended treatment** oral antibiotic for 6 weeks; 
stop topical antibiotics if being used and start with topical 
steroids of moderate potency 
  Second occurrence:  1 dose level 
Initiate or intensify recommended treatment as described 
above 
Grade 3 
(>30% BSA And associated with pruritus; 
limiting self ADL) 
Omit dose until resolved to CTCAE Grade ≤ 1; then  1 dose 
level. 
Start recommended treatment** with oral antibiotic for 6 
weeks. If infection suspected (yellow crusts, purulent 
discharge, painful skin / nares) then switch to broad 
spectrum/gram negative antibiotics; consider skin swab for 
bacterial culture. Add topical steroid of moderate potency.  
Grade 4 
Papules and/or pustules covering any % BSA, 
associated with symptoms or not but associated 
with extensive superinfection 
Permanently discontinue patient from buparlisib/placebo 
**Recommended treatment: please refer to Section 6.2.2.3.4  


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Pruritus 
Clinical Management and placebo/buparlisib dose 
adjustment 
Grade 1 
(Mild or localized pruritus) 
Maintain dose level. Consider to start recommended 
treatment with topical steroid moderate strength or topical 
antipruritics applied twice daily  
 
 
Grade 2 
(Intense or widespread; intermittent;  skin 
changes from scratching; limiting instrumental 
ADL) 
• 
Tolerable: same management as G1 
• 
Intolerable: 
- 
First occurrence:  Omit dose until resolved to Grade 
≤ 1 then: 
• 
If resolved in ≤ 2 weeks, maintain dose level. 
• 
If resolved in more than 2 weeks,  1 dose level. 
Start recommended treatment with topical steroids moderate 
potency  or topical antipruritics twice daily and add oral 
antihistamines 
-  Second occurrence:  1 dose level 
Initiate or intensify recommended treatment as described 
above 
 
Grade 3  
(Intense or widespread; constant; limiting self- 
care ADL or sleep) 
Omit dose until resolved to CTCAE Grade ≤ 1; then  1 
dose level. 
 
Start recommended treatment with: oral corticosteroids or 
oral antihistamines in association with GABA agonists 
 
Grade 4 
Discontinue placebo / buparlisib 
 
Recommended treatment : please refer to Section 6.2.2.3.4  
 
Fatigue (asthenia) 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then: 
• 
If resolved in ≤ 7 days, maintain dose level 
• 
If resolved in  7 days,  1 dose level 
 
Pneumonitis  
 
 
Please see Section 6.2.2.3.1 
Stomatitis/Oral mucositis 
 
 
Grade 1 /Tolerable Grade 2 
 
 
 
Intolerable Grade 2 or Grade 3 
 
 
 
Grade 4 
Maintain dose level.  Non alcoholic or salt water mouth wash  
see also Section 6.2.2.3.2 
• 
First occurrence: hold until ≤ G1 and  1 dose level (if 
stomatitis is 
readily manageable with optimal management, re-
introduction at the same level might be considered at the 
discretion of the investigator). Second occurrence: hold 
until ≤ G1 and  1 dose level. 
 
• 
Permanently discontinue patient from buparlisib/placebo. 


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Other non- hematological adverse events 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Permanently discontinue patient from buparlisib/placebo 
Note: Omit dose for ≥ Grade 3 vomiting or Grade 3 nausea 
only if the vomiting or nausea cannot be controlled with 
optimal antiemetic 
6.2.2.2 
Criteria for paclitaxel dose modifications 
The following guidelines should be considered for dose modifications for AEs that are 
suspected to be caused by paclitaxel.  
• Paclitaxel should be administered only if ANC > 1.500/mm3 (1.5 x 109/L) and platelets > 
100.000/mm3 (100 x 109/L) (Seidman 2008).  
• In case of a life-threatening event, consider discontinuing paclitaxel 
• In case of grade 3 or 4 AEs despite medical management: 
• Hold paclitaxel until the event has resolved to grade 1 or better, then re-introduce at 
the reduced dose.  
• In case of a second episode of the same event at grade 3 or 4, consider discontinuing 
paclitaxel  
• In cases of grade 2 non-hematologic AE (except alopecia) that are persistent despite 
medical management, consider holding paclitaxel until event resolves to grade 1 or better, 
then re-introduce at a reduced dose. 
• The minimum paclitaxel dose allowed on study and the first dose reduction level is 65 
mg/m2 (i.e. only one dose reduction of paclitaxel is permitted to 65 mg/m2).    
Additionally, paclitaxel should be dose adjusted as needed, in accordance with local 
prescribing information and practice. 
Patients who permanently discontinue paclitaxel but continue buparlisib/placebo can reduce 
the frequency of hematology visits as described in Section 7.1. 
6.2.2.3 
Additional follow-up for selected toxicities 
6.2.2.3.1 Management of Pneumonitis in patients receiving buparlisib/placebo 
All patients participating in clinical trials with buparlisib will be routinely asked about and 
observed for the occurrence of adverse events which could include new or changed 
pulmonary symptoms (consistent with lung abnormalities). CT scans and pulmonary function 
tests should be done, as clinically indicated, or if there are symptoms that indicate that the 
patient has developed Pneumonitis. In case of a documented Pneumonitis, the guidelines 
(including dose modifications) in Table 6-4 should be followed. Consultation with a 
pulmonologist is highly recommended for any Pneumonitis case during the study treatment. 
Table 6-4 should be followed. Consultation with a pulmonologist is highly recommended for 
any Pneumonitis case during the study treatment. 


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Table 6-4 
Management of Pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis 
buparlisib/placebo Dose 
Adjustment 
Grade 1 
CT scans with lung 
windows. Repeat at least 
every 8 weeks until return to 
within normal limits. 
No specific therapy 
is required 
Administer 100% of 
buparlisib/placebo dose. 
Grade 2 
CT scan with lung windows. 
Consider pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat at 
least every 8 weeks until 
return to within normal limits. 
Consider a bronchoscopy 
with biopsy and / or BAL.  
Symptomatic only. 
Consider 
corticosteroids if 
symptoms are 
troublesome. 
Reduce buparlisib/placebo 
dose by 1 dose level (see Table 
6-2) until recovery to < Grade 1. 
Study treatment may also be 
interrupted if symptoms are 
troublesome. Patients will 
discontinue study treatment if 
they fail to recover to < Grade 
1 within 3 weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat at 
least every 6 weeks until 
return to within normal limits. 
Bronchoscopy with biopsy 
and / or BAL is 
recommended. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Hold treatment with 
buparlisib/placebo until 
recovery to < Grade 1. May 
restart study treatment within 3 
weeks at a reduced dose (by 
one level) if evidence of clinical 
benefit. 
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing, if possible, 
includes: spirometry, DLCO, 
and room air O2 saturation 
at rest. Repeat at least 
every 6 weeks until return to 
within normal limits. 
Bronchoscopy with biopsy 
and / or BAL is 
recommended if possible. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Discontinue treatment with 
buparlisib/placebo. 
6.2.2.3.2 Guidelines for the treatment of buparlisib/placebo induced stomatitis/oral 
mucositis 
General guidance and management include patient awareness and early intervention. 
Evaluation for herpes virus or fungal infection should be considered. 
Patients should be informed about the possibility of developing mouth ulcers/oral mucositis 
and instructed to report promptly any signs or symptoms to their physician, Patients should be 
educated about good oral hygiene, instructed to avoid spicy/acidic/salty foods, and should 
follow the following guidelines:  
• For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth wash 
or salt water (0.9%) mouth wash several times a day until resolution.  


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• For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate 
oral alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., 
local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®).  
• Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents.  
Antifungal agents should be avoided unless a fungal infection is diagnosed as they may 
interfere with buparlisib metabolism. 
6.2.2.3.3 Guidelines for the treatment of buparlisib/placebo induced diarrhea 
The investigator should consider/investigate potential concomitant medication, food or 
comorbidity driven causes of diarrhea (including infectious causes) and remedy these causes 
if possible (e.g. discontinuation of concomitant medication, dietary modification, treatment of 
comorbidity).   
The patient should be monitored for signs of dehydration and instructed to take preventive 
measures against dehydration as soon as diarrhea occurs.  Concomitant medication for the 
treatment of diarrhea should be considered, as per local practice and best investigator’s 
judgment and may consist for example, as per “the recommended guidelines for the treatment 
of cancer treatment-induced diarrhea” (Benson 2004), of loperamide given at a standard dose 
(e.g. initial administration of 4mg, then 2mg every 4 hours, maximum of 16 mg/day), along 
with oral hydration and dietetic measures could be considered for Grade 1-2 diarrhea.  More 
severe diarrhea should be treated appropriately according to investigator discretion, including 
for example IV fluids. 
Dose adaptations of buparlisib/placebo in case of treatment related diarrhea should follow the 
guidelines presented above for other non-hematological adverse events. 
6.2.2.3.4 Guidelines for the treatment of buparlisib/placebo induced skin toxicity 
Skin toxicity is a class-effect observed with PI3Ki/mTORi agents. Close monitoring of 
potential skin reactions will be performed at each planned visit and will be reported as adverse 
event. The most frequent skin adverse events reported are: maculopapular rash (only a 
minority present acneiform rash) (refer to Table 6-3 for clinical management); pruritus and 
dry skin. The onset is typically within the first 2 months of treatment start and is reversible 
with adequate concomitant medication and treatment interruption if needed. Photographs of 
skin rashes events as well as skin biopsy if possible are recommended. According to the 
investigators discretion, a paired skin biopsy could be obtained (from both an affected and an 
unaffected skin area for local histopathology assessment) to further assess rash if clinical 
appropriate. 
Recommended therapies for skin toxicity events (refer to table 6.3 for specific guidance 
according to the type of skin toxicity): 
• Topical steroids of Moderate Potency (face and folds): triamcinolone 0.025%; 
aclometasone 0.05%  (<8 weeks continuously) 


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• Topical steroids of High Potency (trunk/extremities): fluocinonide 0.05%; clobetasol 
0.05% cream or spray (<8 weeks continuously) 
• Oral antihistamines (sedating, evening): diphenhydramine 25-50mg tid; hydroxizine 25mg 
tid or q.i.d;  
• Oral antihistamines (non-sedating, day time): fexofenadine 180mg QD or 60mg tid 
(monitor the use of this class of drugs since skin toxicity has also been reported) 
• Oral corticosteroids: prednisone 0.5mg/kg or equivalent up to 5 days of treatment 
• Topical antibiotics: clindamycin 1 - 2%; erythromycin 1% -2% (gel or solution 
formulation can be used, ointments cannot be used) ; metronidazole 1%; silver 
sulphadiazine. 
• Oral antibiotics: doxycycline 100mg bd; minocycline 100mg bd; oxytetracycline 500mg 
bd 
• Topical antipruritics (pramoxine 1%, doxepin 5% cream) applied twice daily 
• GABA Agonists: Gabapentin 300mg every 8 hours Pregabalin 50-75 mg every 8 hours (to 
adjust of renal impairment). Depending on patient’s clinical condition be of potential and 
common side effects observed with GABA agonists such as: somnolence, dizziness (both 
drugs) and peripheral edema (Gabapentin) among others AEs. 
Dry skin has been reported, it is recommended that patients with dry skin use mild and 
fragrance free soaps and detergents. According to the severity and BSA extension patients 
may apply mild moisturizers, ammonium lactate cream 12% or salicylic acid cream 6% bid.  
Photosensitivity has been described in patients although preclinical experiments demonstrated 
that buparlisib has no potential phototoxic effect. Patients should be advised to take measures 
to protect themselves from direct exposure to sunlight, including regular use of sunscreen 
(factor 20 at least), wearing of sunglasses, using of hats, and protective clothes when 
outdoors. 
Paronychia and nail changes should also be followed up especially in association with 
taxanes. The following guidelines are proposed: 
Worst Grading  
Clinical Management and Taxane dose 
reduction  
Grade 1:  
(Nail fold edema or erythema;  
disruption of the cuticle) 
Maintain taxane dose.  
Consider start recommended treatment: cooling 
during infusions with ice packs on hands/feet (start 
15 min before, during, and 15 min after infusion) 
Grade 2:  
(nail fold edema or erythema with pain; 
associated with discharge or nail plate 
separation; limiting instrumental ADL) 
Maintain taxane dose.  
Recommended treatment: localized intervention 
(cooling measures) + oral antibiotics intervention 
during 15 days (cephalosporines 1stG, 
ciprofloxacin, trimethroprim/sulfamethoxazole; 
antifungal, cultures if indicated) 
G3 or higher 
(limiting self-care ADL)  
Interrupt taxane and monitor (resume treatment  
decreasing one dose level when G1 or less) 
Start recommended treatment with oral antibiotics 
plus local cooling measures (see above)  


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6.2.2.3.5 Guidelines for the treatment of buparlisib/placebo induced hyperglycemia 
Buparlisib may affect glucose homeostasis which could result in increases of plasma glucose 
and insulin levels. Optimal glucose control should be achieved before starting a patient on 
study treatment and patients requiring insulin should be treated with caution. Patients with 
hyperglycemia should be instructed to follow dietary guidelines provided by the American 
Diabetes Association. They may also need to initiate, continue or intensify medication with 
appropriate anti-diabetic treatment including insulin or oral agents. (Note: some oral anti-
diabetic drugs are CYP2C9 substrate and should be used with caution; others are CYP3A 
inducers or inhibitors and are prohibited; See Appendix 2 and Appendix 3, respectively, for 
more details). Patients who develop Grade 3 or 4 hyperglycemia should be managed urgently 
as per standard clinical practice, with the goal of stabilizing glycemic control within 24 hours. 
6.2.2.3.6 Guidelines for the treatment of buparlisib/placebo induced psychiatric 
disorders 
Psychiatric adverse events will be closely monitored and evaluated at each planned visit until 
recovery to Grade ≤ 1 or baseline status.  The grading of psychiatric adverse events/mood 
alterations must be based on the clinical interpretation of severity according to the NCI- 
CTCAE (v 4.03) guidelines.  
For patients who experience new or worsening of existing psychiatric AEs of Grade ≥1, 
psychiatric consultation should be considered as described in Table 6-3. 
Patient self-reported mood questionnaires (GAD-7 and PHQ-9) will be used for screening and 
during the study treatment phase to aid the investigator in identifying new or worsening of 
events.  For additional information regarding safety assessments based on patient self-reported 
mood questionnaires, please refer to Section 7.2.2.8. 
If question 9 in the PHQ-9 has a positive response (as indicated by selecting "1", "2", or "3"), 
and/or patient presents with suicide ideation,interrupt treatment with study drug and refer the 
patient for psychiatric consultation for optimal management regardless of the total 
questionnaire score or CTCAE grading and confirm if study drug should be interrupted or 
permanently discontinued. In this specific case, the psychiatric advice can overrule the 
patient’s PHQ-9 self-assessment.  
During the study, subjects will be monitored at regular scheduled visits (eg, Day 1 and Day 15 
of Cycles 1, 2 and 3, Day 1 of each subsequent cycle, and at the End of Treatment visit) by 
the investigator/site staff through personal interaction and the two self-reported 
questionnaires.  Additional assessments may be done according to the clinical judgment of the 
investigator if desired. 
6.2.2.3.7 Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total 
bilirubin >2.0x ULN) in patients receiving BKM120/placebo 
Criteria for interruption and re-initiation of BKM120/placebo treatment in case of the 
occurrence of AST, ALT or bilirubin increase are detailed in Section 6.2, Dose Modification 
(Table 6-3). 
Patients with clinically significant liver test abnormalities should perform liver-directed 
medical history, physical examination and other tests as medically indicated to assess 


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potential relationship with study treatment and rule out other underlying causes (e.g. disease 
progression/obstruction, infection/hepatitis or other liver diseases, sepsis, metabolic diseases 
including diabetes, concomitant medications including herbals, alcohol, drug-drug interaction, 
cardiovascular disease/ischemia, other organ injuries, etc.). Any pre-existing liver conditions 
or risk factors should be reported in the respective medical history and concomitant 
medication CRF pages (if not done already). 
All patients with ALT or AST >3.0 x ULN and total bilirubin > 2.0 x ULN in the absence of 
cholestasis (elevation of ALP in patients without bone metastasis or if bone metastasis are 
present elevation of 5’-nucleotidase and ALP liver fraction) must be immediately withdrawn 
from buparlisib/placebo, and every attempt should be made to carry out locally the liver event 
follow-up assessments as described below:  
• Inform the sponsor about the event immediately after its occurrence by reporting the event 
immediately in the clinical database if it meets the criteria for an AE or SAE. 
• Evaluate if associated with the appearance or worsening of clinical symptoms of hepatitis 
or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia, or other organ involvement. 
• Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), and blood count with differential to assess 
eosinophilia. 
• Perform liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease including metastasis or new lesions, obstruction/compression, etc. 
• Perform viral hepatitis and other serology tests: 
• Hepatitis C (HCV) serology and viral RNA, Hepatitis B (HBV) serology and viral 
DNA, Hepatitis A (HAV) Immunoglobulin M (IgM) and HAV total 
• Hepatitis E (HEV) serology: IgM and IgG, viral RNA 
• Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Epstein-Barr viral (EBV) 
serology  
• Obtain PK sample, as close as possible to last dose of study drug if the patient has 
consented for PK Record the date and time of the PK blood sample draw and the date and 
time of the last dose of BKM120/placebo prior to blood sample draw on the eCRF 
• Verify and record the use of concomitant medications, acetaminophen, herbal remedies, 
and other over the counter medications, or putative hepatotoxins, on the concomitant 
medications report form. 
• Consultation with a specialist(s) or a hepatologist(s) is recommended. 
• Liver biopsy as clinically indicated to assess pathological change and degree of potential 
liver injury 
• LFTs should be followed-up weekly until resolve to ≤ grade 1, baseline or stabilization 
(no CTCAE grade change over 4 weeks) and outcome documented on the respective AE 
and lab chemistry pages.  


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6.3 
Concomitant medications 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted (see Section 6.3.1), except as specifically prohibited (see Section 
6.3.2). 
All medications (excluding study treatment and prior antineoplastic treatments), procedures 
and significant non-drug therapies (including physical therapy and blood transfusions) 
administered within 28 days prior to the administration of buparlisib/placebo through 30 days 
after the last dose of study treatment (either buparlisib/placebo or paclitaxel, whichever is 
later) will be recorded in the Concomitant medications or Surgical and medical procedures 
eCRF. Medications include not only physician prescribed medications, but also all over-the 
counter medications, herbal medications (prohibited, see Section 6.3.2.8) and food or vitamin 
supplements.  
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy and blood transfusions) administered during 
the study must be listed on the Concomitant Medications or the Procedures and Significant 
Non-Drug Therapies CRF, respectively. 
6.3.1 
Permitted concomitant therapy 
6.3.1.1 
Corticosteroids 
High dose of corticosteroids administered chronically are known to induce CYP3A enzymes, 
thereby increasing the risk of reducing buparlisib drug exposure to sub-therapeutic levels. A 
clinical pharmacology study evaluated the impact of chronic administration of 4 mg 
dexamethasone on the exposure of buparlisib ([CBKM120C2106]). No impact of 
dexamethasone on the exposure to buparlisib was observed. Based on these new findings the 
administration of corticosteroids to doses equivalent to 4 mg dexamethasone are allowed. 
However to avoid any potential under exposure, the treatment should remain as short as 
possible and should be avoided whenever possible.. In addition, corticosteroids are allowed as 
well in the following situations:  
• topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye 
drops or local injections (e.g., intra-articular); 
• systemic corticosteroids ≤ to the anti-inflammatory potency of 4 mg dexamethasone (e.g. 
for chronic obstructive pulmonary disease, or as an antiemetic); 
• as premedication for paclitaxel, as described in Section 6.1.2.1. 
6.3.1.2 
Drugs that are metabolized by CYP450 enzymes 
In vitro metabolism studies performed to examine the reversible and metabolism-dependent 
inhibition of CYPP450 enzymes showed that buparlisib is a weak, reversible inhibitor of 
CYP3A4/5, CYP2C8, CYP2C9 and CPY2C19. Note that with the data available, it is not 
possible to confirm whether such interactions will occur in patients. Therefore, investigators, 
at their discretion, may administer concomitant medications known to be metabolized by 
CYP3A4/5, CYP2C8, CYP2C9 and CYP2C19. Patients receiving such medications must be 


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monitored for potentiation of toxicity due to any individual concomitant medications, and 
may require dose titration or reduction of the drug substrate.  
Refer to Table 14-2 in Appendix 3: List of CYP450 substrates to be used with caution. 
Particularly, caution is advised when buparlisib is co-administered with drugs that are 
sensitive substrates and/or have a narrow therapeutic index (e.g., SSRI).  
Concomitant treatment of buparlisib/placebo with weak inducers of CYP3A4 is permitted, 
however, duration of concomitant treatment should be kept as short as possible (e.g., less than 
1 week), or fully avoided whenever possible. Note that coadministration of buparlisib/placebo 
with strong inducers is prohibited (refer to Section 6.3.2.7).  
6.3.1.3 
Non-enzyme Inducing Anti-epileptic drugs 
Non-enzyme inducing anti-epileptic medication (Non-EIAED) is allowed, except for those 
listed in Table 14-1 in Appendix 2. 
6.3.1.4 
Bisphosphonates 
The use of bisphosphonates for bone metastatic disease is allowed. If bisphosphonate therapy 
is initiated after start of study medication, the reason for its use must be clearly documented 
and progression as per RECIST 1.1 must be ruled out. 
6.3.1.5 
Drugs with a conditional or possible risk to induce Torsades de 
Pointes 
If a patient, after enrollment in the study, requires the concomitant use of any QT prolonging 
medication with a possible or conditional risk for Torsades de Pointes included in Table 14-4 
of Appendix 5, then investigators, at their discretion, may co-administer such medications. 
Patients receiving such medications must however be closely monitored. 
6.3.1.6 
Gastric protection agents 
Buparlisib is characterized by a pH-dependent solubility. Medicinal products that alter the pH 
of the upper Gastro-Intestinal (GI) tract may alter the solubility of buparlisib and hence its 
bioavailability. These agents include, but are not limited to, proton-pump inhibitors (e.g., 
omeprazole), H2-antagonists (e.g., ranitidine) and antacids. buparlisib/placebo should be 
dosed in a staggered manner at least 1 hour before or 10 hours after dosing with medicinal 
products that may alter the pH of the upper GI tract. 
6.3.2 
Prohibited concomitant therapy 
6.3.2.1 
Other anticancer therapy 
Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) other than the 
study treatments must not be given to patients while the patient is enrolled in the treatment 
portion of the trial. If such agents are required for a patient then the patient must be 
permanently discontinued from the treatment portion of the study. 


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6.3.2.2 
Other investigational therapies 
Other investigational therapies must not be used while the patient is on the study.  
6.3.2.3 
Hematopoietic growth factors 
Prophylactic use of hematopoietic growth factors (e.g. erythropoietins, granulocyte colony-
stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-
CSF)) are not permitted. However, in the event of an emergency (e.g. acute myelosuppression 
with infection), a patient may be given hematopoietic growth factors according to the 
investigator’s judgment, and the sponsor should be notified as soon as possible. Subsequent 
secondary prevention use is permitted at investigator’s discretion. 
Patients who begin erythropoietin or darbepoetin therapy before randomization, may continue 
this treatment at the discretion of the investigator. 
6.3.2.4 
Warfarin and coumarin derivatives 
Therapeutic doses of warfarin sodium or any other coumarin-derivative anticoagulants are not 
permitted. 
Buparlisib is a weak inhibitor of CYP2C8 and 2C9, the major metabolizing enzyme of 
warfarin. Despite the fact that the inhibitory signal was weak, an increase of 40-50% of 
warfarin exposure is possible and for a drug like warfarin, this might be clinically relevant.  
6.3.2.5 
Enzyme-inducing anti-epileptic drug (EIAED) 
Use of enzyme-inducing anti-epileptic drug (EIAED) is not permitted.  Refer to for a list of 
prohibited EIAED. 
If a patient is currently taking EIAED, they must have discontinued the EIAED therapy for at 
least two weeks prior to starting study drug. 
If a patient is previously on a non-EIAED and needs to permanently change the 
anticonvulsant agent, but cannot change to another non-EIAED, the patient will be taken off 
buparlisib/placebo. 
6.3.2.6 
Drugs with a known risk for Torsades de Pointes 
If a patient requires the concomitant use of any medication included in Table 14-3 in 
Appendix 4 entitled “List of Prohibited QT prolonging drugs” (i.e., drugs that are generally 
accepted by the Qtdrugs.org Advisory Board of the Arizona CERT to have a risk of causing 
Torsade de Pointes), study treatment must be delayed. Note that Table 14-3 lists drugs with a 
known risk for Torsades de Pointes (TdP) as well as sensitive CYP3A substrates (with narrow 
TI) with a possible or conditional risk for TdP. Study treatment administration must be 
interrupted as long as the patient requires therapy with the QT prolonging agent. 
6.3.2.7 
Strong CYP3A inhibitors and inducers 
In vitro metabolism studies suggest that oxidative metabolism of buparlisib is predominantly 
mediated by CYP3A4 and UGT1A4. Based on these in-vitro finding, a clinical trial was 
conducted in healthy volunteers. The study investigated then impact of a strong CYP3A4 


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inhibitor, ritonavir, on the pharmacokinetics of buparlisib [CBKM120C2111]. The results 
showed that the contribution of CYP3A4 in-vivo was not as important as initially thought in-
vitro. Exposure of buparlisib increased by 1.73 fold upon concomitant administration of 
ritonavir which suggested that CYP3A4 only contributed to around 40%.  
Based on these findings, strong CYP3A4 inhibitors and inducers are prohibited as they might 
substantially impact buparlisib exposure.  
Please refer to Table 14-1 in Appendix 2 for a list of prohibited drugs. Please note that this list 
may not be comprehensive. 
6.3.2.8 
Herbal medications 
Herbal preparations/medications are not allowed throughout the study, as a potential drug-
drug interaction is always possible.  These herbal medications include, but are not limited to: 
St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. 
Patients should stop using these herbal medications at least 7 days prior to first dose of study 
treatment. 
6.3.2.9 
Hormonal contraception 
Hormonal contraceptives may be affected by cytochrome P450 interactions, and are therefore 
not considered effective for this study, since induction of CYP3A4 may not be excluded in 
patients receiving buparlisib. 
6.4 
Patient numbering, treatment assignment and randomization 
6.4.1 
Patient numbering 
Each patient is identified in the study by a 7-digit Patient Number (Patient No.) that is 
assigned when the patient is first enrolled for screening, and is retained as the primary 
identifier for the patient throughout her entire participation in the trial. 
• The Patient No. consists of the 4-digit Center Number (assigned by Novartis to the 
investigative site) and a sequential 3-digit patient number suffixed to it, so that each 
subject is numbered uniquely across the entire study 
• The investigator or designated staff will contact the Interactive Response Technology 
(IRT) and provide the requested identifying information for the patient to register them 
into the IRT system 
• Once assigned, the Patient No. must not be reused for any other patient and the Patient No. 
for that individual must not be changed, even if the patient is re-screened 
• If the patient fails to be started on treatment for any reason, the reason will be entered into 
the Screening Phase Disposition eCRF 
• IRT should be notified within 2 days if the patient on screening was not started on 
treatment (Section 7.1.2.1) 


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6.4.2 
Treatment assignment and randomization 
Approximately 150 patients will be randomized in a 1:1 ratio to one of the two treatment arms 
(Section 4.1 and Section 6.1).   
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication randomization list will be produced by or under 
the responsibility of Novartis Drug Supply Management using a validated system that 
automates the random assignment of medication numbers to medication packs containing 
each of the study treatments. The randomization number will not be communicated to the 
person contacting the IRT. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms.  The investigator or his/her delegate will contact the IRT 
and confirm that the patient fulfills all the inclusion/exclusion criteria.  The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify unique medication number(s) for the first packages of study treatment to be 
dispensed to the patient.   
6.4.3 
Treatment blinding 
• This is a double blind study. In particular, patients, investigators, local radiologists, , or 
anyone involved in the study conduct will remain blinded to the identity of the treatment 
from the time of randomization until the final OS analysis  
• The Novartis study team remained blinded until the primary analysis. 
• Given the final OS analysis has been completed, unblinding will occur and the 
Investigator will decide whether to continue the patient on study treatment based on 
clinical benefit. 
• Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible to anyone involved in the conduct of the study. The identity of the 
treatments will be concealed by the use of investigational drugs (buparlisib or buparlisib-
matching placebo) that are identical in packaging, labeling, schedule of administration and 
in appearance. Confidentiality of randomization data is required to limit the occurrence of 
potential bias arising from the influence that the knowledge of treatment may have on the 
recruitment and allocation of patients 
• Unblinding of study drug assignment will only occur in the case of patient emergencies,  
for regulatory reporting purposes and at the conclusion of the study, using the IRT system 
• In rare cases when unblinding occurs because of emergency patient management, the 
actual treatment arm will not be communicated to any of the Novartis employees involved 
in running the trial in order to remain blinded 
• An independent statistician, not involved in the trial conduct, will prepare data reports for 
the DMC. Details will be presented in the DMC charter 


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6.5 
Study drug supply 
6.5.1 
Study drug preparation and dispensation 
The study medication packaging has a 2-part label.  A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms.  Study medication will 
be dispensed by an authorized person at the investigator’s site. Investigator staff will identify 
the study drug package(s) to dispense to the patient by using the IRT and obtaining the 
medication number(s).  Investigator staff will add the patient number on the label.  
Immediately before dispensing the package to the patient, investigator staff will detach the 
outer part of the label from the packaging and affix it to the source document (Drug Label 
Form) for that patient’s unique patient number. 
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 buparlisib/placebo on an outpatient basis. The investigator shall provide 
the patient with instructions for buparlisib/placebo administration according to the protocol. 
Paclitaxel should be prepared and dispensed according to the local prescribing information 
and practice. Investigator staff will register paclitaxel dispensation to the patient by using the 
IRT. 
All dosages prescribed to the patient and all dose changes during the study must be recorded 
on the Dosage Administration Record CRF. 
6.5.2 
Study drug packaging and labeling 
Buparlisib/placebo will be supplied as 10-mg and 50-mg hard gelatin capsules, packaged in 
bottles, and will be given orally on a flat scale of mg/day. The capsules are packaged in 
HDPE bottles with a plastic child resistant closure. 
Each bottle received will have a 2-part label.  A unique medication number is printed on each 
part of the label which corresponds to one of the treatment arms. 
Medication labels comply with the legal requirements and are printed in the local language. 
They will supply no information about the patient. The storage conditions for study drug will 
be described on the medication label. 
Table 6-5 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Buparlisib or 
Buparlisib-matching 
placebo 
Capsules in bottle 
10 mg 
50 mg 
Labeled as  “BKM120/Placebo” 
Once daily dosing 
Paclitaxel 
Refer to local product information 
Refer to local product information 
Paclitaxel packaging and labeling will be according to locally available supplies of Paclitaxel 
and according to local regulations. 


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6.5.3 
Drug supply and storage 
Each site will be globally supplied by Novartis with oral buparlisib/placebo bottles. 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 
assistants have access. 
Upon receipt, buparlisib/placebo should be stored according to the instructions specified on 
the drug labels. These instructions should also be made clear to the patient for storage and 
self-administration of buparlisib at home. 
If available, generic paclitaxel should be used for study treatment, when possible.  Paclitaxel 
should be prepared and stored according to the local prescribing information and practice. If 
feasible and available per local practices, patients who are receiving paclitaxel alone may be 
transitioned to commercial drug. 
Site staff will be responsible for managing adequate re-supplies for paclitaxel. For 
buparlisib/placebo, re-supplies are managed with the IRT system, using local depots or 
regional hubs where possible. It is therefore required that the site staff enters any receipt of 
drug supplies and any dispensed drug into the IRT system immediately to not run the risk that 
the IRT cannot provide drug re-supplies on time. 
6.5.4 
Study drug compliance and accountability 
6.5.4.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
using pills counts and information provided by the patient and/or caregiver. Records of study 
medication used, dosages administered, and intervals between visits and the completion of the 
study will be captured in the Drug Accountability Form. This information must be captured in 
the source document at each patient visit. 
A buparlisib/placebo patient medication diary will be provided for each patient. Patients or 
caregivers are required to complete this diary during the study.  
6.5.4.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability ledger. 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 used and 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 ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site. 


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6.5.5 
Disposal and destruction 
The 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. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1a 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). 
Written informed consent must be obtained before any study specific assessments are 
performed, including screening. Baseline radiographic tumor assessments should be 
performed within 28 days prior to treatment start.  Every effort must be made to follow the 
schedule of assessments within the windows outlined in the protocol. 
During the study (post- screening): 
• All assessments have a ± 3 day window unless otherwise indicated 
• Tumor assessments have a window of ± 3  days at cycle 2 Day 1 and  ± 4  days for 
subsequent cycles starting from cycle 3 Day 15 
• Paclitaxel will be administered once weekly (± 1 day).  Missed doses will not be made up. 
• Buparlisib/placebo will be administered once daily, continuously.  Missed doses will not 
be made up. 
• Additional assessments may be performed as clinically indicated. 
• There is no visit or treatment window for Cycle 1 Day 1. 
A complete cycle is defined as 28 days (± 3 days). 
If one or both study drugs are being held due to toxicity, scheduled visits and assessments 
should still be performed (with the exception of the dosing of the held study drug) as 
described in Table 7-1a, unless otherwise specified. 
Patients who permanently discontinue paclitaxel, but continue buparlisib/placebo will have 
assessments only on days 1 and 15 of each subsequent cycle (the patients will not be required 
to come to the investigational site on day 8 and 22 of subsequent cycles except for PK 
sampling on Cycle 1 Day 22). In this case, IRT will be contacted only on days 1 and 15 of 
each cycle. 
Please refer to Table 7-14, Table 7-15 and Table 7-16 for PK sampling windows and to Table 
7-8 for biomarker sampling windows. Similar adherence to the outlined schedule should be 
applied for all biomarker analyses. In general, where possible, every effort must be made to 
follow the schedule outlined in Table 7-1a. 
Table 7-1b lists the assessments for patients receiving paclitaxel alone after unblinding. Those 
patients will be assessed as per local clinical practices and at investigator discretion. 


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Table 7-1c lists all the assessments for patients receiving buparlisib +/- paclitaxel after 
unblinding. 


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Table 7-1a 
Visit evaluation schedule 
 
Category 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
Post 
treatment 
F up 
Survival 
phase 
Cycle Days 
 
 
-35 to -1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Last 
Dose
+≤ 7d 
Safety & 
efficacy 
 F up 
Survival  
F up 
every 3 
months 
Study Informed 
consent 
D 
11.3 
X 
 
Inclusion/Exclusion 
criteria 
D 
5.1 
5.2 
X 
 
Relevant medical 
history/ Current 
medical conditions 
D 
7.1.2.3 
X 
 
Smoking History 
D 
7.1.2.3 
X 
 
Alcohol 
Consumption 
History  
D 
7.1.2.3 
X 
 
Diagnosis and 
extent of cancer 
D 
7.1.2.3 
X 
 
HPV historical 
status (if available) 
D 
7.1.2.3 
X 
 
Prior antineoplastic 
therapy 
(surgery/medication
/radiotherapy) 
D 
7.1.2.3 
X 
 
IRT Registration/ 
Buparlisib/placebo/
paclitaxel 
management  
S 
6.4.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Category 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
Post 
treatment 
F up 
Survival 
phase 
Cycle Days 
 
 
-35 to -1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Last 
Dose
+≤ 7d 
Safety & 
efficacy 
 F up 
Survival  
F up 
every 3 
months 
Eligibility checklist 
via IRT 
S 
7.1.2.1 
X 
 
IRT Randomization 
D 
6.4.2 
 
X 
 
End of Phase 
Disposition 
D 
7.1.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Demography 
D 
7.1.2.3 
X 
 
Weight 
D 
7.2.2.3 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Height 
D 
7.2.2.3 
X 
 
Vital Signs 
D 
7.2.2.2 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Physical 
examination 
S 
7.2.2.1 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
ECOG P.S.  
D 
7.2.2.4 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
PHQ-9 Patient self-
rating mood scale 
D 
7.2.2.8 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
(Cy
cle 
3 
only
) 
 
X 
 
 
GAD7 Patient self-
rating mood scale 
D 
7.2.2.8 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X  
(Cy
cle 
3 
only
) 
 
X 
 
 


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Category 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
Post 
treatment 
F up 
Survival 
phase 
Cycle Days 
 
 
-35 to -1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Last 
Dose
+≤ 7d 
Safety & 
efficacy 
 F up 
Survival  
F up 
every 3 
months 
EORTC QLQ-C30 
+ QLQ-HN35 
D 
7.2.4.1 
X 
 
 
 
 
 
 
         X    Every 6 weeks starting from cycle 
2 day 15 
X 
 
 
Laboratory Assessment 
Hematology 
D 
7.2.2.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Biochemistry  
(full panel) 
D 
7.2.2.5.2 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Biochemistry  
(partial panel) 
(AST, ALT, Alkaline 
phosphatase, total 
bilirubin, creatinine) 
D 
7.2.2.5.2 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
Hepatotoxicity 
follow-up 
testing/procedures 
D 
7.2.2.5.7  
As clinically indicated 
 
Coagulation 
D 
7.2.2.5.4 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Creatinine 
clearance  
D 
7.2.2.5.2 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Lipid profile 
D 
7.2.2.5.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Fasting plasma 
glucose 
D 
7.2.2.5.3 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Fasting C-peptide 
D 
7.2.2.5.3 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
HbA1c 
D 
7.2.2.5.3 
X 
 
 
 
 
 
 
 
 
X (every 3 cycles starting 
cycle3 day 1) 
X 
 
 
Urine dipstick 
D 
7.2.2.5.5 
X 
As clinically indicated 
X 
 
 


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Category 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
Post 
treatment 
F up 
Survival 
phase 
Cycle Days 
 
 
-35 to -1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Last 
Dose
+≤ 7d 
Safety & 
efficacy 
 F up 
Survival  
F up 
every 3 
months 
Pregnancy test,  if 
applicable 
D 
7.2.2.5.6 
X  
X  
 
 
 
X  
 
 
 
X  
 
 
 
X  
 
 
Blood sample for 
BKM120 full PK 
sampling 
 
7.2.5 
 
 
 
X1 
X1 
X1 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
BKM120 sparse PK 
sampling 
 
7.2.5  
 
X2 
 
X2 
X2 
X2 
 
 
 
X2 
(every 
second 
cycle 
until 
cycle 6) 
 
 
 
 
 
 
Trough Blood 
sample for BKM120 
PK sampling 
 
7.2.5 
 
 
 
X3,4 
X3,4 
X3,4 
 
 
 
X3,4 
(every 
second 
cycle 
until 
Cycle 
6) 
 
 
 
 
 
 
Imaging / Other assessments 
Tumor response 
assessment 
(MRI/CT) 
D 
7.2.1 
X  
(window 
 -28 to -1) 
 
 
 
 
X 
 
 
 
 
 
           X  
(every 6 weeks starting 
from cycle 3 day 15) 
X 
X  
(every 6 
weeks) 
 
Pulmonary function 
tests 
D 
6.2.2.3.1 
As clinically indicated for pneumonitis management (refer to Table 6-4) 
 
 
 
12 Lead ECG 
D 
7.2.2.7.1 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 


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Category 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
Post 
treatment 
F up 
Survival 
phase 
Cycle Days 
 
 
-35 to -1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Last 
Dose
+≤ 7d 
Safety & 
efficacy 
 F up 
Survival  
F up 
every 3 
months 
Cardiac 
assessment by 
MUGA/ECHO 
D 
7.2.2.7.2 
X 
 
Cycle 4 day 1 and  
every 4th cycle thereafter 
X 
 
 
Biomarkers 
Tumor biopsy 
(archival or new 
tumor blocks/slides) 
D 
5.1 
X 
 
 
 
Plasma for 
Circulating DNA 
D 
7.2.3 
X 
 
X 
 
 
Safety 
Adverse events 
D 
8.1 
X 
Continuous, up to 30 days after last dose of study treatment 
 
Prior/concomitant 
medications 
D 
6.3 
X 
Continuous, up to 30 days after last dose of study treatment 
 
Prior/concomitant 
medical and 
surgical procedures 
D 
6.3 
 
 
 


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Category 
Protocol 
Section 
Screening 
Cycle 1 
Cycle 2 
Subsequent cycles 
EOT 
Post 
treatment 
F up 
Survival 
phase 
Cycle Days 
 
 
-35 to -1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Last 
Dose
+≤ 7d 
Safety & 
efficacy 
 F up 
Survival  
F up 
every 3 
months 
New antineoplastic 
therapy since EoT 
D 
7.1.4 
7.1.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Survival FU 
1 (every 3 months 
from EoT) 
D 
7.1.5.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
Drug Administration 
buparlisib/ 
placebo  
administration 
D 
6.1.1.1 
 
Daily 
 
 
 
Paclitaxel 
administration 
D 
6.1.1.2 
 
Once a week starting cycle 1 day 1 (days 1, 8, 15,  22 of each cycle) 
 
 
 
1. 
In patients with full PK sampling, pharmacokinetic assessments will be performed on Cycle 1 Day 15 (at pre-dose, at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h [before 
Cycle 1 Day 16 dose ] post-dose). Only pre-dose samples will be collected on Cycle 1 Day 22 and Cycle 2 Day 1. 
2. 
Pharmacokinetic assessments in patients with sparse PK sampling will be performed on Cycle 1 Day 1 at 1, 2, and 6h, and a recommended 9 hours post dose sample. 
Only pre-dose sample will be collected on Cycle 1 Day 15 and 22 and Cycle 2 Day 1. 
3. 
Buparlisib trough concentrations - a PK sample will be collected before drug administration (pre-dose) on Cycle 1 Day 15 and Day 22, Cycle 2 Day 1, Cycle 4 Day 1 
and Cycle 6 Day 1 unless buparlisib/placebo is permanently terminated. 
4. 
For all remaining patients who did not participate for Full PK and Sparse PK sampling 


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Table 7-1b 
Visit evaluation schedule for patients receiving paclitaxel alone after unblinding 
 
Category 
Reference to Section 7.2 
Subsequent cycles – Day 1 
End of treatment 
End of phase disposition 
D 
7.1.4 
 
X 
Paclitaxel administration 
D 
6.1.1.2 
Once a week (days 1, 8, 15, 22 of each cycle) 
 
Adverse events 
D 
8.1 
Continuous up to 30 days after last dose of treatment 
 
Prior/concomitant medications 
D 
6.3 
Continuous up to 30 days after last dose of treatment 
 
Prior/concomitant medical and 
surgical procedures 
D 
6.3 
Continuous up to 30 days after last dose of treatment 
 
Tumor response assessment  
D 
7.2.1 
As per local practices 
Patients receiving paclitaxel alone will be assessed as per standard of care and at investigator discretion. Survival F-up will no longer be collected after 30 day 
safety Follow-up.. 


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Table 7-1c 
Visit evaluation schedule for patients receiving buparlisib +/- paclitaxel after unblinding 
 
Category 
Reference to 
Section 7.2 
Subsequent cycles – Day 1 
End of treatment 
IRT registration 
S 
6.4.2 
X 
X 
End of phase disposition 
D 
7.1.4 
 
X 
Performance status (ECOG) 
D 
7.2.2.4 
X 
X 
Weight  
D/S 
7.2.2.3 
As clinically indicated 
X 
Vital signs 
D/S 
7.2.2.2 
X 
X 
Patient self-reported Mood scales for 
depression (PHQ-9) and anxiety (GAD 7) 
D 
7.2.2.8 
X 
X 
Pulmonary function tests 
D 
6.2.2.3.1 
As clinically indicated 
12-lead ECG 
D 
7.2.2.7.1 
As clinically indicated 
X 
Cardiac imaging (MUGA/ECHO) 
D 
7.2.2.7.2 
As clinically indicated and at least every 4 months 
X (if not done within the 
last 4 months) 
Hematology 
D 
7.2.2.5.1 
X 
X 
Biochemistry 
D 
7.2.2.5.2 
X 
X 
Hepatotoxicity follow-up testing/procedures 
D 
7.2.2.5.7 
As clinically indicated 
Fasting plasma glucose, lipase  
D 
7.2.2.5.3 
X 
X 
Buparlisib administration 
D 
6.1.1.1 
Daily 
 
Paclitaxel administration 
D 
6.1.1.2 
Once a week (days 1, 8, 15, 22 of each cycle) 
 
Adverse events 
D 
8.1 
Continuous up to 30 days after last dose of treatment 
 
Prior/concomitant medications 
D 
6.3 
Continuous up to 30 days after last dose of treatment 
 
Prior/concomitant medical and surgical 
procedures 
D 
6.3 
Continuous up to 30 days after last dose of treatment 
 
Tumor response assessment 
D 
7.2.1 
As per standard of care 
Survival F-up will no longer be collected after 30 day safety Follow-up. 
 


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7.1.1 
Molecular pre-screening 
Not applicable 
7.1.2 
Screening 
After signing the main study ICF (S-ICF), the screening assessments will be done within 1 to 
35 days prior to treatment start (except for radiological tumor assessments which need to be 
done within 1 to 28 days prior to treatment start).  
Re-screening of patients is only allowed once per patient if the patient was not registered as 
entering the treatment phase before (i.e. IRT randomization). In this case the Subject No 
assigned to the patient initially will be used and the patient will be identified with this number 
throughout their entire participation to the study. 
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. In case rescreening occurs, all evaluations re-assessed should meet the eligibility 
criteria. 
For details of assessments, refer to Table 7-1a. 
7.1.2.1 
Eligibility screening 
In order to determine and confirm the eligibility of the patient, once all screening procedures 
are completed, an eligibility checklist must be completed via IRT by the investigator or 
designee prior to receiving the first dose of study drug. 
After the eligibility has been checked and confirmed that the patient is eligible for the trial, 
then the patient can be enrolled into the study. 
The IRT system will randomize patients to treatment in a 1:1 ratio to receive, paclitaxel + 
buparlisib or paclitaxel + buparlisib-matching placebo. 
To evaluate a patient for enrollment into the study: 
• Obtain written consent and complete all the screening evaluations 
• Call the Interactive Response Technology (IRT) as close as possible to the day study 
treatment is due to start. Verification of eligibility criteria must be known prior to 
contacting IRT. Randomization to one of the 2 treatment arms (paclitaxel + buparlisib or 
paclitaxel + buparlisib-matching placebo) will be provided by the IRT. The specific 
information and instructions will be provided separately to each study site. 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign ICF, but are not randomized via IRT for any reason will be considered a 
screening failure. A patient who is randomized via IRT but does not start treatment is not 
considered a screening failure. The reason for not proceeding with the treatment will be 
documented on the End of treatment page. Limited data will be collected for these patients. 


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For screening failure patients, the reason for not proceeding with randomization will be 
entered on the End of Phase Disposition Page. No waivers will be granted. 
The following eCRFs must be completed for screening failure patients: 
• End of phase disposition eCRF page (including reason for not being started on treatment) 
• Informed Consent, including additional biomarker ICF if relevant. 
• Inclusion/Exclusion Criteria 
• Demography 
• Adverse Events (only if the patient experienced a Serious Adverse Event during the 
Screening Period after signing the ICF - see Section 8 for SAE reporting details) 
If a screening failure patient experiences an AE which does not meet the SAE criteria, details 
about the AE will be recorded only in the investigator’s source documents. In case of an SAE, 
data must be recorded on both the AE and SAE forms. 
No other data will be entered into the clinical database for patients who are screen failures. 
If on screening, the patient fails to start on treatment, then IRT must be notified within 2 days 
of the screen failure. 
7.1.2.3 
Patient demographics and other baseline characteristics 
Patient information to be collected at screening will include: 
• Historical HPV status 
• Demography 
• 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 7.2.2.4) 


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• Patient self-rating mood questionnaires (PHQ-9 and GAD7) (See Section 7.2.2.8) 
• Patient self-rating EORTC QLQ-C30 and QLQ-HN35 (See Section 7.2.4.1) 
• ECG (See Section 7.2.2.7.1) 
• Cardiac imaging (See Section 7.2.2.7.2)  
• Radiological assessments (e.g., CT scan) (See Section 7.2.1)  
• Laboratory evaluations (e.g., hematology, coagulation, chemistry, urinalysis) (See Section 
7.2.2.5) 
• Serum pregnancy (See Section 7.2.2.5.6) 
7.1.3 
Treatment period 
Patients will be treated with paclitaxel + buparlisib or paclitaxel + buparlisib-matching 
placebo until disease progression, unacceptable toxicity, death, or discontinuation from the 
study treatment due to any other reason. 
As the Final OS analysis has been performed, unblinding will occur. Patients still on treatment 
may continue to receive study treatment if the investigator considers they are clinically 
benefiting from continuing it. The patient will continue receiving study treatment on or off 
study until physician decision. If feasible and available per local standard of care, patients 
who are receiving paclitaxel alone may be transitioned to commercial drug. 
Patients will continue with a reduced schedule of study evaluations as described in Table 7-1b 
and Table 7-1c. Table 7-1b describes the assessments required for patients receiving 
paclitaxel alone and Table 7-1c describes the assessments required for the patients receiving 
buparlisib alone or in combination with paclitaxel.  
Figure 7-1 
On-treatment patients Follow-up after unblinding (from protocol 
amendment v.03) 
 
For details of assessments, refer to Table 7-1a, Table 7-1b and Table 7-1c. 


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• Visits and associated assessments that occur +/- 3 days from the scheduled date (except 
for cycle 1 Day1 where no visit window is allowed) will not constitute protocol 
deviations. 
• MRI/CT scans must be performed at Cycle 2 Day 1 (+/- 3 days) and every 6 weeks (+/-4 
days) until disease progression, withdrawal consent, lost to follow-up, start of another 
anti-neoplastic therapy, or death, whichever occurs first. 
• Laboratory assessments performed as part of the screening evaluations and within 7 days 
of the first dose of study treatment, are not required to be repeated on the first dosing day. 
 
 
7.1.4 
End of treatment visit 
Patients who completely discontinue study treatment should be scheduled for an End of 
Treatment (EOT) visit within 7 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 7-1a, Table 7-1b and Table 7-1c. 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. 
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. 
The investigator (or designee) must contact IRT to register the patient’s treatment 
discontinuation. 
7.1.4.1 
 
Discontinuation of study treatment 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If 
a patient decides to discontinue from the study treatment, the investigator must make every 
effort (e.g. telephone, e-mail, letter) to determine the primary reason for this decision and 
record this information in the patient’s chart and on the appropriate CRF pages.  They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
The investigator should discontinue the study treatment for a given patient if, he/she believes 
that continuation would be detrimental to the patient’s well-being. 
Study treatment must be discontinued under the following circumstances: 
• Adverse Event 
• Lost to follow-up 
• Non-compliance with study treatment 
• Physician decision 
• Pregnancy 
• Progressive Disease 
• Protocol deviation 


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• Study terminated by sponsor 
• Technical problems 
• Subject/guardian decision 
• Death 
In addition, the following study specific criteria will also require study treatment 
discontinuation: 
• Adjustments to study treatment that result in discontinuation. Please refer to Section 6.2 
• Use of prohibited medication.  Please refer to Section 6.3.2 
• Interruption of study treatment for > 28 days, regardless of reason, from the intended day 
of the next scheduled dose 
The appropriate personnel from the site and Novartis will assess whether the investigational 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason. 
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. They should return for the assessments indicated in Section 7.2.1. If they fail to return 
for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) should 
be made to contact them as specified in Section 7.1.5.4. 
Patients who discontinue study treatment should undergo an end of study visit and then 
enter the follow-up epoch. 
From protocol amendment v.03, regardless of EOT reason, tumor assessments for efficacy 
follow-up will not be assessed and Study Phase Completion eCRF is not applicable; for 
patients still under efficacy follow up at the time of protocol amendment v.03, Study Phase 
Completion eCRF will continue to be completed as per eCRF completion guidelines (eCCG). 
The investigator must also contact the IRT to register the patient’s discontinuation from 
investigational treatment. 
7.1.4.2 
Withdrawal of Consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact. 
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation.  All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up. 


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7.1.5 
Follow up period 
7.1.5.1 
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.) and a Study Phase Completion Disposition eCRF page should be 
completed. 
All new anti-cancer therapies given after the last dose of the study drug will be recorded on 
eCRFs designed to capture anti-neoplastic therapies administered after discontinuation of 
study treatment. 
7.1.5.2 
Efficacy follow-up 
If a patient did not discontinue study treatment due to disease progression, death, start of new 
anti-neoplastic therapies, lost to follow-up, or withdrawal of consent to efficacy follow-up, 
then tumor assessments should continue to be performed every 6 weeks until the start of new 
anti-cancer therapy, disease progression, death, lost to follow-up, or withdrawn consent to 
efficacy follow-up. At that time, the reason for study completion should be recorded on the 
Study Phase Completion Disposition eCRF page. In addition, all new anticancer therapies 
given after the last dose of the study drug, until disease progression, death, lost to follow-up, 
or withdrawal of consent to efficacy follow-up will be recorded in the eCRFs. From protocol 
amendment v.03, regardless of EOT reason, efficacy follow up will be done as per local 
practices. 
7.1.5.3 
Survival follow-up 
All patients will be followed for survival status every 3 months regardless of treatment 
discontinuation reason until death, lost to follow-up, or withdrawal of consent to survival 
follow-up.  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. 
From protocol amendment v.03, survival follow-up will not be performed. 


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7.1.5.4 
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. A patient should not be considered lost to follow-up until due diligence has been 
completed.  
7.1.5.5 
End of post-treatment follow-up (Study phase completion) 
Prior to collecting survival follow-up information, end of post-treatment eCRF (study phase 
completion) will be completed once a patient has discontinued study treatment, completed 
safety follow-up, and can no longer perform efficacy assessment. 
Study phase completion may occur for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• New therapy for study indication 
• Progressive disease 
• Study terminated by the sponsor 
From protocol amendment v.03, End of post-treatment follow-up (Study phase completion) is 
not applicable; for patients still under efficacy follow up Study Phase Completion eCRF will 
continue to be completed as per eCCG. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response will be determined locally according to the Novartis guideline (Appendix 6) 
on the Response Evaluation Criteria in Solid Tumors (RECIST), based on RECIST Version 
1.1. The local investigator’s assessment will be used for the primary endpoint analysis and for 
treatment decision making.  Imaging data will be centrally collected and checked for quality 
by an imaging Contract Research Organization (CRO) designated by Novartis. Central review 
of the imaging data may be performed if deemed necessary.   
The following radiologic and clinical assessments will be performed: 
• All potential sites of tumor lesions will be assessed at screening by radiologic 
techniques (e.g. CT or MRI imaging).  At screening, in addition to CT or MRI scan of 
the primary tumor, all patients must have chest CT (or MRI) and an abdominal/ CT (or 


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MRI) with IV contrast. CT/MRI of the primary tumor, chest and abdomen must be 
performed at every tumor assessment. If no pelvic lesions are suspected at baseline 
then pelvic CT (or MRI) scan does not need to be performed. The preferred radiologic 
technique is CT with intravenous (i.v.). 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 should be performed. 
• If clinically indicated, a full body bone scan at screening for bone lesions should be 
performed at screening according to institutional guidelines (e.g. Tc-99 bone scan, whole 
body bone MRI, sodium fluoride positron emission tomography (NaF PET), or 
Fluorodeoxyglucose PET (FDG PET)).  
• If such a scan was already done during the regular work-up of the patient within 6 
weeks prior to start of treatment, this scan can be considered as the screening scan for 
this study. After screening, scans need not be repeated, unless clinically indicated. If 
indicated, the same methodology as at screening should be used. 
• Localized CT, MRI or X-rays of all skeletal lesions identified on the screening bone scan, 
which are not visible on the chest and abdomen CT (or MRI) must be taken at screening 
and at each subsequent tumor assessment. 
• If brain metastases are suspected at screening, brain CT or MRI scan should be performed. 
Brain CT or MRI will be continued at subsequent tumor assessments if brain metastases 
were identified at screening. 
• If skin lesions are present at screening, color photography should be acquired using a 
digital camera in clear focus, including a scale/ruler, 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. 
• CT or MRI of any other lesion not captured by any of the above listed images (e.g., neck, 
pelvis) at screening and at each subsequent tumor assessment. 
Ultrasound and chest x-ray should not be used to measure tumor lesions. 
Tumor assessment according to Appendix 6 (RECIST 1.1) will be assessed at the following 
time points: 
• Screening Visit 
• All known lesions (measurable, and non-measurable) should be documented  during 
screening to serve as baseline tumor evaluation within 28 days before the start of 
treatment (except for the full body bone scan as described above, within 6 weeks). 
Therefore the first dose of the study drug should be administered within 28 days 
considering the date in which the CT scan/ MRI has been performed and all screening 
procedures should be completed accordingly within this timeframe. 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. 
• During treatment: At Cycle 2 Day 1 (±  3 days) and every 6 weeks (±  4 days) after Cycle 
2 Day 1 


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• Complete tumor assessment is mandatory week 4, 10, 16 and every 6 weeks, as 
defined in Table 7-1a, until disease progression, death, start of new anti-cancer 
therapy, withdrawal of consent to efficacy follow-up or lost to follow up whichever 
occurs earlier, or as clinically indicated. After screening, other imaging studies are 
required at the same interval if lesions were identified at screening (e.g. brain, bone 
lesions) or if there is clinical evidence of a potential new lesion during the study.  
Tumor lesions assessed by physical examination must also be assessed at the same 
schedule. 
• From protocol amendment v3.0, CT/MRI scanning of the head and neck, chest, abdomen 
and pelvis will be performed for all ongoing patients as per local clinical practices. Tumor 
response data will be collected to facilitate investigator assessment of continuing clinical 
benefit.  
• End of Treatment visit:  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 6 weeks (+/- 4 days) prior to end of treatment visit. 
• From protocol amendment v3.0, Tumor assessments at EOT are not  required unless the 
previous assessment was done more than 6 weeks prior to EoT 
• After the End of Treatment visit, continued every 6 weeks (± 4 days) from the 
randomization date, 
• if a patient did not discontinue study treatment due to disease progression, death, start 
of new anti-neoplastic therapies, lost to follow-up, or withdrawal of consent to 
efficacy follow-up, then tumor assessments should continue being performed every 6 
weeks (± 7 days) until the start of new anti-cancer therapy, disease progression, death, 
lost to follow-up, or withdrawn consent to efficacy follow-up. From protocol 
amendment v.03, regardless of EOT reason, tumor assessments for efficacy follow up 
are no longer required. 
All patients who discontinue from study treatment due to disease progression must have their 
progression clearly documented according to the criteria specified in Appendix 6 (RECIST 
v1.1). No additional tumor assessment is required to confirm response (CR or PR) outside the 
protocol specified 6-week tumor assessments. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of oral and intravenous contrast media. 
FDG-PET may be utilized to document progressive disease per 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 v1.1 (Appendix 6).  
Additional CT/MRI safety based assessments are described in Section 7.2.2.6. 


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Table 7-2 
Imaging collection plan  
Procedure 
Screening 
During Treatment1 
During Follow-up1 
CT/MRI of primary 
tumor 
Mandatory 
Mandatory, after completion of 
4, 10, 16 weeks of treatment, 
and every 6 weeks thereafter 
and at the end of study 
treatment 
Mandatory for patients who 
have not progressed at the 
time of treatment 
discontinuation: every 6 weeks 
CT/MRI Chest  
Mandatory  
Mandatory, after completion of 
4, 10, 16 weeks of treatment, 
and every 6 weeks thereafter 
and at the end of study 
treatment 
Mandatory for patients who 
have not progressed at the 
time of treatment 
discontinuation: every 6 weeks 
 
CT/MRI Abdomen 
Mandatory 
Mandatory, after completion of 
4, 10, 16 weeks of treatment, 
and every 6 weeks thereafter 
and at the end of study 
treatment 
Mandatory for patients who 
have not progressed at the 
time of treatment 
discontinuation: every 6 weeks 
CT/MRI Pelvis 
If clinically 
indicated  
If abnormal at screening, after 
completion of 4, 10, 16 weeks 
of treatment, and every 6 
weeks thereafter and at the 
end of study treatment 
If abnormal at screening, for 
patients who have not 
progressed at the time of 
treatment discontinuation: 
every 6 weeks  
Whole body bone 
scan 
If clinically 
indicated 
Only if clinically indicated 
Not applicable 
Bone x-ray, CT or 
MRI (bone lesions 
only) 
Mandatory 
only if 
skeletal 
abnormalities 
identified by 
bone scan at 
screening, 
which are not 
visible on the 
chest and 
abdomen 
CT/MRI 
If bone lesions at screening, 
after completion of 4, 10, 16 
weeks of treatment, and every 
6 weeks thereafter and at the 
end of study treatment 
If bone lesions at screening, for 
patients who have not 
progressed at the time of 
treatment discontinuation: 
every 6 weeks  
Brain CT/MRI 
If clinically 
indicated  
For patients that met the 
eligibility criteria and had brain 
metastases at baseline, after 
completion of 4, 10, 16 weeks 
of treatment, and every 6 
weeks thereafter and at the 
end of study treatment 
For patients that met the 
eligibility criteria and had brain 
metastases at baseline, who 
have not progressed at the 
time of treatment 
discontinuation: every 6 weeks  


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Procedure 
Screening 
During Treatment1 
During Follow-up1 
Skin color 
photography 
 
Mandatory 
only if skin 
lesions at 
screening 
 
If skin lesions at screening, 
after completion of 4, 10, 16 
weeks of treatment, and every 
6 weeks thereafter and at the 
end of study treatment  
If skin lesions at screening, for 
patients who have not 
progressed at the time of 
treatment discontinuation: 
every 6 weeks 
Any of the imaging methods listed above may be acquired at any time during treatment if clinically 
indicated. 
1. From protocol amendment v.03, all procedures during Treatment are performed as per local clinical 
practices to assess continuing treatment  benefit and efficacy Follow-up assessment are not 
required to be performed. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by physical examination, vital signs, weight, performance status 
evaluation, ECG, cardiac imaging, laboratory evaluations including glucose monitoring and 
assessment of patient rated mood scales as shown in Table 7-6 and Table 7-7 below 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. 
If one or both study drugs are being held due to toxicity, scheduled visits and assessments 
should still be performed (with the exception of the dosing of the held study drug) as 
described in Table 7-1a, unless otherwise specified. 
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. 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. 
From protocol amendment v.03, the physical exam will be performed for all patients as per 
investigator discretion. 
7.2.2.2 
Vital signs 
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 
CRF. 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 CRF. 
Vital signs (body temperature, pulse rate, blood pressure) will be monitored once daily before 
administration of buparlisib/placebo at screening, at Day 1 of each cycle and at the EOT visit. 
Blood pressure (systolic and diastolic) and pulse should be measured after the patient has been 
sitting for five minutes. 


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From protocol amendment v.03, patients receiving buparlisib alone or in combination with 
paclitaxel will be followed on day 1 of each cycle and at EOT visit. Patients receiving 
paclitaxel alone will be assessed as per standard of care and at investigator discretion. 
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. Height will be collected at screening only. 
From protocol amendment v.03, weight will be measured as clinically indicated and at EOT 
visit for patients receiving buparlisib alone or in combination with paclitaxel. Patients 
receiving paclitaxel alone will be assessed as per standard of care and at investigator 
discretion. 
7.2.2.4 
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. 
From protocol amendment v.03, performance status will be assessed on day 1 of each cycle 
and at EOT visit for patients receiving buparlisib alone or in combination with paclitaxel. 
Patients receiving paclitaxel alone will be assessed as per standard of care and at investigator 
discretion. 
Table 7-3 
ECOG performance status 
Grade 
ECOG status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
7.2.2.5 
Laboratory evaluations 
Table 7-4 
Local Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
From protocol amendment v.03 assessments will be performed as described in 
Section 7.2.2.5.1 Hematology 
Chemistry  
(full panel) 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Calcium, Chloride, 
Creatinine, Potassium, Sodium, Magnesium, Phosphate 
Direct Bilirubin, Total Bilirubin, , Blood Urea Nitrogen (BUN) or Urea, Uric Acid, 
Total Protein, Amylase, Gamma-glutamyl-transferase (GGT), Lactate 


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dehydrogenase (LDH), Lipase, Creatinine Clearance 
From protocol amendment v.03 assessments will be performed as described in 
Section 7.2.2.5.2 Clinical chemistry 
Chemistry 
(partial panel) 
AST, ALT, Alkaline phosphatase, total bilirubin, creatinine 
From protocol amendment v.03 assessments will be performed as described in 
Section 7.2.2.5.2 Clinical chemistry 
Lipid Profile 
Total Cholesterol, LDL, HDL, Triglycerides 
Urinalysis 
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, WBC, pH, 
Protein, Specific Gravity) 
From protocol amendment v.03 the urinalysis assessment will not be performed  
Coagulation 
Prothrombin time (PT) or International normalized ratio [INR], Activated Partial 
thromboplastin time (aPTT) 
From protocol amendment v.03 the coagulation assessment will not be 
performed 
Additional tests 
Fasting Plasma Glucose (FPG), HbA1C, C-Peptide 
From protocol amendment v.03 assessments will be performed as described in 
Section 7.2.2.5.3 Monitoring FPG, c-peptide and HbA1c 
Pregnancy Test 
Serum hCG at screening, EOT or unscheduled; other time points test serum 
hCG or urine 
From protocol amendment v.03 assessments will be performed as described in 
Section 7.2.2.5.6 Pregnancy and assessments of fertility 
Viral hepatitis 
serologic tests 
and other tests 
for hepatotoxicity 
follow-up * 
HAAb, HBsAg, HBsAb  HBcAb, HCV RNA or HDV RNA (where needed), HEAb, 
CMVAb, EBcAb, ALP, CPK, LDH, WBC (eosinophilia), and others. 
From protocol amendment v.03 assessments will be performed as described in 
Section 7.2.2.5.7 Viral hepatitis serology and other tests for hepatotoxicity follow-
up 
* Hepatotoxicity follow-up testing/procedures will be performed locally (refer to Section 6.2.2.3.7) 
Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) in patients 
receiving BKM120/placebo and Section 7.2.2.5.7 Viral hepatitis serology and other tests for 
hepatotoxicity follow-up). 
Clinical laboratory analyses (Hematology, Biochemistry, coagulation, Fasting Plasma 
Glucose (FPG), HbA1C, C-Peptide and pregnancy test) are to be performed by the local 
laboratory according to the Visit Schedule outlined in Table 7-1a. Visit windows of +/- 3 days 
are allowed (except at cycle 1 Day 1).  Screening laboratory assessments performed seven 
days of first dosing do not need to be repeated at Cycle 1 Day 1.  
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 new effective date. 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.  
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 


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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 AE 
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. 
Hepatotoxicity follow-up testing will be performed when needed (refer to Section 6.2.2.1. 
Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN 
in patients receiving BKM120/placebo. 
7.2.2.5.1 Hematology 
Hematology tests are to be performed according to the Visit Schedules outlined in Table 7-1a, 
Table 7-1b and Table 7-1c. For details of the Hematology panel refer to Table 7-4. 
From protocol amendment v.03 and as detailed in Table 7-1c, the following parameters will 
be assessed on day 1 of each cycle and at EOT visit: hemoglobin, platelet count, total white 
blood cells (WBC) count, and a WBC differential (absolute values) including neutrophils, 
lymphocytes, monocytes, eosinophils and basophils for patients receiving buparlisib alone or 
in combination with paclitaxel. Patients receiving paclitaxel alone will be assessed as per 
standard of care and at investigator discretion. 
7.2.2.5.2 Clinical chemistry 
Clinical chemistry tests are to be performed according to the Visit Schedules outlined in Table 
7-1a, Table 7-1b and Table 7-1c are given in Table 7-4.   
Refer to the dose modification table for buparlisib and paclitaxel Section 6.2.2.1 and Section 
6.2.2.2 (respectively) regarding what tests are mandatory for patients requiring LFT follow up 
due to toxicity. 
From protocol amendment v.03 and as detailed in the Table 7-1c, the following parameters 
will be assessed on day 1 of each cycle and at EOT visit: creatinine, sodium, magnesium, 
potassium, total bilirubin, alkaline phosphatase, AST/SGOT and ALT/SGPT for patients 
receiving buparlisib alone or in combination with paclitaxel. Patients receiving paclitaxel 
alone will be assessed as per standard of care and at investigator discretion. 
7.2.2.5.3 Monitoring FPG, C-peptide, and HbA1C    
Fasting plasma glucose (FPG), C-peptide, and HbA1C will be assessed according to the visit 
schedules in Table 7-1a, Table 7-1b and Table 7-1c. Patients must be fasting overnight for at 
least 10 hours prior to the blood draw. The study personnel will ask the patient whether he/she 
has been fasting, which will be captured in the eCRF as well. 
From protocol amendment v.03 and as detailed in the Table 7-1c, fasting plasma glucose and 
lipase will be assessed on day 1 of each cycle and at EOT visit for patients receiving 
buparlisib alone or in combination with paclitaxel. Patients receiving paclitaxel alone will be 
assessed as per standard of care and at investigator discretion. 


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7.2.2.5.4 Coagulation 
INR or pro-thrombin time (PT), and partial thromboplastin time will be measured according 
the visit schedules (see Table 7-1a, Table 7-1b and Table 7-1c). 
From protocol amendment v.03 the coagulation assessment will not be performed. 
7.2.2.5.5 Urinalysis 
Urinalysis includes dipstick analysis will be performed as outline in Table 7-1a, Table 7-1b 
and Table 7-1c. 
From protocol amendment v.03 the coagulation assessment will not be performed. 
7.2.2.5.6 Pregnancy and assessments of fertility 
All female patients of childbearing potential must undergo a serum pregnancy test at 
screening to confirm eligibility in the trial (≤ 7 days before first dose of either study drug), on 
day 1 of each cycle and at EOT. Women who are not of child-bearing potential do not require 
a pregnancy test, but must fulfill the conditions for the non-childbearing status given in 
Section 5.2. 
In case an additional pregnancy test is indicated during the trial, a serum test should be 
performed. 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. 
7.2.2.5.7 Viral hepatitis serology and other tests for hepatotoxicity follow-up 
During study treatment, viral hepatitis serologic and other tests will be performed as per the 
guidelines of management of hepatotoxicity (ALT or AST >3.0x ULN and total bilirubin > 
2.0x ULN) in patients receiving BKM120/placebo, refer to Section 6.2.2.3.7 Management of 
hepatotoxicity (ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) in patients 
receiving BKM120/placebo for details.  
Viral hepatitis serology includes the following:  
• Hepatitis A IgM antibody and hepatitis A serology total 
• Hepatitis B surface antigen, Hepatitis B Core Antibody (IgM) and viral RNA 
• Hepatitis C serology and viral RNA  
• Hepatitis D RNA (where needed) 
• Hepatitis E IgM and IgG antibody and viral RNA 
Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), and blood count with differential to assess eosinophilia. 
Additional viral serology tests may include: 
• Cytomegalovirus IgM antibody 
• Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing) 
• Herpes Simplex Virus 


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• From protocol amendment v03, patients receiving buparlisib alone or in combination with 
paclitaxel will be followed as clinically indicated. Patients receiving paclitaxel alone will 
be assessed as per standard of care and at investigator discretion. 
7.2.2.6 
Radiological examinations 
An unscheduled CT scan should be performed if any of following criteria is met: 
• For any ≥ CTCAE grade 1 pneumonitis, CT scans with lung windows must be performed 
and repeated at least every 6 weeks until it returns to within normal limits 
• For any CTCAE grade 3 or 4 hepatic toxicity that does not resolve within 7 days to ≤ 
grade 1 (or ≤ grade 2 if liver infiltration with tumor present), an abdominal CT scan must 
be performed to assess any relationship to disease progression. 
• Within 1 week of the first occurrence of any ≥ CTCAE grade 3 of amylase or lipase, a CT 
scan must be performed to assess the pancreas, liver, and gallbladder. 
• Any other additional examination may be performed as deemed necessary by the 
investigator based on clinical assessment of the patient status. 
Efficacy based CT/MRI requirements are described in Section 7.2.1. 
From protocol amendment v03, patients receiving buparlisib alone or in combination with 
paclitaxel will be followed as clinically indicated. Patients receiving paclitaxel alone will be 
assessed as per standard of care and at investigator discretion. 
7.2.2.7 
Cardiac assessments 
7.2.2.7.1 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed 
• at screening and/or baseline 
• at pre-does on day 1 of every cycle 
• at the end of study 
Table 7-5 
Local ECG collection plan 
Visit or Cycle 
Day 
Time 
ECG Type 
1 
-35 to -1 
Pre-dose 
12 Lead 
All Cycles 
1 
Pre-dose 
12 Lead 
End of Treatment 
12 Lead 
Unscheduled visit 
Anytime 
12 Lead 
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG CRF page. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History CRF page. Clinically significant findings 
must be discussed with Novartis prior to enrolling the patient in the study. New or worsened 


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clinically significant findings occurring after informed consent must be recorded on the 
Adverse Events CRF page. 
From protocol amendment v.03, ECG will be done as clinically indicated and at EOT for 
patients receiving buparlisib alone or in combination with paclitaxel. Patients receiving 
paclitaxel alone will be assessed as per standard of care and at investigator discretion. 
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
Cardiac imaging will be performed by Multiple Gated acquisition (MUGA) scan or 
Echocardiogram (ECHO) in order to assess the left ventricular ejection fraction (LVEF). This 
assessment will be performed at screening for confirmation of eligibility and subsequently 
every 4 cycles beginning with Cycle 4 Day 1 visit.  
The same technique (MUGA or ECHO) must be used during the course of the trial, and the 
method used will be recorded in the eCRF. Only clinically significant abnormalities should be 
reported in the Adverse Events eCRF.  
In case a patient develops left ventricular systolic dysfunction while on study treatment dose 
adjustment guidelines described in Table 6-3 must be followed. 
From protocol amendment v.03, cardiac imaging will be done as clinically indicated and at 
least every 4 months. The exam will be performed at EOT if not performed within the last 4 
months for patients receiving buparlisib alone or in combination with paclitaxel. Patients 
receiving paclitaxel alone will be assessed as per standard of care and at investigator 
discretion. 
 
7.2.2.8 
Patient self-rating mood questionnaire 
The Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7) will 
be collected to screen patients for the study and to aid in the identification and severity 
assessment of potential mood alterations.  The PHQ-9 and GAD-7 are validated (Kroenke 
2001, Spitzer 2006, Spitzer 1999) patient self-administered questionnaires developed for use 
in clinical practices.   
The PHQ-9 (Appendix 7, Table 14-5) consists of 9 questions that assess anhedonia, depressed 
mood, sleep, energy, appetite, guilt and worthlessness, concentration, feeling slowed down or 
restlessness, and suicidal thoughts.  For each of these questions, patients are asked to rate how 
much over the past 2 weeks they have been bothered by the symptom.  Scoring of the PHQ-9 
is based on a Likert-type scale from 0 to 3 (0 indicates not at all; 1, several days; 2, more than 
half the days; 3, nearly every day).  The sum of all nine questions is used to determine a total 
PHQ-9 score ranging from 0 to 27. 
The GAD-7 (Appendix 7, Table 14-6) is a one-dimensional questionnaire consisting of 7 
questions.  Similarly to the PHQ-9, in the GAD-7, patients are asked to indicate how often, 
over the past 2 weeks, they have been bothered by each of the seven core symptoms of 
generalized anxiety disorder as referenced in the DSM IV. Response options are ‘‘not at all,’’ 
‘‘several days,’’ ‘‘more than half the days,’’ and ‘‘nearly every day,’’ scored as 0, 1, 2, and 3, 


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respectively.  The sum of all seven questions calculates the total GAD-7 score. Therefore, 
GAD-7 scores range from 0 to 21.  
The patient must complete two different mood questionnaires, (PHQ-9 and GAD-7) according 
to the visit schedule in Table 7-1a,Table 7-1b,Table 7-1c and Table 7-6. Additional 
assessments may be done according to the clinical judgment of the investigator.  
All questionnaires should be given by the site to the patient in the patient’s local language and 
reviewed for completeness and possible adverse events. Additional guidance regarding the 
general administration of patient questionnaires is described in Section 7.2.4 regarding 
Patient-reported Outcomes. 
On visits when additional patient questionnaires (as specified in Section 7.2.4) are also to be 
completed, sites should instruct patients to complete the mood questionnaires after all other 
patient questionnaires and prior to administration of any study-related treatment or clinical 
assessments or procedures.  
From protocol amendment v.03, patients receiving buparlisib alone or in combination with 
paclitaxel will complete PHQ-9 and GAD-7 questionnaires on day 1 of each cycle and at EOT 
visit. Patients receiving paclitaxel alone will be assessed as per standard of care and at 
investigator discretion. 
Table 7-6 
Patient self-reported mood questionnaire collection plan 
Patient 
Questionnaires 
Visit/ Cycle 
Day 
Time 
PHQ-9 
GAD-7 
Screening 
Day -35 to -1 
Prior to any clinical 
assessments, study drug 
dosing or diagnostic testing. 
 
After EORTC QLQ-C30 and 
QLQ-HN35 assessment if 
scheduled for same day.* 
Cycle 1 
Day 1, Day 15 
Cycle 2 
Day 1, Day 15 
Cycle 3 
Day 1, Day 15 
Every Cycle 
Day 1 
End of treatment 
Day of end of treatment 
assessment 
• 
*From protocol amendment v.03, EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires are not 
administered for patients still on study treatment 
The severity classification table described in Table 7-7 for the PHQ-9 and GAD-7 will be 
used in this study to increase the sensitivity of identifying potential anxiety and/or depression 
disorders.  During the study, questionnaire scores and corresponding severity classification 
can be used to aid the investigator in identifying new or worsening of events. However, 
grading must be based on the clinical interpretation of severity according to the NCI- CTCAE 
(v 4.03). 


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Table 7-7 
Classification of severity based on depression and/or anxiety 
questionnaire scores 
PHQ-9 (depression) 
GAD-7 (anxiety) 
Score 
Severity 
Score 
Severity 
0-4 
None 
0-4 
None 
5-9 
Mild 
5-9 
Mild 
10-19 
Moderate 
10-14 
Moderate 
20-27 
Severe 
≥ 15 
Severe 
At Screening, a patient may be judged by the investigator or a psychiatrist to be ineligible 
based on medical mental health history as listed in the exclusion criteria. Alternatively, 
patients who score ≥ 12 on the PHQ-9 or ≥ 15 on the GAD-7 mood scale, respectively, or 
select a positive response of ‘1, 2, or 3’ to question number 9 regarding suicidal thoughts or 
ideation will be excluded from the study.  
A timely interview with the patient after the questionnaire completion is recommended. 
During the treatment phase, patients who indicate a positive response by selecting ‘1, 2, or 3’ 
to question number 9 in the PHQ-9 and/or present with suicidal ideation  must interrupt 
treatment with study drug (buparlisib or placebo) and must be referred for psychiatric 
consultation for optimal management regardless of the total questionnaire score or CTCAE 
grading and to confirm if study drug should be interrupted or permanently discontinued.  In 
this specific case, the psychiatric advice can overrule the patient PHQ-9 self-assessment. If 
question 9 on the PHQ-9 was not answered, or the whole questionnaire was not answered, the 
investigator must assess the patient for suicidal ideation. If the investigator identifies suicidal 
ideation, then study drug must be interrupted and the patient referred for psychiatric 
consultation for assessment. 
Investigators must not encourage the patients to change responses reported in questionnaires.  
Guidelines on how to instruct the patient to complete the questionnaires as well as how to 
determine the scores will be provided with each instrument.  Guidance on scoring 
questionnaires is also provided in Appendix 8. Dosing modification guidelines for 
buparlisib/placebo are provided in Table 6-3. For additional information on AE reporting, 
please refer to Section 8.1. 
7.2.3 
Biomarkers 
Genetic aberrations that lead to a gain in PI3K signaling are observed in squamous cell head 
and neck cancer.  Investigating aberrations of the PI3K pathway in all patients enrolled in this 
study will therefore allow for the assessment of the potential predictive value of pathway 
activation for benefit from buparlisib in metastatic, squamous cell, head and neck cancer. 
 
 
  
Tumor and blood samples will be collected before and during treatment with buparlisib for 
biomarker assessments. 


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All assessments will be performed by a Novartis designated laboratory. Instructions for 
collection, preparation and shipment can be found in the laboratory manual. Required sample 
collection information must be entered on the appropriate eCRF pages and requisition forms 
Table 7-8 
Biomarker sample collection plan 
Sample Type 
Volume 
Visit 
Time point 
Tumor samples 
Mandatory  
Representative baseline tumor 
biopsy or archival paraffin 
embedded tissue 
 
To be evaluated for adequate 
amount of tumor tissue 
N/A 
 
Screening 
 
 
Day -35 to -1 
Sample Type 
Volume 
Visit 
Time point 
Blood samples 
Mandatory 
Blood for circulating DNA 
6 mL 
Screening 
Day -35 to -1 
6mL 
End of Treatment 
Not pre-specified 
7.2.3.1 
Biomarker assessments in tumor samples 
Tumor tissue samples will be collected in this trial for identifying biomarkers that may be 
predictive of benefit from buparlisib. Tumor tissue samples may be archival, however when 
available, new tumor biopsies should be collected.  
In addition, these samples are planned to be used for assessment of HPV status and other 
molecules 
(e.g., 
gene 
expression, 
mutations, 
amplifications 
and/or 
protein 
expression/activation etc.) in the PI3K signaling pathway, such as but not limited to PIK3CA 
mutation, PTEN mutation, PTEN protein expression, AKT, TSC1 and TSC2, KRAS 
mutation, other pathways that may interact with the PI3K pathway, or are thought to be 
important in cancer.   


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If a biopsy is collected at screening, during treatment, or upon progression the PI3K signaling 
inhibition status will be evaluated by assessing changes in activation of relevant downstream 
markers such as S6, AKT and 4EBP1 (e.g. by immunohistochemistry). If a biopsy is collected 
upon progression through treatment other markers potentially relevant to resistance to PI3K 
inhibitors may also be analyzed, depending on sample and assay availability. 
 
 
Table 7-9 
Summary of tissue biomarkers 
Marker 
Tumor sample 
Purpose 
Comments 
Molecular markers 
relevant to the PI3K 
pathway such as- but 
not limited to-PIK3CA 
mutation, PTEN 
mutation, and PTEN 
protein expression 
New pre-treatment tumor biopsy or 
archival sample 
Potential 
predictor of 
efficacy 
All patients 
p-Akt, p-S6, p-4EBP1 
 
New tumor biopsy collected at 
screening, on treatment or upon 
progression  
Drug effect on 
PI3K signaling 
When new tumor 
is available at 
screening, during 
treatment or 
upon 
progression 
Other markers 
relevant to PI3K 
activation pathway 
such as PIK3CA 
amplification (FISH), 
Ki67 and others 
New formalin-fixed pre-treatment 
tumor biopsy or archival sample 
 
Potential 
predictor of 
efficacy 
Potential markers 
of de novo  
resistance 
All patients 
 
 
 
 
  
 
 
 
 
 
7.2.3.1.1 Mandatory tumor tissue required for study participation 
All patients must provide a representative tumor sample (archival or new tumor material) 
during the study.  A FFPE tumor block is preferred. If not available, 15 slides are requested 
(minimum of 12 slides must be provided) at 4 to 5µm on superfrost positively charged slides.  
The number of slides required is indicated based on surgical resection samples. In case 
samples from small biopsies are provided, the number of slides provided should be increased 
according to the sample size.  A pathology report should also be provided. 
The samples will be assessed for tissue quantity and tumor content by a pathologist. If local 
pathologist assessment is preferred, a Novartis defined procedure (See laboratory Manual) can 
be followed allowing faster turnaround time. If tissue does not pass this assessment, additional 
tissue must be provided, otherwise, patient is not eligible for the study (see Section 5.1 
inclusion criteria). Guidelines for optimal sample identification can be found in the 
CBKM120H2201 laboratory manual. 


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Molecular analysis of tumor, in particular- but not limited to - PIK3CA and PTEN molecular 
alterations (PIK3CA and PTEN gene mutation and PTEN expression by IHC) will be 
performed in all samples received. 
 
 
7.2.3.1.2 Optional new tumor tissue collection 
Collection of optional new tumor samples while on treatment or at progression is critical for 
assessing drug effect and understanding mechanisms of resistance. Therefore new tumor 
sampling is encouraged at baseline, anytime during the study and at progression/the end of 
treatment visit, after signature on the appropriate ICF. If a new biopsy sample is collected for 
screening (no archival tissue was available), an additional baseline sample does not need to be 
collected. Patient may have up to three optional biopsies (at screening and/or on treatment 
and/or at the end of treatment in case of disease progression). Please refer to the lab manual 
for sample collection requirements.  
The sample collection date, the exact time of collection, and the time of exposure to fixative 
(formalin) must be entered on the appropriate tumor tissue collection eCRF pages and 
requisition forms.  
 
 
 
 
 
 
Table 7-10 
New biopsies collection: division, priority, disposition 
Tumor Pass 
number 
Disposition 
Priority 
Purpose 
1 
Formalin-fixed 
(immediately after fixation 
to be shipped in ethanol to 
designated lab) 
First 
Primary Biomarker Studies (e.g. 
IHC)  
 
 
7.2.3.2 
Biomarker assessments in blood 
Before and during treatment with buparlisib, at time points detailed in the visit Table 7-1a and 
Table 7-8, blood samples will be collected in order to investigate drug induced changes in 
markers relevant to PI3K signaling and anti-cellular effect. 


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Table 7-11 
Summary of biomarkers in blood 
Marker 
Purpose 
Circulating DNA  
mutational analysis  
 
 
 
7.2.3.2.1 Plasma for circulating DNA  
This will allow additional testing for mutations of genes that are relevant for PI3K signaling 
and cancer, (e.g. PIK3CA mutation, KRAS mutation) and ideally provide a more updated 
description of the tumor molecular profile as compared with a tumor sample from the same 
patient. 
7.2.4 
Patient reported outcomes 
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC QLQ-C30, version 3.0) and head and neck cancer specific 
questionnaire (QLQ-HN35) will be used to explore patient-reported outcome measures of 
health-related quality-of-life, functioning, disease symptoms and treatment-related side effects 
in the current study. The EORTC QLQ-C30 and QLQ-HN35 are recognized reliable and valid 
measures (Aaronson 1993, Bjordal 1999) frequently used in clinical trials of patients with 
non-small cell lung cancer. 


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Health-related quality of life questionnaires, EORTC QLQ-C30 and QLQ-HN35, will be 
administered before any study drug administrations at the visits indicated in Table 7-6. 
Collections of the EORTC QLQ-C30 and QLQ-HN35 have a ±7 day window unless 
otherwise indicated.  All questionnaires should be administered in the patient’s local language 
at the beginning of the study visit prior to any interaction with the study investigator including 
any tests, treatments or receipt of results from any tests. This is to avoid potentially biasing 
patients or their responses to study questionnaires.  Attempts should be made to collect all 
questionnaires for all patients, including those who discontinue prior to the study evaluation 
completion visit. 
Patients should be given sufficient space and time to complete all study questionnaires and all 
administered questionnaires should be reviewed for completeness.  If missing responses are 
noted, patients should be encouraged to complete any missing responses.  Attempts should be 
made to collect responses to all questionnaires for all patients, including from those who 
discontinue prior to the study evaluation completion visit, however, if patients refuse to 
complete questionnaires, this should be documented in study source records.  Patient’s refusal 
to complete study questionnaires are not protocol deviations unless otherwise specified in this 
protocol.  
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the patient, must be reviewed and assessed by the investigator before the 
clinical examination for responses which may indicate potential AEs or SAEs. This review for 
potential AEs or SAEs should be documented in study source records.  
If an AE or SAE is confirmed then the physician should record the event as instructed in 
Section 8 of this protocol.  Investigators should not encourage the patients to change 
responses reported in questionnaires. 
7.2.4.1 
EORTC QLQ-C30 and QLQ-HN35 
The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and 
single-item measures. These include five functional scales (physical, role, emotional, 
cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), 
six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) 
and a global health status/QoL scale (Aaronson 1993). The QLQ-HN35 is used in conjunction 
with the QLQ-C30 and provides additional information on 7 multi-item symptom scales that 
assess pain, swallowing, senses (taste and smell), speech, social eating, social contact, and 
sexuality and 11 single-item scales assessing symptoms of problems with teeth, problems with 
opening one’s mouth, having dry mouth, having sticky saliva, coughing, feeling ill, use of 
pain killers, use of nutritional supplements, use of feeding tube, weight loss, and weight gain. 
All the multi-item scales and single-item measures range in score from 0 to 100 in both the 
QLQ-C30 and QLQ-HN35.  A high scale score represents a higher response level.  Thus a 
high score for a functional scale represents a high / healthy level of functioning; a high score 
for the global health status / QoL represents a high QoL, but a high score for a symptom scale 
item represents a high level of symptomatology / problems.  All scoring will follow the 
scoring procedures defined by the EORTC Scoring Manual (Fayers 2001). 


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The EORTC QLQ-C30 and QLQ-HN35 should be administered as per Table 7-12. From 
protocol amendment v.03, EORTC QLQ-C30 and EORTC QLQ-HN35 questionnaires are not 
administered to patients still on study treatment. 
Table 7-12 
Patient health-related QOL questionnaire collection plan 
Patient 
Questionnaires 
Visit/ Cycle 
Day 
Time 
EORTC QLQ-C30 
EORTC QLQ-HN35  
Screening 
Day of screening 
visit from Day -35 
to Day -1 
Prior to any clinical 
assessments, study drug 
dosing or diagnostic 
testing. 
 
Before PHQ-9 and GAD-7 
assessments if scheduled 
for same day. 
Every 6 weeks after 
randomization until 
progression starting from 
Cycle 2 Day 15  
Day 1 or Day 15 
End of treatment 
Day of end of 
treatment 
assessment 
7.2.5 
Pharmacokinetics 
Blood samples for PK assessment of buparlisib will be collected in randomized patients, 
irrespective of treatment assignment. Full PK sampling will be conducted in approximately 16 
patients, and sparse PK sampling will be conducted in approximately 40 patients. In addition, 
trough samples will be collected from all remaining randomized patients, if applicable. 
Measurement of buparlisib will be performed only in patients randomized to the buparlisib 
arm. An independent bioanalyst not involved in study conduct will be unblinded to treatment 
assignment for analysis purposes. 
An evaluation of PK will be done with the final analysis in approximately 16 patients 
undergoing the Full PK sampling in order to evaluate the exposure of buparlisib in the 
targeted population. For these patients, blood samples will be collected for a full PK profiles 
on D15 according to the following schedule: at pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h and 
24h post-dose. The 24h time point should be collected before the dose administration on D16. 
Additional trough samples (pre-dose samples) will be collected on Cycle 1 Day 22 and Cycle 
2 Day 1 (pre-dose), as indicated in Table 7-14. PK sampling needs to be re-scheduled if 
buparlisib/placebo has been interrupted for 7 days or more. PK sampling needs to be done 
when the patient has a minimum of 7 consecutive doses. 
In addition to the full PK profile collection, PK will be assessed via a sparse PK sampling 
strategy. For these approximately 40 patients, blood for buparlisib pharmacokinetics will be 
collected on Cycle 1 Day 1 (at 1h, 2h, and 6h post dose; a recommended 9h post dose sample 
may be drawn if the patient is still in the clinical center at time of sampling), Cycle 1 Day 15 
and Day 22, Cycle 2 Day 1 Cycle 4 Day1 and Cycle 6 Day 1(pre dose). 
The rationale to collect sparse samples on Cycle 1 Day 1 is to assess absorption and 
distribution phases of the PK and the rationale to collect three other trough samples on 
separate days later in the trial, once PK steady state has been attained, is to capture 
information on buparlisib clearance. The Cycle 1 Day 1 9 hour sample is recommended: this 


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sample is to be collected whenever possible, as it would provide valuable pharmacokinetic 
information on buparlisib in this population. This information will be used to update the 
current population pharmacokinetic model with this new data to better characterize the 
pharmacokinetic of buparlisib with paclitaxel in the targeted population. This updated model 
will be reported independently of this trial. 
Trough PK (pre-dose) samples will be collected on Cycle 1 Day 15, Cycle 1 Day 22, Cycle 2 
Day 1, Cycle 4 Day 1 and Cycle 6 Day 1 for all the remaining randomized patients unless 
buparlisib/placebo is permanently discontinued (Refer to Table 7-16). The trough 
concentration will be used to explore exposure response relationship in the treated population.  
Results from any unscheduled samples will not be a part of the PK analysis and will not be 
made available until the end of the trial. 
To ensure compliance with sampling procedures, on the days of PK collection, patients will 
take their buparlisib/placebo doses at the clinic under the supervision of the investigator or 
his/her designee. Patients who forget to postpone their dose until they arrive at the site on Day 
15 or Day 22 of Cycle 1 or Day 1 of Cycle 2 and instead take their medication at home will 
not participate in pharmacokinetic analysis for that day; they should not have blood samples 
collected. Pharmacokinetic assessment for these patients should be postponed to the next day 
(i.e. Day 16 or Day 23 of Cycle 1 or Day 2 of Cycle 2, respectively). Patients do not need to 
fast specifically for PK sampling (see Section 6.1.1.1.2 for details). 
The collection time of all samples must be documented in the Pharmacokinetic Blood 
Collection eCRF pages. On days of PK collection and on the previous day the exact time of 
oral buparlisib/placebo dosing, date sample taken, and actual time of sampling must be 
entered on the eCRF. Any sampling problems (e.g., patient took study drug before a pre-dose 
sample) must be noted in the comments section of the eCRF.  
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed, and 
medication should resume on the next day. The occurrence and frequency of any vomiting 
during a treatment cycle must be noted in the adverse events section of the eCRF. In addition, 
on days of PK collection, the exact time of the first vomiting episode within the first 4 hours 
post-dosing on that day must be noted. If a vomiting episode occurs within the first 4 hours 
post-dosing during the day of the last dose prior to trough PK samples the exact time 
(whenever possible) must be noted on the eCRF. 
The plasma samples from all patients will be assayed for buparlisib concentrations by 
Novartis or its designee using methods described in the Laboratory manual. Values below the 
assay LLOQ will be reported as 0.00 ng/mL. Missing values will be labeled accordingly. All 
concentrations below the LLOQ or missing data will be labeled as such in the concentration 
data listings. Concentrations below the limit of quantitation will not be imputed and will be 
treated as zero in summary statistics. 


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Non compartmental analysis for patients with full PK sampling 
Pharmacokinetic parameters will be determined for patients with full PK sampling using 
non-compartmental method(s) using Phoenix WinNonlin. PK parameters listed in Table 7-13 
will be estimated and reported, when feasible. Calculation of PK parameters will include up to 
last measurable concentration Tlast, as outlined in the Novartis Internal Guidance 
Standardization of pharmacokinetic parameters. Exploratory analysis will be conducted to 
determine PK parameters using compartmental modeling when necessary. 
Table 7-13 
Non-compartmental PK parameters 
Term 
Definition 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1) 
AUCtau 
The area under the plasma concentration-time curve from time zero to the end of the 
dosing interval, tau (mass x time x volume-1) 
Cmax 
The maximum (peak) observed plasma drug concentration after single dose 
administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma drug concentration after single dose 
administration (time) 
CL/F 
Apparent total body clearance of drug from the plasma after oral administration 
(volume x time-1) at steady-state (based on AUC value from C1D15) 
Rsqadj1 
Square of the correlation coefficient associated with λz 
1 Rsqadj will be used in the interpretation of the primary PK parameters and therefore will be included 
in the listings only. 
Population PK analysis 
A population PK model characterizing the concentration-time profile of buparlisib has been 
developed based on the following trials: [CBKM120X2101], [CBKM120X1101], and 
[CBEZ235A2118]. Further details regarding the model are provided in Section 10.1.4. 
Separate report to document the population PK model will be released before the study results 
are reported. 
7.2.5.1 
Pharmacokinetic blood sample collection and handling 
7.2.5.1.1 Blood collection plan  
Table 7-14 
Pharmacokinetic log table for patients with full PK sampling (16 
patients) 
Cycle 
Day 
Time 
Dose Reference ID3 
PK Sample No 
1 
15 
Pre-dose 
1 
101 
101 
1 
15 
0.5 hour post dose ± 10 min 
1 
 
102 
1 
15 
1 hour post dose ± 15 min 
1 
 
103 
1 
15 
1.5 hour post dose ± 15 min 
1 
 
104 
1 
15 
2 hour post dose ± 15 min 
11 
 
105 
1 
15 
3 hour post dose ± 30 min 
11 
 
106 


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Cycle 
Day 
Time 
Dose Reference ID3 
PK Sample No 
1 
15 
4 hour post dose ± 30 min 
1 
 
107 
1 
15 
6 hour post dose ± 60 min 
1 
 
108 
1 
15 
9 hour post dose ± 60 min 
1 
 
109 
1 
16 
Pre-dose (24 hour post dose ± 120 min) 
1 
102 
110 
1 
22 
Pre-dose1 
2 
201 
111 
2 
1 
Pre-dose1 
3 
301 
112 
 
 
Unscheduled2 
 
1001+ 
1 Take sample immediately before the buparlisib/placebo administration of the current day. 
2 Unscheduled blood samples will be uniquely, sequentially numbered 1001, 1002, etc. 
3 Left column refers to the dose reference ID following the pre-dose sample and right column refers to 
the dose reference ID prior to sampling. 
Sample volume will be 2 mL per collection for all samples 
Table 7-15 
Pharmacokinetic log table for patients with sparse PK sampling (40 
patients) 
Cycle 
Day 
Time 
Dose Reference ID4 
PK sample No 
1 
1 
1 hour post dose ± 15 min 
10 
 
201 
1 
1 
2 hour post dose ± 15 min 
10 
 
202 
1 
1 
6 hour post dose ± 30 min 
10 
 
203 
1 
1 
9 hour post dose ± 60 min  
(recommended)1 
10 
 
204 
1 
15 
Pre-dose2 
11 
111 
205 
1 
22 
Pre-dose2 
12 
121 
206 
2 
1 
Pre-dose2 
13 
131 
207 
4 
1 
Pre-dose 2 
14 
141 
208 
6 
1 
Pre-dose 2 
15 
151 
209 
 
 
Unscheduled3 
 
2001+ 
1 Optional sample: may be drawn if the patient is in the clinical site at the sampling time. 
2 Take sample immediately before the buparlisib/placebo administration of the current day. 
3 Unscheduled blood samples will be uniquely, sequentially numbered 2001, 2002, etc. 
4 Left column refers to the dose reference ID following the pre-dose sample and right column refers to 
the dose reference ID prior to sampling. 
Sample volume will be 2 mL per collection for all samples 
Table 7-16 
Pharmacokinetic log table for patients with trough samples collection 
(all remaining randomized patients) 
Cycle 
Day 
Time 
Dose Reference ID3 
PK sample No 
1 
15 
Pre-dose1 
40 
401 
301 
1 
22 
Pre-dose1 
41 
411 
302 
2 
1 
Pre-dose1 
42 
421 
303 
4 
1 
Pre-dose1,2 
43 
431 
304 
6 
1 
Pre-dose1,2 
44 
441 
305 
 
 
Unscheduled2 
 
3001+ 
1 Take sample immediately before the buparlisib/placebo administration of the current day. 
2 Unscheduled blood samples will be uniquely, sequentially numbered 3001, 3002, etc. 


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Cycle 
Day 
Time 
Dose Reference ID3 
PK sample No 
3 Left column refers to the dose reference ID following the pre-dose sample and right column refers to 
the dose reference ID prior to sampling. 
Sample volume will be 2 mL per collection for all samples 
For detailed instructions for the collection, handling, and shipping of samples refer to the 
[CBKM120H2201 Lab Manual]. 
7.2.6 
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 
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 CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History CRF. Adverse event monitoring should be continued for at 
least 30 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (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) 


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3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
or 
Its relationship to the study treatment (Reasonable possibility that AE is related: No, 
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable) 
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 sequelae, 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 CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (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 that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 


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required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization,  
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.  
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to Novartis. 
Detailed instructions regarding the SAE submission process and requirements for signatures 
are to be found in the investigator folder provided to each site. 


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The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
8.3 
Emergency unblinding of treatment assignment 
Emergency unblinding should only be undertaken when it is essential for effective treatment 
of the patient. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency code breaks are performed using the IRT. When the investigator 
contacts the IRT to unblind a patient, he/she must provide the requested patient identifying 
information and confirm the necessity to unblind the patient. The investigator will then 
receive details of the drug treatment for the specified patient and a fax confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Lead that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The protocol number, study 
treatment name if available, patient number, and instructions for contacting the local Novartis 
CPO (or any entity to which it has delegated responsibility for emergency code breaks) will 
be provided to the patient in case emergency unblinding is required at a time when the 
investigator and backup are unavailable. However, if a mechanism is already in place to 
ensure that the investigator and/or back-up can always be reached in case of emergency then 
the procedure above is not required. 
Study treatment must be discontinued once emergency unblinding has taken place. 


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8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
8.6 
Data Monitoring Committee  
A Data Monitoring Committee (DMC) will be established prior to the randomization of the 
first patient to monitor and review the safety of the study treatment. It is expected that the 
DMC will consist of members who are not involved in patient recruitment or trial conduct. 
There will be a meeting with the DMC to have agreement on their roles and responsibilities 
and the potential data format and procedures that will be reviewed during the course of the 
study. Meetings may be held by sponsor’s requests at the time of some safety issues 
occurrence, especially when serious events (e.g., death) occur on the study or safety 
notifications regarding the study treatment come out and as further described below. 
The DMC will conduct the first safety review 3 to 6 months after the first patient has been 
randomized to determine if the proposed dosing schedule of the combination is safe and 
tolerable for this patient population. Thereafter the DMC will conduct the safety review every 
6 months (+/- 30 days for scheduling purposes). The DMC will also review biomarkers data 
regarding PI3K activation status when approximately 70 patients have been randomized and 
been on the study for at least a month. If the timing of this additional review falls within 1 
month of any of the periodic safety reviews, then this shall be combined with the scheduled 
safety review and will not be done separately. Should the ratio of PI3K activated versus non 
activated population not be as expected, the current protocol may be amended to proceed with 
pre-screening for additional patients.  
It is envisioned that the DMC may make the following type of recommendations, namely: 
1. No safety issues, ethical to continue the study as planned 


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2. Serious safety concerns precluding further study treatment, regardless of efficacy 
3. Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments) 
If the DMC recommends continuing the study, no details about the results of the current 
safety review will be revealed prior to the next scheduled analysis. 
Details regarding the constitution of the DMC and its specific roles will be provided in the 
DMC charter prior to the randomization of the first patient. 
8.7 
Steering Committee  
The 
Steering 
Committee 
(SC) 
will 
be 
established 
comprising 
investigators 
participating/enrolling patients in the trial, i.e., not being members of the DMC, and Novartis 
representatives from the Clinical Trial Team. 
The SC will ensure management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the SC will be defined in a Steering Committee charter. The SC will not 
have access to un-blinded trial data. 
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 follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training. 


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9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they 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. 
PK and Biomarker (blood and tissue) samples drawn during the course of the study will be 
collected from the investigator sites and analyzed by Novartis or a central laboratory 
contracted by Novartis. The site staff designated by the investigator will enter the information 
required by the protocol onto the Biomarker Sample Collection eCRFs, as well as onto the 
designated CRO’s requisition form. One copy of the requisition form will be information 
(including study number, subject ID, etc.) and one copy will be retained by the site. 
Imaging Data used for tumor assessments will be centrally collected and subjected to quality 
control. It will be prospectively reviewed by a BIRC. 
From protocol amendment v03, CT-scans/MRI will no longer be sent to central imaging 
vendor. 


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9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the 
nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff is required to respond promptly to queries and to make any necessary 
changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data for biomarkers, imaging and IRT will be processed centrally and the 
results will be sent electronically to Novartis (or a designated CRO). 
Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The 
system will be supplied by a vendor(s), who will also manage the database. The data will be 
sent electronically to Novartis personnel (or designated CRO). 
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). The occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the treatment codes will be unblinded and 
made available for data analysis. Authorization is required prior to making any database 
changes to locked data, by joint written agreement between the Global Head of Biostatistics 
and Data Management and the Global Head of Clinical Development. 
For EDC studies, 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 
The data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. 
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis.  
The primary statistical analysis will be based on data from all patients up to the time at which 
approximately 120 PFS events have been observed. The final analysis will be performed at 
the end of the study (see Section 4.3 and Section 4.4.for further details). 


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10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who were randomized to study treatment. 
According to the intent to treat principle, patients will be analyzed according to the treatment 
and strata they have been assigned to during the randomization procedure. 
10.1.2 
Safety Set 
The Safety Set includes all patients who received study treatment (either paclitaxel or 
buparlisib) and had at least one post-baseline safety assessment.  Patients will be analyzed 
according to the study treatment they actually received. Treatment actually received is defined 
as the study treatment the patient received on Study Day 1. 
10.1.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) comprises all patients in the FAS who do not have any protocol 
deviations that could confound the interpretation of the primary analyses conducted on the 
FAS.  
10.1.4 
Pharmacokinetic analysis sets 
The Pharmacokinetic Analysis Set (PAS) will include all patients who received at least one 
dose of study medication buparlisib and had at least one evaluable post-treatment 
concentration measurement.   
The Full Sampling Pharmacokinetic Analysis Set (FPAS) will include all patients who 
received buparlisib every day from Cycle 1 Day 1 to the day at which full PK profile is 
collected and have at least one dose of paclitaxel prior to the collection of the PK sample for 
the full PK profile (without any vomiting within 4 hours of any dosing) and had an evaluable 
full PK profile.  
Patients in the FPAS will also be included in the PAS.   
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for all patients in the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
The actual cumulative dose and duration of exposure in days of buparlisib and paclitaxel as 
well as the dose intensity (computed as the ratio of actual cumulative dose received and actual 
duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity 
and planned dose intensity) will be summarized by means of descriptive statistics using the 


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safety set. Dose reductions and interruptions (including the reasons for dose modifications) 
will be summarized for each study drug. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized (by treatment group) for the Safety set. 
10.4 
Primary objective 
The primary objective is to estimate the treatment effect of once daily buparlisib in 
combination with paclitaxel on PFS (based on local radiological assessment) in patients with 
platinum pre-treated recurrent or metastatic head and neck squamous cell carcinoma. 
10.4.1 
Variable 
The primary efficacy variable is PFS as assessed by local radiological reviewed as per 
RECIST v1.1 (see guidelines in Appendix 6). PFS is defined as the time from the 
randomization date until objective tumor progression or death from any cause The date of 
progression is the earliest time when any RECIST progression event (i.e. radiological 
progression or death) is observed with no more than one prior missing assessment. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The primary analysis will be a comparison of PFS between the two treatment groups. The 
hazard ratio (HR) for buparlisib + paclitaxel versus placebo + paclitaxel will be estimated by a 
stratified Cox proportional hazard model, using the randomization strata (prior lines of 
treatment: 1 vs 2) and region of investigator’s site (North America vs Rest of World)). 
The efficacy criteria are: 
• The estimated hazard ratio is equal or less than 0.67 (i.e. 33% reduction in risk of PFS 
event with buparlisib compared to the placebo arm) 
and 
• Posterior probability (HR < 1) > 97.5% (PFS treatment benefit of buparlisib compared to 
the placebo). 
The posterior probability in the second criterion will be derived from the Bayesian posterior 
distribution of the HR. Assuming an uninformative prior distribution, the distribution of the 
HR will be updated with all available data from the patients included in the FAS. (See the 
Statistical Appendix 9 for the details). 
The primary analysis will be performed when approximately 120 PFS events have been 
observed in the FAS. The operating characteristics based on this number of events are 
presented in Section 10.8. 
HR will be presented together with the 95% confidence interval. Numbers and types of PFS 
events (i.e. objective tumor progression, death) will be displayed by treatment group. 
10.4.3 
Handling of missing values/censoring/discontinuations 
For the final analysis, PFS will be censored if no PFS event is observed before the cut-off date 
or on the date a new anti-neoplastic therapy is started. If the patient is alive and progression 
free at the date of the analysis (i.e. cut-off date), the censoring date is the date of the last 


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adequate tumor assessment prior to the cut-off. If the patient starts a new anti-neoplastic 
therapy (including new chemotherapy regimen or radiotherapy), the censoring date is the date 
of the last adequate tumor assessment before the initiation of the therapy, or before the cut-off 
date, whichever comes first. The date of last adequate tumor assessment is the date of the last 
tumor assessment with overall lesion response of CR, PR or SD before an event or a 
censoring reason occurred. In this case, the last tumor evaluation date at that assessment is 
used. If disease progression is documented after two or more missing or non-adequate tumor 
assessments, then the date of PFS will be censored at the date of the last tumor assessment 
with overall lesion response of CR, PR, or SD. If a PFS event is observed after a single 
missing or non-adequate tumor assessment, the actual date of event will be used, as per the 
RECIST 1.1 (Appendix 6). 
10.5 
Secondary objectives 
All secondary analyses will be reported by treatment groups. Analyses will be based on the 
FAS unless otherwise specified. 
10.5.1 
Key secondary objective 
Overall Survival 
OS is defined as the time from randomization to the date of death due to any cause. If a 
patient is not known to have died by the date of analysis cut-off, OS will be censored at the 
date of last contact. 
OS will be described by treatment arm using Kaplan-Meier curves with appropriate summary 
statistics based on FAS. OS will be compared between the two treatment groups. The HR for 
buparlisib + paclitaxel versus placebo + paclitaxel will be estimated by a stratified Cox 
proportional hazard model, using the randomization strata (i.e. prior lines of therapy and 
region (North America vs Rest of the world)). HR will be presented together with the 95% 
confidence interval. OS will also be described using Kaplan-Meier curves with appropriate 
summary statistics.  
In order to guide the Phase III design for this indication, Proof of Concept (PoC) for Overall 
Survival is defined based on the following criteria:  
• The estimated hazard ratio is equal or less than 0.77 (i.e. 23% reduction in risk of OS 
event with buparlisib compared to the comparator arm) 
and 
• Posterior probability (HR < 1) > 90% (OS treatment benefit of buparlisib compared to the 
control). 
The posterior probability of HR < 1 will be derived from the Bayesian posterior distribution 
of the HR for Overall Survival. Assuming an uninformative prior distribution, the distribution 
of the HR will be updated with all available data from the patients included in the FAS. (See 
the Statistical Appendix 9 for the details). 
The PoC analysis of OS will be performed at the time approximately 112 deaths have been 
recorded. 


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10.5.2 
Other secondary efficacy objectives 
All secondary analyses will be reported for the full population and by treatment groups. 
Analyses will be based on the FAS unless otherwise specified. 
Overall response rate 
Overall response rate (ORR) is defined as the proportion of patients with a best overall 
response of complete response (CR) or PR, based on the investigator assessment (see RECIST 
Version 1.1 guidelines, Appendix 6). In this study, the objective responses must be confirmed 
as per RECIST criteria. 
The ORR and corresponding exact 95% confidence intervals (Clopper 1934) will be presented 
by treatment group. 
Disease control rate 
Disease control rate (DCR) is defined as the proportion of patients with a best overall 
response of CR, PR or stable disease (SD), based on the investigator assessment (see RECIST 
Version 1.1 guidelines, Appendix 6). 
The DCR and corresponding exact 95% confidence intervals (Clopper 1934) will be presented 
by treatment group. 
Duration of response 
Duration of overall response (DR) is defined only for the responder subset, i.e. patients with 
confirmed CR or PR based on the investigator assessment. It is the elapsed time between the 
date of first documented response and the following date of event defined as the first 
documented progression or death due to underlying cancer. If a patient has not had an event, 
DoR is censored at the date of last adequate tumor assessment. 
DR will primarily be listed. It may be described using Kaplan-Meier curves and any related 
statistics if relevant and will be presented by treatment group. 
10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
All safety analyses for both stages will be carried out on the Safety set. The assessment of 
safety will be based mainly on the frequency of AEs and on the number of laboratory values 
that fall outside of pre-determined ranges. Other safety data (e.g., ECG, vital signs) will be 
considered as appropriate. 
The safety data will be summarized and listed by study treatment. The overall observation 
period for all safety analyses will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication. 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication. 


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3. post-treatment period: starting at day 31 after last dose of study medication. 
10.5.3.2 Adverse events (AEs) 
Summary tables for AEs will include AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs. Summary of deaths will include on-treatment and post-
treatment deaths. However, all safety data (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades 
version 4.03), type of AE, relation to study treatment. 
Deaths reportable as SAEs and non-fatal serious AEs will be listed by patient and tabulated by 
type of AE. 
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). SEC will be defined at project level 
and may be regularly updated. The grouping of AEs in SEC according to project standards 
will be specified in the project level master statistical analysis and/or the study RAP. For each 
specified SEC, number and percentage of patients with at least one event part of the SEC will 
be reported. 
10.5.3.3 Laboratory abnormalities 
Laboratory data will be graded according to CTCAE version 4.03, if applicable. For 
laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values not 
graded as 1 or higher. Grade 5 will not be used. 
For some cases, (e.g. white blood cell differentials), the lower limits of normal ranges used in 
CTCAE definition have to be replaced by a clinical meaningful limit expressed in absolute 
counts. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests: 
• Number and percentage of patients with laboratory abnormalities, by parameter and worst 
post-baseline CTC grade. Each patient will be counted only for the worst grade observed 
post-baseline, regardless of the baseline status. 
• 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. 


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In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the project level master statistical analysis and/or the study RAP. 
10.5.3.4 Other safety data 
Other safety data collected will be listed and summarized using descriptive statistics as 
appropriate. Notable values may be flagged. Notable/Abnormal values for safety data will be 
further specified in the statistical analysis plan and will be used for shift tables. 
ECG and cardiac imaging 
• shift table of ECG parameters from baseline to worst on-treatment result 
• listing of ECG evaluations for all patients with at least one abnormality 
• a summary of baseline, worst post-baseline and change from baseline for LVEF values 
• listing of cardiac imaging evaluations, LVEF values and overall interpretation for all 
patients, by visit 
Vital signs / WHO performance status 
Definitions of notably abnormal results will be included in the RAP. 
• shift table baseline to worst on-treatment result 
• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
10.5.3.5 Supportive analyses for secondary objectives  
There is no supportive analysis planned. 
10.5.3.6 Tolerability 
Tolerability will be studied in terms of dose reductions or drug interruption due to an AE. 
10.5.4 
Pharmacokinetics 
FPAS will be used in the non-compartmental analysis and PAS will be used in the population 
PK analysis. 
Non compartmental analysis 
The aim of this PK analysis is to have a preliminary PK assessment of buparlisib exposure 
when administered in combination with paclitaxel in this specific population. Descriptive 
graphical plots of geometric mean and arithmetic mean (SD) buparlisib plasma concentration 
– time profiles at cycle 1 Day 15 will be generated. Additionally graphical plots of individual 
buparlisib plasma concentration – time profiles may be generated. Further graphical 
exploratory analyses may be carried out if deemed appropriate.  
PK parameters of buparlisib will be summarized using descriptive statistics presenting 
number of observations, arithmetic mean, SD, coefficient of variation CV (%), geometric 
mean, geometric CV%, median, minimum and maximum. For Tmax only median, minimum 


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and maximum will be provided. Similarly summary statistics will be provided for 
concentration by scheduled time point including both n(number of values to be reported) and 
m(number of non-zero values to be reported) in addition to the summary statistics listed 
above. 
The derived PK parameters will be compared with PK data collected in other trials with 
[CBEZ235A2118] or without paclitaxel [CBKM120A2101]. This analysis aims to further 
characterize buparlisib exposure in this specific population but no formal analysis will be 
conducted. 
Population pharmacokinetic analysis 
A population PK model has been developed for buparlisib: The pharmacokinetics of 
buparlisib could be described with a linear two-compartment model with a lag-time and first 
order absorption. The model appears to provide an overall good fit to the data. Further details 
regarding the model can be found in the population PK report. All the parameters of this 
model, fixed and random effects will be fixed to their estimated values. (Hong Y, 2013)These 
parameters will be used to provide Empirical Bayes Estimates of individual PK parameters 
from concentrations available in this trial, if deemed appropriate. Depending on the quality of 
the data available, additional exploratory analyses may be performed. 
Once generated the model derived PK parameters will be compared to the theoretical 
distribution of the parameters obtained from the model and derived parameters collected in 
other trials with [CBEZ235A2118] or without paclitaxel [CBKM120A2101]. No formal 
statistics will be conducted. 
10.5.5.1 Outline of the data analysis 
No adjustment for multiple comparisons is planned. The following structured approach is 
proposed.  The first core step involves producing tables, listings and preferably visual displays 
to describe the data, detect trends and draw preliminary conclusions.  
 
 
 
  
 
 
 
 


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There may be circumstances when a decision is made to stop a sample collection, or not 
perform or discontinue the analysis of blood/archival tumor due to either practical or strategic 
reasons (e.g. issues related to the quality and or quantity of samples). Under such 
circumstances, the number of samples may be inadequate to perform a rigorous data analysis 
and the available data will only be listed. 
10.5.5.2 Data handling principles 
Biomarker analyses will be done on the subset of the FAS population for whom the relevant 
biomarker data is available. 
Biomarker values below the lower limit of quantification (LLOQ) will be considered as 
0.5*LLOQ. 
For IHC variables the H-score will be calculated using the following standard algorithm 
H-score = Low level stain *1+ medium level stain *2+ high level stain *3. 
Data handling will be further addressed in the statistical analysis plan. 
10.5.5.3 Data analysis principles 
10.5.5.3.1 
Analysis sets 
The FAS set will be used for all biomarker analysis depending on the study phase to be 
analyzed. Unless otherwise specified, all statistical analyses of biomarker data will be 
performed on patients with biomarker data. 
10.5.5.3.2 
Basic tables, figures and listings 
The biomarker data analysis will include the following: 
Description of distribution of baseline level by using mean, standard deviation, median, 
minimum and maximum of raw data for quantitative biomarker data collected only at 
baseline. 
Categorical markers, such as mutation or amplification status, will be summarized using 
frequency and percentages for all baseline and post baseline time points. 
Mean, standard deviation, median, minimum, and maximum of raw data, absolute change 
from baseline and relative change or fold increase from baseline for IHC measured at baseline 
and at different time points.  
Mean, standard deviation, median, minimum, and maximum, geometric mean and CV% 
geometric-mean of raw data and fold increase from baseline for ELISA data measured at 
baseline and at different on treatment timepoints. 


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If any trends appear from these graphical more advance analysis might be performed in order 
to better quantify the potential concentration effect relationship between the buparlisib plasma 
concentration and the different pathways inhibition.  
 
  
 
 
All these analyses will be outlined in full in the statistical analysis plan. 
10.5.6 
Patient-reported outcomes  
The EORTC QLQ-C30 questionnaire along with the head and neck cancer module (QLQ-
HN35) will be used to collect data on patient’s QoL.  Scoring and handling of missing QoL 
data will be in accordance to the EORTC scoring manual (Fayers 2001).  No imputation will 
be applied if the total or subscale scores are missing at a visit.  
The global health status/QoL scale and pain score of the QLQ-C30 and QLQ-HN35 are 
identified as the primary patient-reported outcome of interest. Physical functioning, emotional 
functioning and social functioning scale scores of the QLQ-C30 and the head and neck cancer 
symptom scales for swallowing, sense and speech of the QLQ-HN35 are identified as 
secondary patient-reported QoL variables of interest. No formal statistical test will be 
performed and hence no multiplicity adjustment will be applied.  
Descriptive statistics will be primarily used to summarize the scored scales at each scheduled 
assessment time point.  Additionally, change from baseline in the domain scores at the time of 
each assessment will be summarized.  Patients with an evaluable baseline score and at least 
one evaluable post baseline score during the treatment period will be included in the change 
from baseline analyses. 
Mixed effect model for repeated measures (MMRM) will be used to compare the two 
treatment arms in terms of change from baseline in the global health status / QoL, physical 
functioning, emotional functioning, social functioning, and HN35 subscales for pain, 
swallowing, senses and speech over time.  All available data during the study will be used in 
the MMRM analyses which assume that the missing scores at any time point are missing-at-
random. Additional sensitivity analysis may be performed to assess the possible violation of 
missing-at-random assumption for the missing data mechanism if deemed appropriate. Details 
will be specified in the RAP. 
The number of patients completing the EORTC QLQ-C30 and QLQ-HN35 questionnaires 
and the number of missing or incomplete assessments might also be summarized by each 
treatment group for each scheduled assessment time points. Appropriate methods to handle 
missing data will be described in the RAP. 


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Time to definitive 10% deterioration in the global health status / QoL, physical functioning, 
emotional functioning, social functioning, and head and neck cancer symptoms scales for 
pain, swallowing, senses, and speech will be assessed in the two treatment arms in the FAS.  
The time to definitive 10% deterioration is defined as the time from the date of randomization 
to the date of event, which is defined as at least 10% relative to baseline worsening of the 
corresponding scale score or death due to any cause. If a patient has not had an event, time to 
deterioration will be censored at the date of the last adequate QoL evaluation. The distribution 
will be presented descriptively using Kaplan-Meier curves. Summary statistics from Kaplan-
Meier distributions will be determined, including the median time to definitive 10% 
deterioration along with two-sided 95% confidence interval. Additionally, time to definitive 
deterioration with different cutoff definitions (e.g. 5%, 15%) may be specified in the RAP as 
deemed appropriate. A stratified Cox regression will be used to estimate the hazard ratio 
(HR), along with two-sided 95% confidence interval. 
10.7 
Interim analysis 
No formal interim analysis is planned.  
10.8 
Sample size calculation 
Most of the studies that evaluated chemotherapy agents for the treatment of 
recurrent/metastatic HNSCC were small, not randomized or even retrospective, with a 
heterogeneous patient population. More specifically, 2 studies evaluating single-agent taxanes 
in platinum-pretreated patients have been reported and considered for the purpose of the 
current study: 1. A single-agent paclitaxel study reported a mTTP of 3.4 months (Tahara 
2011); 2. A single-agent docetaxel study reporting a mTTP of 3.2 months (Koussis 2007). It 
must be noted that the paclitaxel study used a definition of mTTP that considers death as a 
progression event, and included a mixed patient population with paclitaxel administered as 1st 
line treatment for metastatic disease in 77% and 2nd line treatment for metastatic disease in 
23% of patients, respectively (Tahara 2011). Based on these observations, also considering 
that in the current study all the patients enrolled will be pretreated with platinum-based 
regimens as 1st line treatment for metastatic disease and also might have received cetuximab 
as 2nd line, it is expected a median PFS in the paclitaxel arm (control arm) would be 
approximately 3 months. A 50% increase in median PFS from 3.0 to 4.5 months can be 
considered clinically meaningful in this setting (e.g. a HR of 0.67).  
Proof of concept (PoC) will be declared if there is sufficient clinical and statistical evidence 
based on the criteria listed below that the buparlisib-containing regimen is superior to 
matching placebo in the full population 


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• The estimated hazard ratio is equal or less than 0.67 (i.e. 33% reduction in risk of PFS 
event with buparlisib compared to the comparator arm) 
and 
• Posterior probability (HR < 1) > 97.5% (PFS treatment benefit of buparlisib compared to 
the control). 
Approximately 150 patients (75 per arm) have to be randomized in the study in order to 
observe 120 PFS events, assuming a true median PFS of 3 months in the control arm, a HR of 
0.67, a recruitment rate of 10 patients/month and a drop-out rate of 15%. Given the above 
assumptions, the primary analysis is expected to occur after approximately 19 months if the 
true HR is 0.67. 
A minimum number of 114 PFS events is required so that the operating characteristics of the 
design (obtained by simulation) provide adequate properties (i.e. if the true HR is 1, the 
probability to obtain a positive conclusion is less than 0.05; if the true HR is 0.67, the 
probability to obtain a positive conclusion is approx. 0.50). However with consideration given 
to OS objectives and other exploratory objectives the required number of events is raised to 
120. Table 10-1 presents the Operating Characteristics of the design for the Primary Objective 
of study with 120 PFS events and the expected duration till the primary analysis under 
different scenarios of True Hazard Ratio of PFS. 
Table 10-1 
Study Operating Characteristics 
True HR(buparlisib / Control) 
True Median 
PFS 
(buparlisib+paclitaxel) 
Probability  
of PFS 
PoC(Power) 
Expected 
Duration for PFS 
events (months) 
1 
3.0 
0.012 
17.12 
0.86 
3.5 
0.09 
17.67 
0.75 
4.0 
0.246 
18.27 
0.67 
4.5 
0.512 
18.92 
0.6 
5.0 
0.730 
19.57 
0.55 
5.5 
0.877 
20.14 
0.5 
6.0 
0.943 
20.92 
10.9 
Operating characteristics of key secondary variables 
OS will likely be considered as a primary endpoint for a confirmatory registration study in 
this indication.  
Based on literature review in this indication, also considering that in the current study all the 
patients enrolled will be pretreated with platinum-based regimens as 1st line treatment for 
metastatic disease and also might have received cetuximab as 2nd line, it is expected a median 
OS in the paclitaxel arm (control arm) would be approximately 7 months. A 2 month increase 
in median OS from 7 to 9 months can be considered clinically meaningful in this setting (e.g. 
a HR of 0.77). A Phase III combination study of Cetuximab in association with Platinum 
based chemotherapy as a 1st line therapy reported a median OS of 7.4 months for the patients 
in the platinum arm and 10.1 months for the patients in the Cetuximab + Platinum arm. 


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In order to guide the Ph III design for this indication, Proof of Concept (PoC) is defined based 
on the following criteria: 
• The estimated hazard ratio is equal or less than 0.77 (i.e. 23% reduction in risk of OS 
event with buparlisib compared to the comparator arm) 
and 
• Posterior probability (HR < 1) > 90% (OS treatment benefit of buparlisib compared to the 
control). 
With a total of 150 randomized patients (75 per arm) with a recruitment rate of 10 
patients/month and a drop-out rate for OS of 5%, the OS analysis is expected to occur 
approximately 25 months after FPFV. 
A minimum of 112 OS events is required so that the operating characteristics for OS PoC 
based on the current design have adequate properties (obtained by simulation)  (i.e. if the true 
HR is 1, the probability to obtain a positive conclusion is less than 0.10; if the true HR is 0.70, 
the probability to obtain a positive conclusion is approximately 0.70). 
Table 10-2 
Study Operating Characteristics to meet Proof of Concepts for OS 
True Median OS 
True HR 
Expected  
 Probability of OS  
buparlisib + paclitaxel 
buparlisib/control 
Duration for 
OS Events  
Proof of Concept(Power) 
7 
1.00 
23 
0.093 
7.5 
0.93 
23 
0.162 
8 
0.88 
24 
0.246 
8.5 
0.82 
24 
0.356 
9 
0.78 
25 
0.477 
9.5 
0.74 
25 
0.587 
10 
0.70 
26 
0.695 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 


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Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in  
Section 4.4 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 


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Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the CRFs and all other required reports. Data 
reported on the CRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the CRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
CRF should be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. For electronic CRFs an audit trail will be maintained by the system. The 
investigator should retain records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 


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12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days. 


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13 
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14 
Appendices 
14.1 
Appendix 1: Gilbert syndrome 
Gilbert syndrome is an autosomal recessive medical condition characterized by deficiency of 
the enzyme uridine diphosphate glucuronyl transferase (UGT), which causes unconjugated 
hyperbilirubinemia and intermittent jaundice, abdominal pain, weakness and fatigue. Gilbert 
syndrome may also be asymptomatic.  
Hyperbilirubinemia is mild (total bilirubin < 6 mg/dL) and most patients exhibit total bilirubin 
levels of <3 mg/dL. Daily and seasonal variations are observed, and bilirubin levels 
occasionally can be normal in 33% of patients.  
Gilbert syndrome may be precipitated by dehydration, fasting, menstruction, or stress, such as 
an intercurrent illness or vigorous exercise. These episodes resolve spontaneously, and no 
treatment is required, except for supportive care. 
Pathophysiology 
Unconjugated hyperbilirubinemia in Gilbert syndrome is due to underactivity of the 
conjugating enzyme system bilirubin uridine diphosphate glucuronyltransferase (bilirubin-
UGT) (Lee P 2007). Bilirubin-UGT is one of several UGT enzyme isoforms responsible for 
the conjugation of a wide array of substrates that include carcinogens, drugs, hormones, and 
neurotransmitters.  
Knowledge of these enzymes has been enhanced greatly by characterization of the UGT1 
gene locus in humans. The gene that encodes bilirubin-UGT has a complex structure and is 
located on chromosome 2 (Ferraris 2006, Hsieh 2007; Ostanek 2007; Petit 2007; Rigato 2007; 
Ehmer 2008). 
There are 5 exons, of which exons 2-5 at the 3' end are constant components of all isoforms of 
UGT, and these encode the UDP-glucuronic acid-binding site. 
Exon 1 encodes a unique region within each UGT that confers substrate specificity. However, 
multiple exon 1 variants (at least 13) exist. Exons 1a and 1d encode the variable region for 
bilirubin UGT1*1 (also known as UGT1A1) and UGT1*2, respectively. UGT1*1 is 
responsible for virtually all bilirubin conjugation, and UGT1*2 has little, if any, known 
physiological role. Expression of UGT1*1 expression is regulated by a promoter region 5’ of 
exon 1 that contains a TATAA box. Impaired bilirubin glucuronidation can result from 
mutations in exon 1a, its promoter, or exons common to UGT alleles. The genetic basis of 
Gilbert syndrome has been shown in some instances to comprise abnormalities in the TATAA 
region of the promoter. The addition of 2 extra bases (TA) to the TATAA region interferes 
with binding of the transcription factor IID (TF-IID) and results in reduced expression of 
bilirubin-UGT1 (30% of normal). In the homozygous state, diminished bilirubin 
glucuronidation is observed, with bile containing an excess of bilirubin monoglucuronide over 
diglucuronide. Moreover, additional mutations have been identified.  
Some healthy Asian patients with Gilbert syndrome do not have promoter mutations but are 
heterozygous for missense mutations (Gly71Arg, Tyr486Asp, Pro364Leu) in the coding 


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region. These individuals also have significantly higher unconjugated bilirubin levels than do 
those with the wild-type allele. 
Whether reduced bilirubin-UGT activity results from a reduced number of enzyme molecules 
or from a qualitative enzyme defect is not known in every instance. Moreover, other factors 
such as occult hemolysis or hepatic transport abnormalities can modify the clinical expression 
of Gilbert syndrome. Many individuals homozygous for the TATAA defect do not 
demonstrate unconjugated hyperbilirubinemia, and patients with reduced levels of bilirubin-
UGT, as observed in some granulomatous liver diseases, do not develop hyperbilirubinemia. 
Because of the high frequency of mutations in the Gilbert promoter, heterozygous carriers of 
Crigler –Najjar syndrome types 1 and 2 can also carry the elongated Gilbert TATAA 
sequence on their normal allele. Such combined defects can lead to severe hyperbilirubinemia 
and also help explain the finding of intermediate levels of hyperbilirubinemia in family 
members of patients with Crigler-Najjar syndrome. Gilbert syndrome can also frequently 
coexist with the conditions associated with unconjugated hyperbilirubinemia, such as 
thalasemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency (Seo 2007; 
Udomuksorn 2007). 
Epidemiology  
The worldwide prevalence of Gilbert syndrome varies considerably depending on which 
diagnostic criteria are used, such as number of bilirubin determinations, method of analysis, 
bilirubin levels used for diagnosis, and whether the patient was fasting. This may be 
complicated further by polymorphisms in the TATAA promoter region, which are present in 
as many as 36% of Africans but only 3% of Asians. The clinical phenotype may not be as 
apparent as the determined genotype because of environmental influences, such as alcohol-
induced bilirubin glucuronidation, which can reduce bilirubin levels. The prevalence of 
Gilbert syndrome in the United States is 3-7% of the population. Population studies show that 
Gilbert syndrome occurs predominately in men, with a male-to-female ratio ranging from 2-
7:1. 
Gilbert syndrome is usually diagnosed around puberty, possibly because of the inhibition of 
bilirubin glucuronidation by endogenous steroid hormones. 
In older persons, the diagnosis is usually made when unconjugated hyperbilirubinemia is 
noted on routine blood test results or is unmasked by an intercurrent illness or stress. 
Clinical Features  
Gilbert syndrome is a benign condition with no associated significant morbidity or mortality.  
At least 30% of patients are asymptomatic, although nonspecific symptoms, such as 
abdominal cramping, fatigue, and malaise, are common. Abdominal symptoms in these 
patients are a poorly defined entity and may be secondary to underlying anxiety. However, not 
all patients with Gilbert syndrome and abdominal symptoms are anxious; nevertheless, they 
appear to have organic-type discomfort that is hard to characterize and frequently eludes 
diagnosis. No relationship exists between these abdominal symptoms and plasma bilirubin 
levels. Abdominal symptoms apparently may be multifactorial, with underlying anxiety 
probably playing an important role. 


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Mild jaundice is present intermittently in some individuals, but no other abnormal physical 
examination findings are evident. Infants homozygous for Gilbert syndrome may have a 
greater increase in neonatal jaundice when breastfed or when other disorders of heme 
metabolism are co-inherited (Papez MJ 2009; Tapan S 2009) 
Exacerbating conditions: Dehydration, fasting, (which causes an increase in the plasma 
unconjugated bilirubin level), intercurrent illness, menstruation, and stress (such as trauma 
and strenuous exercise). 
Diagnosis 
Diagnosis of Gilbert syndrome can be made in the presence of (1) unconjugated 
hyperbilirubinemia noted on several occasions; (2) normal results from a CBC count, 
reticulocyte count, and blood smear; (3) normal liver function test results; and (4) an absence 
of other disease processes 
Laboratory data  
• CBC count (including reticulocyte count and blood smear): This is a useful screening test 
to exclude hemolysis as a cause of hyperbilirubinemia. Rarely, red blood cell 
abnormalities resembling variegate porphyria have been described in persons with Gilbert 
syndrome, possibly due to the increased hepatocellular bilirubin concentration.  
• Lactate dehydrogenase: Levels are elevated in persons with hemolysis but are normal in 
those with Gilbert syndrome.  
• Liver function tests: With the exception of unconjugated hyperbilirubinemia, standard 
liver function test results are normal. However, a familial increase in serum alkaline 
phosphatase levels has been reported in some persons with Gilbert syndrome. 
Imaging Studies 
• Imaging studies are not routinely required to confirm a diagnosis of Gilbert syndrome. 
Other Tests 
Additional tests are rarely required, but the following investigations are occasionally 
performed to confirm a diagnosis of Gilbert syndrome.  
• Fasting: This usually results in a 2- to 3-fold rise in the plasma unconjugated bilirubin 
level within 48 hours of a fast that returns to normal levels within 24 hours of resuming a 
normal diet. Although unconjugated bilirubin levels also rise with fasting in patients with 
hemolysis or liver disease, the magnitude of the rise is less than that observed with Gilbert 
syndrome. A similar rise in plasma bilirubin is also observed with normocaloric diets 
deficient in lipids and reverses promptly with lipid replacement. The fasting test remains 
of historic interest and has limited usefulness in the diagnosis of Gilbert syndrome.  
• Nicotinic acid: Intravenous administration of 50 mg of nicotinic acid results in a 2- to 3-
fold rise in plasma unconjugated hyperbilirubinemia within 3 hours. The mechanisms are 
multifactorial and probably related to (1) elevated osmotic fragility of red blood cells, (2) 
increase in splenic production of bilirubin, (3) transient inhibition of hepatic bilirubin-
UGT activity, and (4) increased splenic heme oxygenase activity. Similar but less 


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impressive increase is observed in healthy individuals. The nicotinic test, does not clearly 
distinguish patients with Gilbert syndrome from those who are healthy or who have other 
disease processes.  
• Phenobarbital: Phenobarbital and other enzyme inducers of the bilirubin-UGT system will 
normalize plasma bilirubin in patients with Gilbert syndrome. Steroids can also reduce 
plasma bilirubin levels in Gilbert syndrome by increasing hepatic uptake and storage of 
bilirubin.  
• Radioactive-labeled chromium: This is used to measure red blood cell survival. As many 
as 60% of patients with Gilbert syndrome have a mild and fully compensated state of 
hemolysis together with increased hepatic heme production. As a result, 
hyperbilirubinemia may be due to reduced bilirubin clearance and increased production, 
the latter from increased erythroid or hepatic heme turnover.  
• Thin-layer chromatography: This test is diagnostic for Gilbert syndrome when it shows a 
significantly higher proportion of unconjugated bilirubin compared with individuals with 
chronic hemolysis or liver disease or those who are healthy. If confirmation of the 
diagnosis is truly essential, chromatographic determination is of potential use. This shows 
an increased ratio of bilirubin monoglucuronide to diglucuronide, reflecting reduced 
bilirubin-UGT activity.  
• Drug clearance: Approximately 30% of patients have impaired clearance of 
bromosulfophthalein, indocyanine green, and free fatty acid, suggesting an abnormality in 
hepatic uptake, transport, or both. The metabolic clearance of tolbutamide is also reduced 
in persons with Gilbert syndrome, but, because it does not undergo glucuronidation, 
hepatic uptake appears to be defective. Plasma clearance of most drugs that undergo 
glucuronidation (eg, benzodiazepines) is unaffected. However, with regard to 
acetaminophen, patients with Gilbert syndrome are a heterogeneous group, with some 
demonstrating normal metabolism and others exhibiting marked reduction in 
glucuronidation and an increase in oxidation.  
• Polymerase chain reaction: Polymerase chain reaction is a novel and rapid method of 
identifying genetic polymorphisms in the TATA box of the UGT1*1 gene using 
fluorescence resonance energy transfer. 
Liver Biopsy 
• Liver biopsies are not performed routinely and are rarely necessary. The liver is normal 
histologically, except for occasional accumulation of a lipofuscinlike pigment around the 
terminal hepatic venules. 


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References 
Ehmer U, Lankisch TO, Erichsen TJ, et al. (2008) Rapid allelic discrimination by TaqMan 
PCR for the detection of the Gilbert's syndrome marker UGT1A1*28. J Mol Diagn.; 10(6) : 
549-52. 
Ferraris A, D'Amato G, Nobili V, et al. (2006) Combined test for UGT1A1 -3279T-->G and 
A(TA)nTAA polymorphisms best predicts Gilbert's syndrome in Italian pediatric patients. 
Genet Test.;10(2):121-5. 
Hsieh TY, Shiu TY, Huang SM, et al. (2007) Molecular pathogenesis of Gilbert's syndrome: 
decreased TATA-binding protein binding affinity of UGT1A1 gene promoter. Pharmacogenet 
Genomics.;17(4):229-36. 
Lee P, Jones G, Seibel MJ. (2007) Dual polymorphisms in UDP-glucuronosyltransferases 
1A1 and 1A6: a novel mechanism for hyperserotoninaemia in Gilbert's syndrome mimicking 
carcinoid syndrome? Eur J Gastroenterol Hepatol.;19(4):337-40. 
Ostanek B, Furlan D, Mavec T, Lukac-Bajalo J. (2007) UGT1A1(TA)n promoter 
polymorphism--a new case of a (TA)8 allele in Caucasians. Blood Cells Mol Dis.;38(2):78- 
82. 
Papez MJ, Civalier CJ, Thorne LB, et al. (2009) UGT1A1 promoter genotype is not strongly 
associated with severity of coronary artery disease. Diagn Mol Pathol. ; 18: 226–231. 
Petit FM, Hebert M, Gajdos V, et al. (2007) Comments on seven novel mutations of the 
UGT1A1 gene in patients with unconjugated hyperbilirubinemia by D'Apolito et al. 
Haematologica.;92(7):e80. 
Rigato I, Cravatari M, Avellini C, et al. (2007) Drug-induced acute cholestatic liver damage in 
a patient with mutation of UGT1A1. Nat Clin Pract Gastroenterol Hepatol. ;4(7):403-8. 
Seo YS, Keum B, Park S, et al. (2007) Gilbert's syndrome phenotypically expressed as 
Crigler-Najjar syndrome type II. Scand J Gastroenterol. ;42(4):540-1. 
Tapan S, Dogru T, Tasci I, et al. (2009) Soluble CD40 ligand and soluble P-selectin levels in 
Gilbert's syndrome: a link to protection against atherosclerosis? Clin Biochem.;42(9):791-5. 
Teng HC, Huang MJ, Tang KS, et al. (2007) Combined UGT1A1 and UGT1A7 variant alleles 
are associated with increased risk of Gilbert's syndrome in Taiwanese adults. Clin 
Genet;72(4):321-8. 
Udomuksorn W, Elliot DJ, Lewis BC, et al. (2007) Influence of mutations associated with 
Gilbert and Crigler-Najjar type II syndromes on the glucuronidation kinetics of bilirubin and 
other UDP-glucuronosyltransferase 1A substrates. Pharmacogenet Genomics.;17(12):1017- 
29. 


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14.2 
Appendix 2: List of prohibited CYP3A inhibitors and inducers 
Table 14-1 
List of prohibited CYP3A inhibitors and inducers 
Strong CYP3A 
inhibitors 
Moderate CYP3A 
inhibitors 
Strong CYP3A  
inducers 
Moderate CYP3A  
inducers 
clarithromycin 
amprenavir 
carbamazepine * 
felbamate * 
conivaptan 
aprepitant 
phenobarbital * 
topiramate * (>200 
mg/day) 
indinavir 
atazanavir 
phenytoin * 
oxcarbazepin * 
itraconazole 
cimetidine 
fosphenytoin * 
eslicarbazepin * 
ketoconazole 
ciprofloxacin 
primidone * 
rufinamide * 
lopinavir 
darunavir 
avasimibe 
bosentan 
mibefradil 
diltiazem 
rifabutin 
efavirenz 
nefazodone 
elvitegravir 
rifampin 
etravirine 
nelfinavir 
erythromycin 
St. John's Wort 
modafenil 
posaconazole 
fluconazole 
 
nafcillin 
ritonavir 
grapefruit juice 
 
ritonavir 
saquinavir 
schisandra sphenanthera 
 
talviraline 
telithromycin 
tipranavir 
 
tipranavir 
troleandomycin 
tofisopam 
 
 
voriconazole 
verapamil 
 
 
* These drugs are Enzyme  Inducing Anti-Epileptic drugs 
This database of CYP inhibitors and inducers was compiled from the Indiana University School of 
Medicine’s “Clinically Relevant” Table, from the University of Washington’s Drug Interaction Database 
based on in vitro studies and from the FDA’s “Guidance for Industry, Drug Interaction Studies;” from 
the Indiana University School of Medicine’s “Clinically Relevant” Table; and from (Pursche 2008). 


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14.3 
Appendix 3: List of CYP450 substrates to be used with caution 
Table 14-2 
List of CYP450 substrates to be used with caution* 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A** 
amodiaquine 
celecoxib 
amitriptyline 
adinazolam 
felodipine1 
cerivastatin 
diclofenac 
citalopram 
alfentanil1,2 
fentanyl2 
pioglitazone 
flurbiprofen 
clobazam 
alpha-
dihydroergocryptine1 
flunitrazepam 
repaglinide 
fluvastatin 
clomipramine 
alprazolam 
fluticasone1 
rosiglitazone 
glibenclamide 
(glyburide) 
clopidogrel  
amlodipine 
lovastatin1 
torasemide 
gliclazide 
diazepam 
aripiprazole 
maraviroc1 
troglitazone 
glimepiride 
fluoxetine 
atorvastatin 
midazolam1 
 
glipizide 
imipramine 
brecanavir 
nifedipine 
 
indomethacin 
lansoprazole 
brotizolam1 
nisoldipine 
 
irbesartan 
mephobarbital 
budesonide1 
nitrendipine 
 
ketobemidone 
moclobemide 
buspirone1 
perospirone1 
 
lornoxicam 
omeprazole 
capravirine 
quinine 
 
losartan 
pantoprazole 
cerivastatin 
sildenafil1 
 
meloxicam 
progesterone 
chlorpheniramine 
simvastatin1 
 
naproxen 
quazepam 
cyclosporine2 
sirolimus1,2 
 
nateglinide 
rabeprazole 
darifenacin1 
tolvaptan 
 
piroxicam 
sertraline 
diazepam 
trazodone 
 
rosiglitazone 
S-mephenytoin 
diergotamine2 
triazolam1 
 
S-ibuprofen 
 
ebastine1 
 
 
sulfamethoxazole 
 
eletriptan1 
 
 
tenoxicam 
 
eplerenone1 
 
 
tolbutamide 
 
ergotamine2 
 
 
torasemide 
 
estazolam 
 
 
valdecoxib 
 
everolimus1 
 
* This database of CYP substrates was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table, and from (Zhou 2009) 
** CYP3A substrates were compiled from the Indiana University School of Medicine’s “Clinically 
Relevant” Table; and supplemented by the FDA’s “Guidance for Industry, Drug Interaction Studies” 
and the University of Washington’s Drug Interaction Database. 
(1) Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a potent inhibitor of the respective enzyme. 
(2) Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious 
safety concerns (e.g., Torsades de Pointes). 


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14.4 
Appendix 4: Prohibited QT prolonging drugs with risk of 
Torsades de Pointes 
All QT-prolonging drugs listed in Table 14-3 are prohibited for all patients from screening 
through permanent discontinuation of study treatment. Table 13-2 lists drugs with a known 
risk for Torsades de Pointes (TdP) as well as sensitive CYP3A substrates (with narrow TI) 
with a possible or conditional risk for TdP. 
Table 14-3 
List of prohibited QT prolonging drugs 
Drug 
QT risk(*) 
Comment 
Amiodarone 
Known risk for TdP 
Females>Males, TdP risk regarded as low 
Arsenic trioxide 
Known risk for TdP 
 
Astemizole 
Known risk for TdP 
No Longer available in U.S. 
Bepridil 
Known risk for TdP 
Females>Males 
Chloroquine 
Known risk for TdP 
 
Chlorpromazine 
Known risk for TdP 
 
Cisapride 
Known risk for TdP 
Restricted availability; Females>Males. 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
 
Domperidone 
Known risk for TdP 
Not available in the U.S. 
Droperidol 
Known risk for TdP 
 
Halofantrine 
Known risk for TdP 
Females>Males 
Haloperidol 
Known risk for TdP 
When given intravenously or at higher-than- 
recommended doses, risk of sudden death, QT 
prolongation and torsades increases. 
Ibutilide 
Known risk for TdP 
Females>Males 
Levomethadyl 
Known risk for TdP 
 
Mesoridazine 
Known risk for TdP 
 
Methadone 
Known risk for TdP 
Females>Males 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 
Probucol 
Known risk for TdP 
No longer available in U.S. 
Procainamide 
Known risk for TdP 
 
Quetiapine 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
Quinidine 
Known risk for TdP 
Females>Males 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
 
Tacrolimus 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate with 
narrow TI 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
 
Vardenafil 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-
administered with a potent inhibitor of the respective enzyme. 
Note: drugs with a known risk for TdP that are also moderate or strong inhibitors of CYP3A are not repeated here 
and only mentioned in Table 14-1. 


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14.5 
Appendix 5: List of QT prolonging drugs to be used with caution 
Patients receiving any study treatment may use the following medications but should be 
monitored closely. 
Table 14-4 
List of QT prolonging drugs to be used with caution 
Drug 
QT risk (*) 
Alfuzosin 
Possible risk for TdP 
Amantadine 
Possible risk for TdP 
Amitriptyline 
Conditional risk for TdP 
Azithromycin 
Possible risk for TdP 
Chloral hydrate 
Possible risk for TdP 
Citalopram 
Conditional risk for TdP 
Clomipramine 
Conditional risk for TdP 
Clozapine 
Possible risk for TdP 
Desipramine 
Conditional risk for TdP 
Diphenhydramine 
Conditional risk for TdP 
Dolasetron 
Possible risk for TdP 
Doxepin 
Conditional risk for TdP 
Dronedarone 
Possible risk for TdP 
Escitalopram 
Possible risk for TdP 
Flecainide 
Possible risk for TdP 
Fluoxetine 
Conditional risk for TdP 
Foscarnet 
Possible risk for TdP 
Galantamine 
Conditional risk for TdP 
Gatifloxacin 
Possible risk for TdP 
Gemifloxacin 
Possible risk for TdP 
Granisetron 
Possible risk for TdP 
Imipramine 
Conditional risk for TdP 
Indapamide 
Possible risk for TdP 
Isradipine 
Possible risk for TdP 
Levofloxacin 
Possible risk for TdP 
Lithium 
Possible risk for TdP 
Mexiletine 
Conditional risk for TdP 
Moexipril/HCTZ 
Possible risk for TdP 
Moxifloxacin 
Possible risk for TdP 
Nicardipine 
Possible risk for TdP 
Nortriptyline 
Conditional risk for TdP 
Octreotide 
Possible risk for TdP 
Ofloxacin 
Possible risk for TdP 
Ondansetron 
Possible risk for TdP 
Oxytocin 
Possible risk for TdP 


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Drug 
QT risk (*) 
Paliperidone 
Possible risk for TdP 
Paroxetine 
Conditional risk for TdP 
Perflutren lipid microspheres 
Possible risk for TdP 
Protriptyline 
Conditional risk for TdP 
Ranolazine 
Possible risk for TdP 
Risperidone 
Possible risk for TdP 
Roxithromycin* 
Possible risk for TdP 
Sertindole 
Possible risk for TdP 
Sertraline 
Conditional risk for TdP 
Solifenacin 
Conditional risk for TdP 
Tizanidine 
Possible risk for TdP 
Trazodone 
Conditional risk for TdP 
Trimethoprim-Sulfa 
Conditional risk for TdP 
Trimipramine 
Conditional risk for TdP 
Venlafaxine 
Possible risk for TdP 
Ziprasidone 
Possible risk for TdP 


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14.6 
Appendix 6: Guidelines for response, duration of overall 
response, TTF, TTP, progression-free survival and overall 
survival (based on RECIST 1.1) 
List of Contributors 
Authors (Version 3.1): 
Authors (Version 3): 
Authors (Version 2): 
Authors (Version 1): 


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Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
MRI 
Magnetic resonance imaging 
LPLV 
Last patient last visit 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 


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1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse, et al 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer, et al 2009). 
The efficacy assessments described in Section 2 and the definition of best response in 
Section 3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions and 
rules for determination of best response. Section 3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 4 of this 
guideline describes data handling and programming rules. This section is to be referred to in 
the RAP (Reporting and Analysis Plan) to provide further details needed for programming. 
2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse, et al 2000), New 
Guidelines to Evaluate the Response to Treatment in Solid Tumors, Journal of National 
Cancer Institute, Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer, et 
al 2009) European Journal of Cancer; 45:228-247. 
2.1 
Definitions 
2.1.1 Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in 
order to classify lesions appropriately at baseline. In defining measurability, a distinction also 
needs to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 3.2.8 
Measurable lesions (both nodal and non-nodal) 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 


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baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease. 
• Cystic lesions:  
• Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
• Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with  
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
2.2.1 Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). 
However, it is recommended that patients be excluded from trials where the main focus is on 
the Overall Response Rate (ORR). Guidance on how patients with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses is 
given in Section 3.2.8. 
2.2 
Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique 
should be used to characterize each identified and reported lesion at baseline and 
during follow-up. Contrast-enhanced CT of chest, abdomen and pelvis should 
preferably be performed using a 5 mm slice thickness with a contiguous 
reconstruction algorithm. CT/MRI scan slice thickness should not exceed 8 mm cuts 
using a contiguous reconstruction algorithm. If, at baseline, a patient is known to have 


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a medical contraindication to CT contrast or develops a contraindication during the 
trial, the following change in imaging modality will be accepted for follow up: a non-
contrast CT of chest (MRI not recommended due to respiratory artifacts) plus 
contrast-enhanced MRI of abdomen and pelvis. 
• A change in methodology can be defined as either a change in contrast use (e.g. 
keeping the same technique, like CT, but switching from with to without contrast use 
or vice-versa, regardless of the justification for the change) or a change in technique 
(e.g. from CT to MRI, or vice-versa), or a change in any other imaging modality. A 
change in methodology will result by default in a UNK overall lesion response 
assessment. However, another response assessment than the Novartis calculated UNK 
response may be accepted from the investigator or the central blinded reviewer if a 
definitive response assessment can be justified, based on the available information. 
• FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline with a positive FDG-PET at follow-up: 
• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan). 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, some 
disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, PSA 
for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be integrated 
as non-target disease. If markers are initially above the upper normal limit they must 


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normalize for a patient to be considered in complete clinical response when all lesions 
have disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
2.3 
Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ). 
Minimum target lesion size at baseline 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 2.1.1. 
• Nodal target: See Section 2.1.1. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. 
Each target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 


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2.4 
Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 2-5) and non-target lesions (Table 2-6) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 2-7) as well as the presence or absence of new lesions. 
2.4.1 Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for 
the evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate 
lesion evaluation data are examined by the investigator in order to derive the overall visit 
response. Therefore all such data applicable to a particular visit should be associated with the 
same assessment number. 
2.4.1.1 
Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance 
of the cut from the longest diameter; such lesions may appear to have responded or progressed 
on subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement.  This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size 
(e.g., borders of the lesion are confounded by neighboring anatomical structures), no 
measurement should be entered and the lesion cannot be evaluated. 
2.4.1.2 
Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are 
not expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement.  This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 


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However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
2.4.2 Determination of target lesion response 
Table 2-5 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis 
to < 10 mm 1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking 
as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameter of all measured target 
lesions, taking as reference the smallest sum of diameter of all target 
lesions recorded at or after baseline. In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 
mm2. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in 
lesions which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a different method 
than baseline.3 
SOD for CR may not be zero when nodal lesions are part of target lesions 
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and 
all nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
Methodology change See Section 2.2. 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance 
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following three possibilities: 
• The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
• The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 2-5 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at 
or after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section. 


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• For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation. 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters.  


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2.4.3 Determination of non-target lesion response 
Table 2-6 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions. In addition, all lymph nodes 
assigned a non-target lesions must be non-pathological in size (< 10 mm 
short axis) 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target lesions 
have not been assessed or have been assessed using a different method 
than baseline. 
Although a clear progression of non-target lesions only is exceptional, in such circumstances, the 
opinion of the treating physician does prevail and the progression status should be confirmed later on 
by the review panel (or study chair). 
Notes on non-target lesion response 
• The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e.  10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD). 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 2.4.2 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied. 
2.4.4 New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
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• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 2.5). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to  10 mm for the first time in the study plus 5 
mm absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 2.2. 
2.5 
Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in  
Table 2-7. 
Table 2-7 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall 
lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
This overall lesion response also applies when there are no non-target lesions identified at baseline. 
Once confirmed PR was achieved, all these assessments are considered PR. 
As defined in Section 2.4. 
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK). 
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
3 
Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at 
baseline. Section 3.2.8 outlines the special considerations that need to be given to patients 
with no measurable disease at baseline in order to apply the same concepts. 


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3.1 
Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the 
protocol should specifically describe if these will be included in the determination of best 
overall response and/or whether these additional assessments will be required for sensitivity 
or supportive analyses. As a default, any assessments taken more than 30 days after the last 
dose of study treatment will not be included in the best overall response derivation. If any 
alternative cancer therapy is taken while on study any subsequent assessments would 
ordinarily be excluded from the best overall response determination. If response assessments 
taken after withdrawal from study treatment and/or alternative therapy are to be included in 
the main endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• For non-randomized trials where response is the primary endpoint, confirmation is needed. 
• For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 
• PD = progression  12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks) 
Overall lesion responses of CR must stay the same until progression sets in, with the 
exception of a UNK status. A patient who had a CR cannot subsequently have a lower status 


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other than a PD, e.g. PR or SD, as this would imply a progression based on one or more 
lesions reappearing, in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective 
status at that assessment should be SD. Once a confirmed PR was seen, the overall lesion 
response should be considered PR (or UNK) until progression is documented or the lesions 
totally disappear in which case a CR assignment is applicable. In studies where confirmation 
of response is not required after a single PR the overall lesion response should still be 
considered PR (or UNK) until progression is documented or the lesion totally disappears in 
which case a CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the 
subsequent visits. Assuming that non-target lesions did not progress, the overall lesion 
response would be PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the 
PR for this patient. All subsequent assessments are considered PR even if tumor 
measurements decrease only by 20% compared to baseline (200 mm to 160 mm) at the 
following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 
Disease control rate (DCR) is the proportion of patients with a best overall response of CR 
or PR or SD. 


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Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be 
at 8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with 
an unknown (UNK) assessment at that time point and no PD before, will not be counted as 
early progressors in the analysis but may be included in the denominator of the EPR rate, 
depending on the analysis population used. Similarly when examining overall response and 
disease control, patients with a best overall response assessment of unknown (UNK) will not 
be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT approach). 
3.2 
Time to event variables 
The protocol should state which of the following variables is used in that study. 
3.2.1 Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 
3.2.2 Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date 
the patient was last seen alive / last known date patient alive, the date of death and the reason 
of death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be 
censored at the date of last known date patient alive. 
3.2.3 Time to progression 
Some studies might consider only death related to underlying cancer as an event which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer. 


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Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment. 
3.2.4 Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation 
is typically related to intolerance of the study drug. In some protocols, time to treatment 
failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation 
due to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to 
treatment failure for patients who did not experience treatment failure will be censored at last 
adequate tumor assessment. 
3.2.5 Duration of response 
The analysis of the following variables should be performed with much caution when 
restricted to responders since treatment bias could have been introduced. There have been 
reports where a treatment with a significantly higher response rate had a significantly shorter 
duration of response but where this probably primarily reflected selection bias which is 
explained as follows: It is postulated that there are two groups of patients: a good risk group 
and a poor risk group. Good risk patients tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk patients tend to 
be difficult to achieve a response, may have a longer time to respond, and tend to relapse 
quickly when they do respond. Potent agents induce a response in both good risk and poor 
risk patients. Less potent agents induce a response mainly in good risk patients only. This is 
described in more detail by Morgan (1988) 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then 
interpreted with caution by evaluating the results in the context of the observed response 
rates... If an inferential comparison between treatments is required this should only be 
performed on all patients (i.e. not restricting to “responders” only) using appropriate statistical 
methods such as the techniques described in Ellis, et al (2008). It should also be stated in the 
protocol if duration of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression. 


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The following two durations might be calculated in addition for a large Phase III study in 
which a reasonable number of responders is seen. 
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to 
be confirmed) or SD the start and end date as well as censoring is defined the same as that for 
time to progression. 
3.2.6 Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be 
confirmed depending on the type of study and its importance. Where the response needs to be 
confirmed then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be 
performed on the “responders” subset only, in which case the results should be interpreted 
with caution and in the context of the overall response rates, since the same kind of selection 
bias may be introduced as described for duration of response in Section 3.2.5. It is 
recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. Where an 
inferential statistical comparison is required, then all patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 
who did not achieve a response (which may have to be a confirmed response) will be censored 
using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
3.2.7 Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 


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assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number. 
Start dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
• Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
• Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
• Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 3.2.8). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
3.2.8 Handling of patients with non-measurable disease only at baseline 
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 
with PFS as the primary endpoint). In such cases the handling of the response data requires 


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special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations. 
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 3-1. 
Table 3-1 
Overall lesion response at each assessment: patients with non-
target disease only 
Non-target lesions 
New Lesions 
Overall lesion 
response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 2.4. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”.  
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular patients. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from patients with only non-
measurable disease. 
3.2.9 Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as 
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after a 
long period of a patient being lost to follow-up? It is important that the protocol and RAP 


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specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed. 
Based on definitions outlined in Section 3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered: 
Table 3-2 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified differently 
in the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of 
treatment3 
Censored 
B 
Progression at or before next scheduled 
assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 Progression or death after exactly one 
missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 Progression or death after two or more 
missing assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
E 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. clinical 
progression based on investigator claim 
(1) N/A 
(2) Date of discontinuation (visit date at 
which clinical progression was 
determined) 
Ignored 
Progressed 
F 
New anticancer therapy given 
(1) Date of last adequate assessment 
(2) Date of secondary anti-cancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) N/A 
Censored 
Censored 
Event 
Ignored 
G 
Deaths due to reason other than 
deterioration of ‘Study indication’ 
(1) Date of last adequate assessment 
Censored 
(only TTP 
and duration 
of response) 
=Definitions can be found in Section 3.2.7. 
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 3.2.7. 
=The rare exception to this is if the patient dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death. 
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e. 
• (C1) taking the actual progression or death date, in the case of only one missing 
assessment. 


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• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as patients without 
documented PD should be followed for progression after discontinuation of treatment. 
However, option (2) may be used as sensitivity analysis. If progression is claimed based on 
clinical deterioration instead of tumor assessment by e.g. CT-scan, option (2) may be used for 
indications with high early progression rate or difficulties to assess the tumor due to clinical 
deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for 
potential bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for 
censoring and events only at scheduled visit dates. The latter could be handled by replacing in 
Table 3-2 the “Date of last adequate assessment” by the “Date of previous scheduled 
assessment (from baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on 
the individual requirements for the specific study and disease area and have to be specified in 
the protocol or RAP documentation. 
4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
4.1 
Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 


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The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
4.2 
End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee 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. 
The end of treatment visit and its associated assessments should occur within 7 days of the 
last study treatment.  
Patients may discontinue study treatment for any of the following reasons: 
• Adverse event(s) 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
4.3 
End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 


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• Subject/guardian decision 
• Death 
• New therapy for study indication 
• Progressive disease 
• Study terminated by the sponsor 
4.4 
Medical validation of programmed overall lesion response 
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) 
and not available evaluations (i.e. if any target or non-target lesion was not evaluated the 
whole overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on 
RECIST criteria. This may be queried for clarification. However, the investigator or central 
reader’s response assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly 
documented in the RAP documentation and agreed before database lock. This dataset should 
be created and stored as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
4.5 
Programming rules 
The following should be used for programming of efficacy results: 
4.5.1 Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
4.5.2 Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 3.2.7). If all measurement dates have no 
day recorded, the 1st of the month is used. 


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If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
4.5.3 Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
4.5.4 Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
4.5.5 Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
4.5.6 Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
• Ongoing without event 
• Lost to follow-up 
• Withdrew consent 
• Adequate assessment no longer available* 
• Event documented after two or more missing tumor assessments (optional, see Table 3-2) 
• Death due to reason other than underlying cancer (only used for TTP and duration of 
response) 
• Initiation of new anti-cancer therapy  
*Adequate assessment is defined in Section 3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted: 


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• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment. 
• This reason will also be used to censor in case of no baseline assessment. 
5 
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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14.7 
Appendix 7: Patient Self-Reported Mood Questionnaires  
Table 14-5 
PHQ-9 Depression Scale 
Over the last 2 weeks, how often have you been 
bothered by any of the following problems? 
(Use “✔” to indicate your answer”) 
Not at 
all 
 
Several 
days 
 
More 
than 
half the 
days 
 
Nearly 
every 
day 
1. Little interest or pleasure in doing things 
0 
 
1 
 
2 
 
3 
2. Feeling down, depressed, or hopeless. 
0 
 
1 
 
2 
 
3 
3. Trouble falling or staying asleep, or sleeping 
too much 
0 
 
1 
 
2 
 
3 
4. Feeling tired or having little energy. 
0 
 
1 
 
2 
 
3 
5. Poor appetite or overeating 
0 
 
1 
 
2 
 
3 
6. Feeling bad about yourself - or that you are a 
failure or have let yourself or your family down 
0 
 
1 
 
2 
 
3 
7. Trouble concentrating on things, such as 
reading the newspaper or watching television. 
0 
 
1 
 
2 
 
3 
8. Moving or speaking so slowly that other 
people could have noticed? Or the opposite - 
being so fidgety or restless that you have been 
moving around a lot more than usual 
0 
 
1 
 
2 
 
3 
9. Thoughts that you would be better off dead or 
of hurting yourself in some way 
0 
 
1 
 
2 
 
3 
For Office Coding 
__0__ 
+ 
_____ 
+ 
_____ 
+ 
_____ 
 
= Total Score: _____ 
If you checked off any problems, how difficult have these problems made it for you to do your work, 
take care of things at home, or get along with other people? 
Not difficult 
at all 
Somewhat 
difficult 
Very 
difficult 
Extremely 
difficult 
Note:  The questionnaire provided here is a sample for information purposes only.  Paper 
questionnaires for patient completion in the study will be provided by Novartis to be used as 
source documents. 


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Table 14-6 
GAD-7 Anxiety Scale 
Over the last 2 weeks, how often have you been 
bothered by the following problems? 
(Use “✔” to indicate your answer”) 
Not at 
all 
 
Several 
days 
 
More 
than 
half 
the 
days 
 
Nearly 
every 
day 
1. Feeling nervous, anxious or on edge 
0 
 
1 
 
2 
 
3 
2. Not being able to stop or control worrying 
0 
 
1 
 
2 
 
3 
3. Worrying too much about different things 
0 
 
1 
 
2 
 
3 
4. Trouble relaxing 
0 
 
1 
 
2 
 
3 
5. Being so restless that it is hard to sit still 
0 
 
1 
 
2 
 
3 
6. Becoming easily annoyed or irritable 
0 
 
1 
 
2 
 
3 
7. Feeling afraid as if something awful might 
happen 
0 
 
1 
 
2 
 
3 
(For office coding: Total Score T 
_____ 
= 
_____ 
+ 
_____ 
+ 
_____) 
Note:  The questionnaire provided here is a sample for information purposes only.  Paper 
questionnaires for patient completion in the study will be provided by Novartis to be used as 
source documents. 
14.7.1 
Scoring the PHQ-9 and GAD-7 
14.7.1.1 Calculating the Total Score for the PHQ-9 
Total scores from the PHQ-9 will be calculated to assess depression severity according to the 
developer’s guidelines [Instruction Manual: Instructions for Patient Health Questionnaire 
(PHQ) and GAD-7 Measures.  Accessed on 2010 Sept 9 from:.phqscreeners.com].  This is 
calculated by assigning scores of 0, 1, 2, and 3, to the response categories of “not at all,” 
“several days,” “more than half the days,” and “nearly every day,” respectively.  PHQ-9 total 
score for the nine items ranges from 0 to 27. 
PHQ-9 Scoring Example: 
In the example below, the Total Score for the PHQ-9 depression severity is 8, where the score 
is the sum of four items scored “0” (questions: #3, 7, 8, 9), three items scored “1” (questions: 
#1, 4, 6), one item scored “2” (question: #2), and one item scored “3” (question: #5). 


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14.7.1.2 Calculating the Total Score for the GAD-7 
Similar to the PHQ-9, scores for the GAD-7 will calculated to assess anxiety severity 
according to the developer’s guidelines [1].  This is calculated by assigning scores of 0, 1, 2, 
and 3, to the response categories of “not at all,” “several days,” “more than half the days,” and 
“nearly every day,” respectively.  A total score for the GAD-7 can range from 0 to 21. 


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GAD-7 Scoring Example: 
In the example below, the Total Score for the GAD-7 anxiety severity is 9, where the score is 
the sum of two items scored “0” (questions: #6, 7), two items scored “1” (questions: #2, 3), 
two items scored “2” (questions: #1, 5), and one item scored “3” (question: 
#4).
Column totals:
0
2
4
3
+
+
+
GAD-7 TOTAL SCORE:
9
 


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14.8 
Appendix 8: Health Related Quality of Life Questionnaires 
Figure 14-1 
EORTC QLQ-C30 (version 3) 
 
Note:  The questionnaire provided here is a sample for information purposes only.  Paper 
questionnaires for patient completion in the study will be provided by Novartis to be used as source 
documents 


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Note:  The questionnaire provided here is a sample for information purposes only.  Paper 
questionnaires for patient completion in the study will be provided by Novartis to be used as source 
documents 


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Figure 14-2 
EORTC QLQ-HN35 (version 1.0) 
 
Note:  The questionnaire provided here is a sample for information purposes only.  Paper 
questionnaires for patient completion in the study will be provided by Novartis to be used as source 
documents 


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Note:  The questionnaire provided here is a sample for information purposes only.  Paper 
questionnaires for patient completion in the study will be provided by Novartis to be used as source 
documents 


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14.9 
Appendix 9 
The study is designed based on a double criteria for Proof of Concept that is defined for 
Primary endpoint (PFS) and Key Secondary endpoint (OS).   
14.9.1.1 Primary Endpoint – Progression Free Survival  
The Proof of Concept criteria are: 
1. Estimate of HR is ≤ 0.67. 
2. The posterior probability that HR is < 1 is at least 97.5%. 
14.9.1.2 Key Secondary Endpoint – Overall Survival  
The Proof of Concept criteria are: 
1. Estimate of HR is ≤ 0.77. 
2. The posterior probability that HR is < 1 is at least 90%. 
It must be noted here that the threshold for HR in the double criteria setup is not the same as 
the classical alternative as would be used in a  hypothesis testing with a given Type 1 Error 
(2.5%) and power (90%) in a standard design. For example if 90% power were needed for the 
alternative log-HR = log(0.67), the critical value for the estimated log(HR) would be 
approximately log(0.80), which for our study is not of clinical interest. The threshold denoted 
in the Criteria 1 for each of the endpoints represents the indifference point for the 
improvement in the endpoint above which there would be reasonable clinical interest in the 
treatment.  
For a standard design with effect size δ the critical value for statistical significance is defined 
as where α and β are the Type 1 and Type 2 Error respectively.   
14.9.1.3 Posterior Distribution of HR 
Let θ2 denote the natural logarithm of the hazard ratio (HR). Assume θ2 follows a normal prior 
distribution: 
 
[θ2] ~ N (m0, 4/n0) 
where m0 is the assumed prior mean and n0 is the number of events worth of prior 
information. 
Let y2 denote the log(HR) observed in the current study based on n2 observed events, with 
likelihood function 
 
[Y2 | θ2] ~ N (θ2, 4/n2). 
The posterior distribution is therefore given by 
[θ2 | y2] ~ N (y2 + (1 – )m0, 4/(n0 + n2)), where  = n2 /(n0 + n2). 
For no prior information (uninformative prior distribution for θ2), this simplifies to 
 
[θ2 | y2] ~ N (y2, 4 / n2) 
(1). 


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Due to the computational complexity arising out of multiple criteria, the variation in the 
enrollment rate and censoring, no analytic formula is used to derive the sample size. 
Simulations, described in detail in Section 14.9.1.5, were used to determine sample size, 
number of events and operating characteristics. 
14.9.1.4 Joint distribution of PFS and OS 
Even though there is uncertainty on how good is PFS is a surrogate of OS, one cannot 
necessarily assume them to be independent because any death event of a subject is counted 
both as a PFS and OS event. Time to PFS event is defined as the minimum of the time to 
progression (TTP) and time to death(OS). If TTP and OS are assumed to be independent, then  
P(PFS ≥ x) = P(TTP ≥ x). P(OS ≥ x)              (2) 
In this study we assume that both TTP and OS are exponentially distributed with hazard rates 
λTTP and λOS. Therefore based on Equation (2) PFS should follow an exponential distribution 
with hazard rate as λTTP + λOS.  
The clinical assumptions for PoC are given in terms of improvement in terms of median PFS 
and median OS. However in order to do the simulation for evaluating the operating 
characteristics of the design one needs to generate the PFS data based on the OS and TTP 
data. In order to the following transformations are used  
λOS = log(2)/mOS ; λPFS = log(2)/mPFS      (3.1) 
λTTP  = λPFS - λOS                                                  (3.2) 
For each scenario described in the simulations in section the trial data is generated using a 
given mTTP and mOS such that the mPFS and mOS are what the clinical assumptions 
require.  
14.9.1.5 Scenarios 
Following scenarios were considered for the evaluation of the design in terms of the 
probability of meeting the Proof of Concept criteria  
Median PFS (months) 
placebo+paclitaxel buparlisib + paclitaxel 
3 
3 3.5 
4 4.5 
5 5.5 
6 
 
Median OS (months) 
placebo+paclitaxel buparlisib + paclitaxel 
7 
7 7.5 8 8.5 9 9.5 10 
14.9.1.6 Data Simulation 
1. For each patient, we randomly assigned treatment group based on randomization ratio  
2. Without loss of generality, we assumed the order of patients was their enrollment order. 
For example, if the enrollment rate was 10 patients per month, then we assumed the first 


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Amended Protocol Version 03 Clean 
 
Protocol No. CBKM120H2201 
 
10 simulated patients were enrolled in the 1st month, and the next 10 patients were 
enrolled in the 2nd month. The date of enrollment within that month was randomly 
determined using a uniform distribution U(0,30), assuming each month has 30 days.  
3. Study cutoff date was assumed to be the date when a pre-specified number of events had 
occurred. For example, if it were pre-specified that 125 events were needed and the 125th 
event happened on Study Day 200, then the study would end after 200 days. In this study 
we have two cutoff dates - one for PFS analysis and second for OS analysis. 
4. Each patient's TTP and OS event time was simulated from one of the two different 
exponential distributions: control group, treatment group, depending on the patient's 
randomization. The PFS event time was derived as the minimum of the TTP and OS event 
times.  
5. In addition the patient drop out event was simulated based on hazard for dropout 
(λDropout) . Different dropout rates were considered for OS and PFS. Any patient whose 
dropout event occurred before the event time was considered to be censored due to 
dropout. Of those patients who were not censored due to dropouts a study cutoff date was 
derived as described in Step 3.   If the event time plus enrollment date was longer than 
study cutoff date, then the event time was censored; otherwise, it was observed. In other 
words, if a patient did not have event before the study end date, then the event time of this 
patient was censored; otherwise, the event time was observed. 
14.9.1.7 Data Analysis 
1) An R function coxph() from the package survival was applied to each simulated trial 
dataset, first using all the observations  to estimate the point estimate and standard error 
of the HR for PFS and OS.  
2) Number of trials were counted that met the PoC criteria for PFS and the PoC criteria for 
OS. 
3) A non-informative prior (n0=0) was used to derive the posterior distribution of θ 
14.9.1.8 Results Summary  
The simulation results were summarized in terms of the probabilities of PoC for PFS in Table 
10-1 and PoC for OS in Table 10-2 in Section 10.  

SAP_000.pdf: 
Clinical Development
BKM120 (Buparlisib)
Study Number: CBKM120H2201 / NCT01852292
Phase II multicenter randomized, double blind, placebo controlled 
study assessing the efficacy of buparlisib (BKM120) plus paclitaxel 
vs. placebo plus paclitaxel in patients with platinum pre-treated 
recurrent or metastatic head and neck squamous cell carcinoma
RAP Module 3 – Detailed Statistical Methodology
Amendment 2
Author:
Document type:
RAP Documentation
Document status:
Final v3.0
Release date:
22 Apr 2016
Number of pages:
55
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 RAP module 3.
Version
Date
Changes
0.1
09-12-2013
Initial version for RAP meeting I
1.0
09-01-2014
Final version 
2.0
15-Sep-15
Sec 2.1,2.2,2.5
Alignment with MAP
- Definition of Baseline, Last contact date, Screened Patients, aligned with 
current standard
- Handling of data analyses in case of withdrawal of consent aligned with 
current standard 
- Pharmacokinetics analysis set and Full Pharmacokinetic analysis set 
added due to addition of PK in protocol amendment 1
- Per protocol set definition updated to exclude patients who were 
randomized but not treated.
- PK analyses added based on protocol amendment 1
- BOR-unknown reason SD too early clarified as per current standard
-Determination of missing adequate Tumor assessments – definition of D1 
modified to 31 days.
- Included summarizing of Unknown/Missing Tumor assessments  by 
treatment groups. 
Sec 3.5
-It is clarified that HPV status will be derived using central lab data and 
historical HPV status will be listed.  
-Sec 3.5.7 : Added an additional summary of prior antineoplastic by 
number of lines in Recurrent/Metastatic setting. Drugs being classified as 
EGFR inhibitors are mentioned in M8. 
Sec 3.6 
- Added a dose window for Paclitaxel to take into account the variation of 
total dose due to BSA changes
- Updated cumulative dose calculations for BKM intermittemt dosing 
based on current program standards
- Updated dose interruptions / reductions based on current program 
standards
Sec 3.8.
-As per protocol amendment 2, it is mentioned that primary analysis will be 
done after approximately 120 PFS events are documented. Final Analysis 
will be done after approximately 112 Deaths are observed.
Sec 3.8.1.2 
-Updated the methodology for median time to censoring (Schemper, M ; 
Smith, TL , 1996)
Sec 3.8.1.3 
-Sensitivity analyses added to repeat primary analysis based on 
stratification variables derived from eCRF in addition to the primary 
analysis based on IRT strata.


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Version
Date
Changes
Sec 3.8.2.4 
-Analysis time windows for EORTC PRO questionnaire added to take into 
account the unscheduled assessments. 
-Repeated measures mixed effect model removed only Time to 
deterioration analyses retained 
-Censoring definitions of time to deteriorations aligned with program 
standards. 
Sec 3.8.3 
-Gap Analysis - Gap time only calculated from time to censoring to 
analysis cutoff date 
Sec 3.9.1.4
-Reporting of AEs updated to align with current standards.
Sec 3.9.4 
- Reporting of deaths updated to reflect the new death reporting standards, 
-Added - most frequent SAE, suspected of study treatment relationship by 
primary SOC and PT.
Sec 3.9.2 
-Updated the definition of baseline for labs for duplicate assessments for 
CTC gradable and non-CTC gradable labs
-Liver enzyme elevation summary updated to align with the current 
program standards.
Sec 3.9.4
-Updated clinical notable criteria in vital signs for weight
Sec 3.9.5 
-ECOG - analysis window added to take into account the unscheduled 
assessments 
Analysis for Time to definitive deterioration of ECOG PS added. 
Sec 3.10 Subgroup Analyses
-Only median PFS with Kaplan Meier estimates will be presented. No 
forest-plots will be provided.
Sec 3.11
-Non Compartmental analysis for for PK parameter based on full PK 
sampling added. 
- Population PK analysis based on Sparse PK samples added 
- Exposure - response analysis for PFS based on Trough PK sampling 
added.


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Version
Date
Changes
Sec 3.12
- Archival tumor based Pi3K activation definition revised and now based 
only on PIK3CA mutation and PTEN loss of expression
V 3.0
This Amendment is necessitated to detail the planned analyses for 
final OS analyses. There is no change proposed to the analyses 
plan and outputs from the RAP version dated: 21Oct2015 detailed 
for the Primary CSR. In addition, sensitivity analyses of 
PFS/ORR/DoR based onCentral radiology assessments will be 
summarized based on data cut-off date:31Aug2015 used for final 
PFS analyses reporting effort. DoR will also be summarized based 
on data cutoff for OS analysis to include additional information.
 
The 
following additional analyses have been added for
Efficacy:
-
PFS summary and HR as per central radiology assessment to 
be included.
-
Comparison of PFS events type and timing of PFS events
between local investigator assessment and central radiology 
assessment 
-
Comparison of Best Overall response between local 
investigator’s assessment and central radiology assessment 
-
Additional analyses for Duration of Overall response and Time 
to Overall response based on Kaplan Meier method is included.
PK
Section 3.11.2 (population PK Analysis) and 3.11.3 (Exposure 
response Analyses) are deleted because of limited data.
Table of contents
Table of contents .................................................................................................................4
1
Introduction .........................................................................................................................9
2
Definitions and general methodology .................................................................................9
2.1
Definitions ...............................................................................................................9
2.1.1
Study drug and study treatment...............................................................9
2.1.2
Date of first administration of study drug...............................................9
2.1.3
Date of last administration of study drug................................................9
2.1.4
Date of first administration of study treatment .....................................10
2.1.5
Date of last administration of study treatment ......................................10


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2.1.6
Last date of exposure to study drug/treatment ......................................10
2.1.7
Study day...............................................................................................10
2.1.8
Baseline.................................................................................................11
2.1.9
On-treatment assessment/event.............................................................11
2.1.10
Last contact date....................................................................................12
2.1.11
Screening failure ...................................................................................12
2.1.12
Time Units.............................................................................................12
2.1.13
Time/Assessment windows...................................................................13
2.1.14
Data included in the analyses................................................................13
2.1
Definitions of analysis sets ....................................................................................13
2.1.1
Screened patients...................................................................................13
2.1.2
Full analysis set.....................................................................................13
2.1.3
Safety set ...............................................................................................13
2.1.4
Per-protocol set .....................................................................................14
2.1.5
Pharmacokinetic analysis set (PAS)......................................................14
2.1.6
Full Sampling Pharmacokinetic analysis set (FPAS)............................14
2.2
Protocol Deviations ...............................................................................................15
2.3
Concomitant medications with specific impact on the analysis...........................15
2.4
Implementation of RECIST...................................................................................15
2.4.1
Disease Progression ..............................................................................15
2.4.2
Best Overall Response (BOR) ..............................................................15
2.4.3
Change in imaging modality.................................................................16
2.4.4
Determination of missing adequate tumor assessments........................16
2.4.5
No Baseline tumor assessments ............................................................17
3
Subject disposition, background and demographic characteristics ...................................18
3.1
Enrollment status ...................................................................................................18
3.2
Subject disposition.................................................................................................18
3.3
Protocol deviations ................................................................................................19
3.4
Analysis sets ..........................................................................................................19
3.5
Background and demographic characteristics .......................................................19
3.5.1
Basic demographic and background data..............................................19
3.5.2
HPV Status............................................................................................19
3.5.3
PI3K pathway activation.......................................................................19
3.5.4
Randomization stratification.................................................................20
3.5.5
Diagnosis and extent of cancer .............................................................20
3.5.6
Medical History.....................................................................................20


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3.5.7
Anti-neoplastic therapy .........................................................................20
3.6
Study treatment......................................................................................................21
3.6.1
Duration of exposure to study drug/treatment ......................................21
3.6.2
Cumulative dose....................................................................................22
3.6.3
Dose intensity and relative dose intensity.............................................23
3.6.4
Dose reduction, interruption and permanent discontinuation ...............24
3.7
Prior and Concomitant therapy..............................................................................26
3.8
Efficacy evaluation ................................................................................................27
3.8.1
Primary efficacy endpoints ...................................................................27
3.8.2
Secondary efficacy endpoints ...............................................................31
3.8.3
Follow-up of the study ..........................................................................37
3.9
Safety evaluation ...................................................................................................37
3.9.1
Adverse events data...............................................................................38
3.9.2
Laboratory data .....................................................................................41
3.9.3
Patient self-reported Mood assessments ...............................................43
3.9.4
Vital signs..............................................................................................44
3.9.5
Performance Status................................................................................45
3.9.6
Cardiac assessments..............................................................................47
3.10
Subgroup analyses .................................................................................................48
3.10.1
Efficacy .................................................................................................48
3.11
Pharmacokinetic Analysis .....................................................................................49
3.11.1
Non compartmental analysis.................................................................49
3.12
Biomarkers.............................................................................................................50
3.13
Interim safety review analyses...............................................................................52
4
General statistical methodology ........................................................................................52
4.1
Baseline comparability ..........................................................................................52
4.2
Center pooling .......................................................................................................52
4.3
One-sided vs. two-sided test..................................................................................53
4.4
Time-to-event analyses..........................................................................................53
4.4.1
Analysis of time-to-event data with ties................................................53
4.4.2
Kaplan-Meier estimates ........................................................................53
4.4.3
Hazard ratio...........................................................................................53
4.5
Bayesian methodology for the PFS and OS analyses............................................54
4.6
Confidence intervals for response rate and disease control rate............................54
5
References .........................................................................................................................54


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List of abbreviations
AE
adverse event
ATC
Anatomical Therapeutic Chemical
BOR
best overall response
BSA
body surface area
CBR
clinical benefit rate
CI
Confidence Interval
CR
complete response
CRS
case retrieval strategy 
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTC 
Common Terminology Criteria  
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DAR
dosage administration record
DI
dose intensity
DMC
Data Monitoring Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report/record form
EOT
end of treatment
FAS
full analysis set
FPAS
full sampling pharmacokinetic analysis set
GAD
generalized anxiety disorder assessment
GPS
global programming & statistical environment
HLGT
High level group term
HR
Hazard ratio
IRT
interactive response technology
MedDRA
Medical Dictionary for Regulatory Activities
MRI 
magnetic resonance imaging
NCRNPD
Non-CR/Non-PD
NMQ
Novartis MedDRA queries
ORR 
overall response rate 
OS
overall survival 
PAS
pharmacokinetic analysis set
PD
progressive disease
PD
protocol deviation
PD
pharmacodynamic
PDI
planned dose intensity
PFS
progression-free survival
PHQ
patient health questionnaire
PK
pharmacokinetic
PoC
proof of concept
PR
partial response


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PT
preferred term
RAP
report and analysis plan
RDI
relative dose intensity
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
serious adverse event
SD
stable disease
sd
standard deviation
SEC
safety event categories
SMQ
standardized MedDRA queries
SOC
system organ class
SSD
Study specifications document
SPP
Safety Profiling Plan
TA
tumor assessment
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
UNK
unknown
WHO
World Health Organization 


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1
Introduction
This document describes the detailed statistical methodology of the Reporting and Analysis Plan (RAP) 
of study CBKM120H2201: A Phase II multicenter randomized, double blind, placebo controlled study 
assessing the efficacy of buparlisib (BKM120) plus paclitaxel vs. placebo plus paclitaxel in patients 
with platinum pre-treated recurrent or metastatic head and neck squamous cell carcinoma.
This RAP Amendment 2 (v3.0) details planned analyses for final OS analysis reporting effort 
corresponding to protocol version dated: 2nd July 2015. There is no change proposed to the analysis 
plan, methodology and outputs detailed in RAP Amendment 1(v 2.0) for primary CSR. 
In addition, sensitivity analyses of PFS,ORR, and DoR based on central radiology assessments will be 
summarized based on the data cut-off date used for the final PFS analysis reporting effort. 
The data will be analyzed by Novartis and/or a designated CRO. It is planned that the data from all 
centers that participate in this study will be used.
2
Definitions and general methodology
2.1
Definitions
2.1.1
Study drug and study treatment
Study drug refers to BKM120/BKM120-matching placebo and paclitaxel with which the patient is 
treated during the study. Study drugs may also be referred to as components of study treatment.
Study treatment refers to BKM120 in combination with paclitaxel or BKM120-matching placebo in 
combination with paclitaxel.
BKM120-matching placebo will be referred to as “placebo” in the remainder of this document.
2.1.2
Date of first administration of study drug 
The date of first administration of study drug is derived as the first date when a non-zero dose of study 
drug (BKM120/placebo or paclitaxel) is administered. For the sake of simplicity, the date of first 
administration of study drug is referred to as start date of study drug. Start date of study drug is 
defined for each drug which is part of study treatment.
The date of first administration for BKM120/placebo or paclitaxel is recorded on the corresponding 
“dosage administration record” (DAR) eCRF page.
2.1.3
Date of last administration of study drug 
The date of last administration of study drug is defined as the last date when a non -zero dose of study 
drug is administered. This date will also be referred to as last date of study drug. Last date of study 
drug is defined for each drug which is part of study treatment.
The date of last administration for BKM120/placebo or paclitaxel is recorded on the corresponding 
“DAR” eCRF page.
Note 1: Last date of study drug exposure may not be the same as the last date of study drug (see 
Section 2.1.6). 


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2.1.4
Date of first administration of study treatment  
The date of first administration of study treatment is derived as the first date when a non-zero dose of 
any component of the study treatment (BKM120/placebo or paclitaxel) is administered. For the sake of 
simplicity, the date of first administration of study treatment will also be referred to as start date of 
study treatment. 
For example: if the 1st dose of BKM120/placebo is taken on 05JAN2011, and 1st dose of paclitaxel, is 
taken on 03JAN2011, then the date of first administration of study treatment is 03JAN2011.
2.1.5
Date of last administration of study treatment
The date of last administration of study treatment is defined as the last date when a non-zero dose of 
any component of the study treatment (BKM120/placebo or paclitaxel) is administered. For the sake of 
simplicity, the date of last administration of study treatment will also be referred as last date of study 
treatment. 
For example: if the last dose of BKM120/placebo is taken on 15APR2011, and the last dose of 
paclitaxel is taken on 17MAY2011, then the date of last administration of study treatment is on 
17MAY2011.
2.1.6
Last date of exposure to study drug/treatment
The study schedule is organized in cycles of 28 days.
BKM120/placebo is administered daily on a continuous once daily dosing schedule; paclitaxel is 
administered weekly on D1, D8, D15 and D22 of each cycle.
The last date of exposure to BKM120/placebo is the date of last administration of BKM120/placebo. 
The last date of exposure to paclitaxel is calculated as follows: 

Paclitaxel is administered over several regular weekly doses (every 7 days). The last date of 
exposure is calculated according to the planned dose schedule of the cycle. 

The last date of exposure to paclitaxel is calculated as: (last date of administration of paclitaxel) + 
(length of time interval - 1) i.e. [last date of paclitaxel + (7-1)]. 
If the patient died or was lost to follow-up within last date of administration of paclitaxel + 6 days, 
the last date of exposure to paclitaxel is the date of death or the date of last contact, respectively. 
‘Date of last administration of study drug’ and ‘Date of last contact’ are defined in Sections 2.1.3 and 
10.
The last date of exposure to study treatment is derived to be the later of the last dates of exposure to 
BKM120/placebo and paclitaxel.
2.1.7
Study day
The study day describes the day of the event or assessment date, relative to the reference start date 
(randomization date or start date of study treatment). The study day will be displayed in the data 
listings. It is not to be used for numerical computations for example calculating exposure.
The reference start date is designated as Study Day 1. Study Day –1 is the day that precedes Day 1. 
Study Day 0 is not defined. 
The study day will be calculated as:


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The date of the event (visit date, onset date of an event, assessment date etc.) minus reference 
start date + 1 if the event is on or after the reference start date. 
The date of the event (visit date, onset date of an event, assessment date etc.) minus reference 
start date if the event precedes the reference start date.
The reference start date 

for all safety assessments (e.g. adverse event onset, laboratory abnormality occurrence, mood 
disorder assessment, vital sign measurement, dose interruption etc.) will be the start date of study 
treatment,

for all efficacy assessments (e.g. tumor assessment, death) will be the randomization date,

for any non-safety screening assessments or events such as baseline disease characteristics or 
medical history (e.g., time since diagnosis of disease) that occurred prior to randomization the 
reference start date will be the randomization date.
The study day will be displayed in the data listings.
2.1.8
Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient, defined 
as the period from the date of signing any informed consent document to the start date of study 
treatment or the date of randomization. Assessments, specified to be collected post-dose on the first 
date of treatment are not considered as baseline values.
For efficacy evaluations: the last non-missing assessment, including unscheduled assessments on or 
before the date of randomization is taken as “baseline” value or “baseline’ assessment. In the context 
of the definition of baseline, the efficacy evaluations also include PRO, biomarkers and ECOG 
performance status. 
For safety evaluations (i.e. laboratory, mood disorder assessment and vital signs): the last non-missing 
assessment, including unscheduled assessments on or before the date of start of study treatment is 
taken as “baseline” value or "baseline” assessment. 
For duplicate laboratory measurements taken at the last assessment date on or before the start date of 
study treatment, the value of lower CTC grade will be considered as the baseline value. 
For Mood questionnaires (PHQ-9 and GAD-7), if the questionnaire is fully completed at screening and 
partially completed at Cycle 1 Day 1, the questionnaire partially completed will be considered as the 
baseline and then the total score will be missing at baseline in the analyses. If the screening visit, 
Cycle 1 Day 1 and the treatment start day are identical, then the screening assessment will be 
considered as baseline.
If patients have no value as defined above, the baseline value will be missing.
2.1.9
On-treatment assessment/event
Safety summary tables and selected summaries of deaths will summarize only on-treatment 
assessments/events. 
An on-treatment adverse event is defined as any adverse event reported in the following time interval 
(including the lower and upper limits): 


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
date of first administration of study treatment; date of last administration of study treatment + 30 
days 
An on-treatment assessment is defined as any assessment performed after the date of first 
administration of study treatment i.e. assessments performed in the following time interval (including 
the lower and upper limits): 

date of first administration of study treatment + 1; date of last administration of study treatment + 
30 days  
Furthermore, assessments collected post-dose on the date of first administration of study treatment are 
on-treatment assessments. 
If the last date of study treatment is missing, on-treatment assessments/events include any 
assessment/event recorded in the database and which occur after the start date of study treatment.
Data listings will include all assessments/events, flagging those which are not on-treatment 
assessments/events.
Note: The date of first administration of study treatment and the date of last administration of study 
treatment are defined in Sections 2.1.4 and 2.1.5, respectively.
2.1.10
Last contact date
The last contact date is derived for patients not known to have died at the analysis cut -off date, and is 
based on the latest complete date among the following:


Actual assessment dates (Labs, vital signs, performance status, tumor imaging, EOT 
completion, PK sample collection dates).

Antineoplastic therapies administered after study drug discontinuation.

Adverse events dates

“Last known date patient alive” collected on the “Survival information” eCRF page.

Study treatment start/end date 
The last contact date is defined as the latest complete date from the above list or the cut -off date,
whichever comes first. 
The last contact date is used for censoring of patients in the analysis of overall survival.
2.1.11
Screening failure
Screening failures are patients who have signed informed consent and failed screening criteria in the 
study. These patients are not randomized.
Patients who are randomized, but never received study treatment are not screening failures. 
2.1.12
Time Units
A month length is 30.4375 days (365.25 / 12). If duration is to be reported in months, duration in days 
is divided by 30.4375. If duration is to be reported in years, duration in days will be divided by 365.25.


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2.1.13
Time/Assessment windows
In order to summarize over time, parameters recorded at each visit (i.e. PRO measures, performance 
status, PK, vital signs), assessments (including unscheduled ones) will be time-slotted. 
The way to deal with multiple assessments within a time window is specified for each assessment type 
in the relevant sections. 
Note: Do not have gap between time window. For assessments done at EoT those should be associated 
to the corresponding visit window.
2.1.14
Data included in the analyses
The final analyses and the periodic safety reviews by DMC will be performed using all data collected 
in the database up to the data cut-off date. A cut-off date will be defined for each of these analyses
and will be specified in the outputs.
Any data collected beyond the cut-off date for an analysis will not be included in the analysis. Only 
data with an assessment date or event start date (e.g. vital sign assessment date or start date of an 
adverse event) prior to or on the cut-off date will be included in the analysis. For example, if the cut-
off date is 15 June 2010 then an AE starting on 13 June 2010 will be reported, whereas an AE with 
start date on 17 June 2010 will not be reported.
All events with an event start date either before or on the cut-off date and an event end date after the 
cut-off date will be reported as “continuing at the cut-off date”. The same rule will be applied to events 
starting either before or on the cut-off date and not having a documented end date. This approach 
applies, in particular, to adverse event and concomitant medication reports. For these events, the end 
date will not be imputed and therefore will appear as missing in listings.
If it is required to impute an end date to be able to perform a specific analysis (e.g. end date after the 
cut-off date) the cut-off date needs to be imputed as an end date (to allow for calculation of treatment 
exposure duration and dose intensity for instance). The imputed date will be displayed and flagged in 
the listings. A detailed description for handling of missing data including imputation rules will 
provided in the RAP Module 8 .
2.1
Definitions of analysis sets
2.1.1
Screened patients 
Screened patients consists of all patients who signed informed consent and completed the Screening 
disposition eCRF page. 
2.1.2
Full analysis set
The Full analysis set (FAS) includes all patients who were randomized to study treatment.  According 
to the intent-to-treat principle, patients will be analyzed according to the treatment and strata they have 
been assigned during the randomization procedure. The FAS will be the main population for analyses 
of patient disposition, demographics and other baseline characteristics. The FAS will be the primary 
population for the efficacy analyses.
2.1.3
Safety set
The Safety set includes all patients who received at least one dose of study treatment (either paclitaxel
or BKM120/placebo) and had at least one post-baseline safety assessment. Patients will be analyzed 


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according to the study treatment they actually received, which is defined as the treatment the patient 
received on the first day of study treatment. 
A record of death or “no adverse event” constitutes a valid safety assessment.  
Data for patients with no post-baseline safety assessment will only be listed in the FAS. 
2.1.4
Per-protocol set
The Per-protocol set (PPS) consists of all patients in the FAS who do not have any protocol 
deviations (see Section 2.2) that could confound the interpretation of the primary analyses conducted 
on the FAS. Details regarding protocol deviation leading to exclusion from the PPS will be specified 
in the study specifications document (SSD). In addition to such protocol deviations additional patient 
classifications may be used exclude patients from PPS. Patients who are randomized but not treated 
will be excluded from the PPS.  
The PPS may be used to perform sensitivity analysis for the primary efficacy endpoint (i.e. PFS) if 
Proof of concept (PoC) for the primary endpoint of PFS is established (See Section 3.8.1.3.2). 
2.1.5
Pharmacokinetic analysis set (PAS)
The Pharmacokinetic Analysis Set (PAS) will include all patients who received at least one dose of 
study medication BKM120 and had at least one evaluable post-treatment concentration measurement.  
2.1.6
Full Sampling Pharmacokinetic analysis set (FPAS)
The Full Sampling Pharmacokinetic Analysis Set (FPAS) will include all patients in the PAS who :

received the planned dose of BKM120 i.e. 100 mg daily every day for the last consecutive 7 
days (including Cycle 1 Day 15) preceding full PK profile assessment on Cycle 1 Day 15 

did not vomit within 4 hours of BKM120 dosing after Cycle 1 Day 15 administration

had at least one dose of paclitaxel prior to the collection of the PK sample for the full PK 
profile 

had an evaluable full PK profile i.e. at least 7 PK samples (including pre-dose, 0.5h, 1h, 1.5h, 
and 24h post-dose) available on the day of full PK assessment Cycle 1 Day 15
Note : Patients in the FPAS will also be included in the PAS.
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all further 
participation in the trial, will not be included in the analysis data sets.  The date on which a patient 
withdraws full consent is recorded in the eCRF.
Note: Patients who withdraw consent from treatment but consent to post-treatment follow up and/or 
survival follow up are not considered as having withdrawn full consent and no such withdrawal of 
consent date is recorded in the eCRF. Such post-treatment assessments will be included in the analysis 
data sets.
Any data that is entered in the clinical database after the date of full consent withdrawal will be 
excluded from the analysis sets. Only exceptions are the information entered to close a page to reflect 
this event and happens after the date of withdrawal of consent e.g End of Treatment, End of Post 
treatment follow-up, DAR. Deaths happening after withdrawal of consent not confirmed by 
public registry will be excluded from PFS (if it is an event), OS and deaths in safety.


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Third party data e.g PK, biomarker etc, collected in the clinical database without having obtained 
consent for collection will not be included in the analysis data sets. Data from such samples if 
collected prior to the date of consent withdrawal will be included in the analysis unless specific request 
is made by the patient not to analyze the sample.   
2.2
Protocol Deviations
The protocol deviations leading to exclusion of a patient from the Per-protocol set (major protocol 
deviations) are defined in the SSD.CSR Reportable protocol deviations will be identified, summarized 
and listed.
2.3
Concomitant medications with specific impact on the analysis
Concomitant treatment of BKM120/placebo and weak inducers of CYP3A4 is permitted, during a 
period of time that should be as short as possible (e.g., less than 1 week). Co-administration of 
BKM120/placebo with strong CYP3A inducers or inhibitors is prohibited. 
Concomitant medications that are inducers or inhibitors of CYP3A4 or substrates of CYP450, non 
enzyme inducing ant-epileptic drugs, bisphosphonates and permitted QT prolonging drugs as defined 
in the Appendix 2 of the CSP will be identified and classified (review to be performed by a Clinical 
Pharmacologist) and then tabulated and/or listed in the Clinical Study Report as appropriate.
2.4
Implementation of RECIST
Response and progression evaluation will be performed according to the RECIST 1.1 (as described in 
detail in Appendix 6 of the CSP). The text below gives more detailed instructions and rules to provide 
further details needed for programming.
2.4.1
Disease Progression
Only objective progressive disease (PD) per RECIST 1.1 i.e. PD identified using objective tumor 
assessment method (e.g. CT scan/MRI, photos for skin lesions, etc.) is considered.
In particular, discontinuation due to PD (from the “End of Treatment Phase Completion” eCRF 
page), without supporting objective evidence (as defined above), will not be considered as PD in the 
determination of best overall response(BOR) and in the analysis of progression-free survival(PFS). 
2.4.2
Best Overall Response (BOR)
The evaluation of BOR will be assessed by RECIST1.1 criteria. The derivation of Best Overall 
Response in this study will be based on confirmed CR, PR or SD. The definitions and the details on 
the derivation are given in Appendix 6 of the CSP. 
Only tumor assessments performed before the start of any further anti-neoplastic therapies (i.e. any 
additional secondary anti-neoplastic therapy with the exception of control drug monotherapy) will be 
considered in the assessment of BOR.
Further, anti-neoplastic therapies will be identified from the data collected on ‘antineoplastic therapy 
since discontinuation of study treatment – medication’ , ‘antineoplastic therapy – radiotherapy’ 
and‘antineoplastic therapy - surgery’. 


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Continuation of control drug monotherapy as 1st new anti-neoplastic therapy after end of treatment 
without prior PD and collected in the ‘antineoplastic therapy since discontinuation of study treatment-
Medication’ eCRF page, will not be considered as an anti-neoplastic therapy for the assessment of 
BOR and for PFS analyses.
Since the tumor assessments are performed 4 weeks after randomization and thereafter every 6 weeks, 
the standard definition of a best overall response evaluation of “stable disease”, “progressive disease” 
or “unknown” given in the Appendix 6 of the CSP requires an adjustment. 
Best overall response for each patient is determined from the sequence of overall (lesion) responses 
according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression

PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not 
qualifying for a CR)

SD = at least one SD assessment (or better) ≥25 days after randomization date (and not 
qualifying for CR or PR).

PD = progression ≤ 77 days after randomization date (and not qualifying for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after more than  
25 days or early progression within the first 77 days)
Patients with BOR ‘unknown’ will be summarized by reason for having unknown status. The 
following reasons will be used:

No valid post-baseline assessment 

All post-baseline assessments have overall response UNK

New anti-neoplastic therapy started before first post-baseline assessment

SD too early (< 25 days after randomization and not qualifying SD, CR or PR in any following 
assessment)

PD too late (for example, > 77 days after randomization and not qualifying for CR, PR and SD)
2.4.3
Change in imaging modality
Per RECIST 1.1, a change in methodology can be defined as either a change in contrast use (e.g. 
keeping the same technique, like CT, but switching from with to without contrast use or vice -versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to MRI, or vice-
versa), or a change in any other imaging modality. A change in methodology will result by default in 
an UNK (unknown) overall lesion response assessment as per Novartis calculated response. However, 
another response assessment other than the Novartis calculated UNK response may be accepted from 
the investigator or the central reviewer if a definitive response assessment can be justified based on the 
available information.
Potential discrepancies between the modality used and overall lesion response (e.g. change in modality 
but response is different from ‘Unknown’) will be queried during the data validation process. 
2.4.4
Determination of missing adequate tumor assessments
The term ‘missing adequate tumor assessment’ is defined as a tumor assessment (TA) not done or 
tumor assessment with overall lesion response ‘Unknown’. For the sake of simplicity, a ‘missing 
adequate tumor assessment’ will also be referred to as a ‘missing assessment’. 


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As described in Table 3-2 in Section 3.2.9 of RECIST1.1 Novartis guidelines, the PFS censoring and 
event date options depend on the presence and the number of missing tumor assessments. For example, 
in the primary analysis of PFS, an event occurring after two or more missing assessments is censored 
at the last adequate tumor assessment.
An exact rule based on two thresholds D1 and D2 is used to determine whether there is no, 
one or two missing TAs between the last adequate tumor assessment and a PFS event. This 
rule is based on the interval between the last adequate tumor assessment date and the event 
date. 
If the interval is greater than threshold D2, then the number of missing assessments is 2 or more. If the 
interval is greater than D1 and less than or equal to D2 then the number of missing assessments is 1. If 
the interval is less than D1 then there is no missing assessment 
In this study tumor assessments are not being done at equal time intervals or with equal time windows. 
The first scheduled tumor assessment is 4 weeks after randomization with an allowed time window of 
± 3 days. Subsequent tumor assessments are scheduled after every 6 weeks with an allowed time 
window of ± 4 days. Therefore the thresholds D1 and D2 are defined for two scenarios of last adequate 
tumor assessment date. 
Scenario 1 – Baseline tumor assessment is the last adequate tumor assessment 

The threshold D1 is defined as the protocol-specified interval between the first TA and date of 
randomization plus the protocol-allowed time window around the first TA. Therefore D1= 31 days 
(4 weeks*7 + 3 days) 

The threshold D2 is defined as the protocol-specified interval between the first TA and the date of 
randomization and the interval between the first TA and the second TA plus the sum of protocol-
allowed time windows around the first and second TAs. Therefore D2 = 77 days (10weeks*7 + 3
days + 4 days)
Scenario 2 – There is at least one post baseline adequate tumor assessment 

The threshold D1 is defined as the protocol-specified interval between the TAs subsequent to the 
first 1st TA plus twice the protocol-allowed time window around the assessments. Therefore D1 = 
46 days (6 weeks*7 + 4 days)

The threshold D2 is defined as twice the protocol-specified interval between the TAs subsequent 
to the first 1st TA plus twice the protocol-allowed time window around the assessments. Therefore 
D2 = 92 days (12 weeks*7 + 4 days*2)
Therefore, using the D2 definition above, the censoring of an event occurring after ≥ 2 missing TAs 
(in primary PFS analysis in Section 3.8.1.2) can be refined as follows: if the distance between the last 
adequate TA date and the PFS event date is larger than D2 then the patient will be censored and the 
censoring reason will be 'Event documented after two or more missing tumor assessments'.
Number of patients with one or more than one missing/unknown tumour assessments will be 
summarized by treatment groups. Also number of patients with one or more than one 
missing/unknown assessments between last adequate tumour assessment(as per RECIST 1.1) and PFS 
event/cut-off will also be summarized by treatment group. 
2.4.5
No Baseline tumor assessments
As specified in [Table 3-2 in Section 3.2.9 of the Appendix 6 of the CSP], since the timing of disease 
progression cannot be determined for patients with missing Baseline tumor assessment, these patients 


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are censored in the PFS analysis at the date of randomization. This rule, only applies to the 
‘progressive disease’ component of the PFS assessment.
Patients without any Baseline tumor assessment who die within D2 (77 days) (Section 2.4.4) from date 
of randomization will be counted as having an event in the primary analysis of PFS. All deaths will be 
counted in the overall survival analysis regardless of presence or absence of the baseline tumor 
assessment.
3
Subject disposition, background and demographic 
characteristics
3.1
Enrollment status 
The number (%) of patients screened and randomized will be summarized by country and center, 
overall and by treatment. 
3.2
Subject disposition
The number (%) of randomized patients included in the FAS will be presented overall and by 
treatment group. The number (%) of screened (not-randomized ) patients and the reasons for 
not completing screening phase will also be displayed in a table. 
The number (%) of patients in the FAS who are still on treatment, who discontinued the study 
phases (treatment and post-treatment follow-up) and the reason for discontinuation will be 
presented overall and by treatment group.
The following summaries will be provided (% based on the total number of FAS patients):

Number (%) of patients who were randomized (based on IRT‘)

Number (%) of patients who were randomized but not treated (based on ‘DAR’ eCRF page 
not completed)

Primary reason for not being treated (based on “End of Treatment Phase Completion” eCRF 
page) 

Number (%) of patients who were treated (based on ‘DAR BKM120/placebo’ and ‘DAR 
paclitaxel’ eCRF pages completed with non-zero dose administered)

Number (%) of patients who are still on-treatment (based on the ‘End of Treatment Phase 
Completion’ eCRF page not completed) 

Number (%) of patients who discontinued the study treatment phase (based on the ‘End of 
Treatment Phase Completion’ eCRF page completed) 

Primary reason for study treatment phase discontinuation (based on the ‘End of Treatment 
Phase Completion’ eCRF page completed)

Number (%) of patients who have entered the post-treatment follow-up (based on the ‘End of 
Treatment Phase Completion’ eCRF page completed)

Number (%) of patients who have discontinued from the post-treatment follow-up (based on 
the ‘End of post-treatment follow-up Phase’ eCRF page completed)

Primary reason for discontinuation from the post-treatment follow-up (based on the ‘End of 
post-treatment follow-up Phase’ eCRF page completed). 


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In a separate summary the reasons for patients not completing the screening phase will be presented 
overall based on “Screening Phase Disposition” eCRF page.
3.3
Protocol deviations
The number (%) of patients in the FAS with any CSR reportable protocol deviation 
 will be tabulated by deviation category (as specified in the Study Specifications Document) 
overall and by treatment group.  
The protocol deviations leading to exclusion from analysis sets will be tabulated separately by 
treatment group. All protocol deviations will be listed.
3.4
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.1) will be summarized overall 
and by treatment group and stratum. 
3.5
Background and demographic characteristics
The FAS will be used for all Baseline and demographic summaries and listings.
3.5.1
Basic demographic and background data
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will be presented 
for continuous variables. The number and percentage of patients in each category will be presented for 
categorical variables. All summaries will be presented overall and by treatment group in the FAS. For 
categorical variables, the number and percentage of patients with missing data will be 
provided.
This analysis will include the following: age, gender, race, ethnicity, height, weight, body surface area 
(BSA) , Alcohol History, Smoking History and ECOG performance status at Baseline. 
BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using weight at Baseline. BSA at 
Baseline will be calculated using Mosteller formula, i.e., BSA (m2) = (weight(kg)×height(cm)/3600) 
using weight at Baseline.
3.5.2
HPV Status
The Historical HPV status, method used to assess HPV status and time since date of assessment of 
HPV status will be listed overall and by treatment group in the FAS.
The HPV status derived from the central lab will be summarized by treatment group and overall. 
3.5.3
PI3K pathway activation
The type of PI3K pathway activation based on archival tumor status will be described (PIK3CA 
mutation, , PTEN loss of expression) overall and by treatment group in the FAS. Characteristics of 
biomarker assessment samples (archival tumor or fresh tumor) will be described.


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3.5.4
Randomization stratification
The number (%) of patients in each stratum (number of prior lines of treatment and region of 
investigator site) based on data obtained from the IRT system will be summarized overall and by 
treatment group for the FAS. Discrepancies between the stratum at randomization (IRT) and the actual 
stratum recorded in the clinical database will be summarized.
3.5.5
Diagnosis and extent of cancer
Summary statistics will be tabulated overall and by treatment group for diagnosis and extent of cancer
in the FAS. According to the data collected on the eCRF, this analysis will include the following: 
primary site of cancer, histologic grade, time since initial diagnosis of primary site, disease stage (at 
initial diagnosis/at study entry), HPV status from Central Lab assessment, time since initial diagnosis 
to first recurrence/progression, time since most recent relapse/progression, presence/absence of target 
and non-target lesions at Baseline, disease metastasis summarized by location and number of 
metastatic sites .
These event times (in months) are defined as (for example):
[(reference start date) – (date of initial diagnosis of primary site)]/30.4375
3.5.6
Medical History
Medical history will be summarized overall and by treatment group.
Medical history and current medical conditions, including cancer-related conditions and symptoms 
entered on the Relevant medical history / current medical conditions CRF will be summarized overall 
and by treatment group and listed in the FAS. Separate summaries will be presented for current and 
historical medical conditions. The summaries will be presented by primary system organ class (SOC) 
and preferred term (PT).
Medical history/current medical conditions will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA). The MedDRA dictionary version used for reporting the study will be specified 
in the CSR. The latest version available at the time of the analyses will be used.
3.5.7
Anti-neoplastic therapy 
Anti-neoplastic therapy will be summarized overall and by treatment group.
Prior anti-neoplastic therapy will be listed in three separate listings: medications, radiotherapy and 
surgery. 
The number (%) of patients receiving prior anti-neoplastic therapy, prior anti-neoplastic medication, 
prior anti-neoplastic surgery and prior anti-neoplastic radiotherapy respectively will be summarized 
overall and by treatment group in the FAS. 
Prior anti-neoplastic medications will be summarized by :
number of therapies, 
therapy type (chemotherapy,  targeted therapy, and other), 
setting (metastatic, therapeutic, neo-adjuvant, adjuvant), 
last therapy before study entry and its outcome (type of therapy, setting, best response),


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time since last treatment and  its outcome (setting, best response and time since last treatment to 
progression) will be summarized. Last therapy is defined as the last therapy of the last regimen.. Refer 
to M8 for definitions of last treatment.
A summary table of regimens using ATC class and preferred term will be provided. Prior radiotherapy 
and prior surgery will be listed. 
The medication therapy type of any combination therapy will be classified based on the following 
order: chemotherapy, biologic therapy, targeted therapy, hormonal therapy. For example, a 
combination therapy of chemotherapy and hormonal therapy will be classified as chemotherapy.
Number (%) of patients and best response with prior pretreatment using taxanes and/or cetuximab 
prior to study entry will be summarized by treatment group.
An additional summary of  number (%) of patients by prior Lines of anti-neoplastic therapy received  
in recurrent/metastatic setting and the medications in each line (e.g Chemotherapy , EGFR inhibitor , 
Chemotherapy + EGFR inhibitor) will be provided. Any drug (monoclonal antibody or a kinase 
inhibitor) for which EGFR is known to be as a primary target of action will be considered as an EGFR 
inhibitor(details provided in RAP Module 8).
Anti-neoplastic medications administered since discontinuation of study treatment will be listed and 
summarized by ATC class, preferred term, overall and by treatment group.
Anti-neoplastic medications will be coded using the WHO Drug Reference List; Anti-neoplastic 
surgery will be coded using MedDRA dictionary. 
The MedDRA dictionary and WHO Drug 
Reference List version used for reporting the study will be specified in the CSR. The latest version 
available at the time of the analyses will be used.
3.6
Study treatment
The number (%) of patients who received BKM120/placebo starting dose (100 mg daily) and reduced 
dose of BKM120/placebo due to dose modification (80 mg daily, 100 mg 5 days out of 7 and 80 mg 5 
days out of 7) will be summarized by treatment group based on the Safety set. 
Similarly, the number (%) of patients who were administered paclitaxel starting dose (80 mg/m2) and 
reduced dose of paclitaxel due to dose modification (65 mg/m2) will also be summarized in the safety 
set by treatment group. The “dose received” (in mg/m2) for paclitaxel is considered:
o
‘80 mg/m²’ for a dose received is between 72 mg/m2 and 92 mg/ m²  (inclusive).
o
‘65 mg/m²’ for a dose received is between 55 mg/m² (inclusive) and less than 72 mg/ m²
o
‘Any other dose’ for a dose received is below 55 mg/m2 or above than 92 mg/ m2.
Paclitaxel total dose received  in mg/m2 at a dosing visit is defined as   [Total dose 
administered(mg) at the visit  / BSA(m2) measured at the visit] 
In addition, the following parameters will be listed, and summarized by treatment group for the Safety 
set:
3.6.1
Duration of exposure to study drug/treatment
Duration of exposure to study drug (for BKM120/placebo and paclitaxel) is defined according to 
dosing regimen for each study drug as outlined in Section 2.1.6.


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Duration of exposure (days) = (last date of exposure to study drug) – (date of first administration of 
study drug) + 1
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to each study drug:
Duration of exposure (days) = (last date of exposure to study treatment) – (date of first administration 
of study treatment) + 1, 
The duration includes the periods of temporary interruption. ‘Date of first administration of study 
drug/treatment’ and ‘last date of exposure to study drug/treatment’ are defined in Sections 2.1.2/2.1.4
and 2.1.6.
Duration of exposure to study drug/treatment will be categorized into time intervals. Time interval 
units will be months. Summaries (i.e. mean, standard deviation etc.) will be displayed in months.
3.6.2
Cumulative dose  
Cumulative dose is defined as the total dose given during the study treatment exposure and will be 
summarized for each study drug separately. For patients who do not receive any study drug, the 
cumulative dose will be set to zero.
The cumulative dose for BKM120/Placebo in a given dosing period is derived from the DAR defined 
according to the type dosing schedule of the drug as follows:
a.
Daily Dosing (qd): Sum of doses of the study drug administered to the patient from the start 
date to the end date of the study drug administration.
b.
Intermittent dosing (5 out of 7 days) :  The study administered at X mg /day and dosing 
schedule of 5 days on 2 days off : 
Cumulative dose (mg) = X(mg)*5*W + X(mg)*min(D,5),
where 
W = integer part of (intermittent dosing period on X(mg)) which represents the number of 
weeks the patient is on this dosing period prior to the last week of this dosing period, and 
D = ( duration of the intermittent dosing period on X(mg) – 7*W), which is the number of 
days the patient is on this X(mg) intermittent dosing in the last week. 
Below are some examples of cumulative dose calculations: 
Planned
Actual 
Day
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cum Dose Cum Dose
Assumed Dose
100
100
80
80
X
X
100
100
100
100
100
X
X
100
100
DoE
Data from DAR
15
1500
1060
Assumed Dose
100
100
100
100
100
100
100
X
X
100
100
100
100
100
X
Data from DAR
15
1500
1200
Assumed Dose
100
100
X
X
100
100
100
80
80
80
Data from DAR
10
1000
740
100 mg qd
0 mg 
80 mg (5/7)
100 mg (5/7)
100 mg qd
80 mg qd
0 mg 
100 mg (5/7)
100 mg qd
0 mg 
100 mg  (5/7)


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Example 1: A patient’s duration of exposure is 15 days where a patient has been treated with 100 
mg/day on days 1–2, 80 mg/day on days 3–4, zero dose on days 5-6 and 100 mg/day (intermittent 
dosing) on days 7-15. For the intermittent dosing, W=1 and D=2.  In this case the planned cumulative 
dose is 100*15=1500 mg and the actual cumulative dose = 2*100 + 2*80 + [(100*5*1) + 
(100*min(2,5)] = 1060 mg.
Example 2: A patient’s duration of exposure is 15 days where a patient has been treated with 100 
mg/day on days 1–7, zero dose on days 8-9 and 100 mg/day (intermittent dosing) on days 10-15. For 
the intermittent dosing, W=0 and D=6. In this case the planned cumulative dose is 100*15=1500 mg 
and the actual cumulative dose = 7*100 + 0 + [(100*5*0) + (100*min(6,5)] = 1200 mg.
Example 3: A patient’s duration of exposure is 10 days where a patient has been treated with 100 
mg/day on days 1–2, zero dose on days 3-4, 100 mg/day (intermittent dosing) on days 5-7, 80 mg/day 
(intermittent dosing) on days 8-10. For the intermittent dosing at each of 80 mg/day and 100mg/day, 
W=0 and D=3.  In this case the planned cumulative dose is 100*15=1500 mg and the actual 
cumulative dose = 2*100 + 0 + [(100*5*0) + (100*min(3,5)] + [(80*5*0) + (80*min(3,5)]  = 740 mg. 
The cumulative dose for paclitaxel is calculated from the DAR eCRF pages and is expressed in mg/m2:
It is the sum of (‘dose administered’ (mg) / BSA (m2)) during the exposure to paclitaxel.
Notes: 
1.
BSA (m2) = (wt(kg)×ht(cm)/3600) (Mosteller formula)
2.
Weight in BSA at administration time point is the last non-missing assessment, including 
unscheduled assessments, on or before the start date of paclitaxel administration (from Vital Signs 
eCRF page).
For Paclitaxel, which is administered and dosed weekly, cumulative dose will be based on the entire 
duration of exposure for the cycle. 
Cumulative dose should be reported in the same units as the prescribed dose.
3.6.3
Dose intensity and relative dose intensity
Dose intensity (DI) and Relative dose intensity (RDI) will be summarized separately for each study 
drug, using the individual exposure duration for each study drug.
Dose intensity (DI) for patients who receive study drug (i.e. patients with non-zero duration of 
exposure) is defined as follows:
DI (dosing unit / unit of time) = Cumulative dose (dosing unit) / Duration of exposure (unit of time).
For patients who do not receive any study drug, the DI will be set to zero.
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to patients as per 
protocol in the same dose unit and unit of time as that of the Dose Intensity.
For BKM120/placebo:

DI (mg/day) = Cumulative dose (mg) / duration of exposure (days)

PDI is 100 mg/day

RDI (%) = DI (mg/day) / PDI (mg/day) *100
For paclitaxel:


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
DI (mg/m2/week) = Cumulative dose (mg/m2) / (duration of exposure (days)/7).

PDI is 80 mg/m2/week

RDI (%) = DI (mg/m2/week) / PDI (mg/m2/week) * 100
The categorical summaries of RDI and the continuous summaries of RDI (i.e. mean, standard 
deviation etc.) will be presented. 
3.6.4
Dose reduction, interruption and permanent discontinuation
The number (%) of patients with dose reductions or interruptions and permanent discontinuations, and 
associated reasons, will be summarized separately for each study drug. 
‘Dose administered (mg) and dosing frequency from the DAR eCRF pages will be used to determine 
the dose reductions. Fields with zero dose administered will be used to determine interruptions.
‘Dose permanently discontinued’ ticked box from the DAR eCRF page will be used to determine the 
permanent discontinuations. 
3.6.4.1
Dose interruption
For BKM120/placebo, dose administered at 100 mg daily or 80 mg daily, an interruption is defined as 
a zero dose on one or more days between two non-zero doses. For BKM120 dose administered at 100 
mg 5 days out of 7 and 80 mg 5 days out of 7, an interruption is defined as a zero dose on the 
scheduled 5 days. As per protocol, a change from continuous schedule to intermittent (5 days out of 7) 
must be preceded by 2 days without treatment. This protocol required interruption will be counted as 
an interruption with the reason “As per protocol”.
For Paclitaxel, an interruption is defined as a zero dose administered on the scheduled day of 
administration.
Note: The last zero dose of BKM120/placebo or paclitaxel (followed by permanent discontinuation) is 
not considered as a dose interruption. Additionally, two consecutive zero doses of BKM120 (e.g. in 
the sequence 100 mg daily, 0 mg, 0 mg, 100 mg daily) or paclitaxel will be counted as 1 interruption if 
the reasons for these two consecutive dose interruption are the same.
The number (%) of dose interruptions along with reasons will be summarized. In addition, reasons for 
permanent discontinuation from the study drug will be summarized for both BKM120/placebo and 
paclitaxel.
3.6.4.2
Dose reduction
For BKM120/placebo: A dose reduction is defined as a decrease in dose from the protocol planned 
starting dose (from 100 mg daily to 80 mg daily) or a change in dosing frequency (i.e. from 80 mg 
daily to 100 mg 5 days out of 7 or from 100 mg 5 days out of 7 to 80 mg 5 days out of 7), even if the 
dose decrease or change in dosing frequency has been directly preceded by an interruption.  For 
example, in the sequence 100mg – 0mg – 80mg, the 80mg dose is a dose reduction and 100 mg 5 days 
out of 7 is the dose reduction in the 80 mg-0mg-100mg 5 days out of 7.  
If, due to a dosing error, a patient receives higher than protocol planned starting dose and moves down 
to the planned starting dose then this is not a dose reduction, however if the change is directly from a 
higher than planned starting dose down to a lower than protocol planned starting dose, then this is a 
dose reduction.


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If, due to a dosing error, a patient receives lower than previous non-zero dose and resumes later at the 
protocol specified  dose reduction , then  lower dose received due to dosing error and protocol 
specified dose reduction are dose reductions (e.g. in the sequence 100mg od - 70mg od - 80mg od, 
then 70 mg and 80 mg are dose reductions).
If, due to a dosing error, a patient receives lower than previous non-zero dose and resumes later at 
lower than previous non-zero dose, then 2 dose reductions will be counted (e.g. in the sequence 100 
mg od - 70mg od - 60mg od, 70 mg and 60 mg are dose reductions). 
For example,
Sequence
Reduction
With dose change
100 mg od - 80 mg od-0mg-80 mg od 
1 reduction (the 1st 80mg od)
100 mg od – 100 mg od – 0 mg - 80 mg od
1 reduction (80mg od)
100mg od – 0mg – 80mg od
1 reduction (80mg od)
With dose frequency change
100mg od - 80mg od - 80mg 5 days out of 
7 - 80mg od
2 reductions (80 mg od, 80mg 5 days out of 7)
100 mg od - 100mg 5 days out of 7-0mg-
100mg 5 days out of 7
1 reduction  (the 1st 100mg 5 days out of 7)
With dose change & dose frequency change
100 mg od- 0mg - 80 mg od-0mg-100mg 5 
days out of 7
2 reduction (80mg od, 100 mg 5 days out of 7 )
100 mg od – 0mg - 80 mg od-0mg-100mg 
5 days out of 7-0mg-80mg 5 days out of 7
3 reductions (80 mg od, 100 mg 5 days out of 7, 80 mg 
5 days out of 7 )
100mg od- 0mg – 80mg od – 0mg– 100 mg 
5 days out of 7-0mg- 80mg 5 days out of 7 
– 70mg* 5 days out of 7 – 0mg - 80mg 5 
days out of 7
4 reductions (80mg od, 100 mg 5 days out of 7, the 1 st
80mg 5 days out of 7, 70 mg 5 days out of 7)
With interruption 
100 mg od-0mg-100 mg od 
0 reduction 
100mg 5 days out of 7-0mg-100mg 5 days 
out of 7
0 reduction
With dosing error
100mg od - 80mg od - 70mg od* - 60mg 
od
3 reductions (80 mg od, 70mg od and 60mg od)
100mg od - 70mg od* - 100mg od
1 reduction (70mg od)
100mg od - 70mg od* - 80mg od
2 reductions (70mg od, 80mg od)
100mg od - 300mg od* - 250mg od*
0 reduction


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Sequence
Reduction
100mg od - 200mg od* - 100mg od*
0 reduction
100mg od - 50mg od* - 100mg od
1 reduction (50 mg od)
With dosing error at the 1st administration
50mg od* - 100mg od
1 reduction (50 mg od)
50mg od* - 0mg – 50 mg*- 100mg od
1 reduction (50 mg od)
50mg od* - 100mg od – 0mg - 80 mg od
2 reductions (50 mg od and 80mg od)
*dosing error
The number (%) of dose reductions along with reasons will be summarized.
For paclitaxel: A dose reduction is defined as a decrease in dose administered (mg/m2) from the 
protocol planned dose of 80 mg/m2.The count of dose reduction will follow the same logic as 
BKM120/Placebo. If the patient receives 65 mg/m2 dose of paclitaxel, it will be considered as 1 
reduction. If the patient further goes on to receive a dose lower than 65 mg/m2 , it will be considered as 
2 reductions. The range of dose for paclitaxel considered for 80 mg/m2 and 65 mg/m2 is described 
earlier in Section 3.6.  
The number (%) of dose reductions along with reasons will be summarized.
3.6.4.3
Permanent Discontinuation 
“Dose permanently discontinued” ticked box from the DAR eCRF page will be used to determine the 
permanent discontinuations. Reasons for permanent discontinuation from the study drug will be 
summarized for the study drug.
3.7
Prior and Concomitant therapy
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) other than 
the study treatment administered to a patient coinciding with the study treatment period. Concomitant 
therapy include medications (other than study drugs) starting on or after the start date of study 
treatment or medications starting prior to the start date of study treatment and continuing after the start 
date of study treatment. 
Concomitant therapy will be summarized for the Safety set.
Concomitant medications will be coded using the WHO Drug Reference List and summarized by ATC 
class and preferred term. Surgical and medical procedures will be coded using MedDRA dictionary 
and summarized by primary SOC and PT. 
The MedDRA dictionary and WHO Drug Reference List version used for reporting the study will be 
specified in the CSR. The latest version available at the time of the analyses will be used.
Concomitant medications, procedures and significant non-drug therapies taken concurrently with study 
treatment will be listed and summarized by ATC class/SOC using frequency counts and percentages. 
Any prior medications, procedures or significant non-drug therapies starting and ending prior to the 
start date of study treatment will be listed. Analysis will be based on Safety set. 


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Analysis will be based on Safety set.
3.8
Efficacy evaluation
Efficacy analyses will include all data observed in patients from FAS population.
The efficacy endpoints based on the tumor assessments will be derived according to the RECIST 1.1 
(see Appendix 6 of the CSP for details).
The tumor endpoints derivation is based on the sequence of overall lesion responses at each 
assessment/time point. However, the overall lesion response at a given assessment/time point 
will be provided from different sources as illustrated in Table 3-1.
Table 3-1
Sources for overall lesion response
Source 1 
Local radiologist/investigator reported overall lesion response
Source 2 
Central radiology (from Bioclinica) reported overall lesion response 
The primary efficacy analysis will be based on local (investigational) radiologist/Investigator 
tumor assessment data and will use Source 1 in Table 3-1 as a basis for endpoint derivation. In 
particular, the final local investigator visit response for each assessment/time point collected 
on the RECIST 1.1 overall response category collection eCRF page will be used to derive the
primary efficacy endpoints. Sensitivity analysis will be based on source 2. The assessment 
time point dates will be derived by Novartis using the dates of the individual lesion 
assessments.
3.8.1
Primary efficacy endpoints
The primary efficacy endpoints will be analyzed based on the data observed in the FAS, according to 
the treatment group patients were randomized and the strata (Number of prior lines of therapy, Region 
of Investigator Site) they were assigned at randomization. 
Progression Free Survival (PFS) is the primary endpoint of this study. The primary analysis will be 
done after approximately 120 PFS events are documented in the clinical database. The derivation of 
tumor endpoints is based on the sequence of overall lesion responses at each assessment. The primary 
and secondary efficacy analyses will be based on the local investigator’s tumor assessment data as a 
basis for endpoint derivation. In particular, the final local investigator visit response for each 
assessment collected on the RECIST 1.1 overall response category collection eCRF page will be used 
to derive the primary efficacy endpoints. The assessment time point dates will be derived by Novartis 
using the dates of the individual lesion assessments
3.8.1.1
Primary variable
PFS derived from investigator assessment will be used as the primary efficacy variable. 
The PFS is defined as the time from the date of randomization to the date of the first documented 
disease progression or death due to any cause. The date of progression is the earliest time when any 
RECIST progression event is observed with no more than one prior missing assessment. If a patient 
has not progressed or died at the analysis cut-off date or when the patient receives further anti-


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neoplastic therapy, PFS will be censored on the date of the last adequate tumor assessment before the 
earlier of the cut-off date or start of the further anti-neoplastic therapy date. The PFS censoring reasons 
are defined in Section 3.8.1.2.
The date of last adequate tumor assessment is the date of the last tumor assessment with overall lesion 
response of CR, PR, or SD before an event or a censoring reason occurred. In this case the last tumor 
evaluation date at that assessment is used. If no post-baseline assessments are available (before an 
event or a censoring reason occurred) the date of randomization is used.
Further anti-neoplastic therapies will be identified from the data collected on all anti-neoplastic 
therapy (See Section 2.4.2).
3.8.1.2
Data analysis
The primary analysis will be a comparison of PFS between the two treatment groups. The hazard ratio 
(HR) for BKM120 + paclitaxel versus placebo + paclitaxel will be estimated by a stratified Cox 
proportional hazard model, using the randomization strata (prior lines of treatment: 1 vs 2) and region 
of investigator’s site (North America vs Rest of World)). The strata information will be based on the 
data obtained from IRT that was utilized for randomization.
The efficacy criteria are:

The estimated hazard ratio is equal or less than 0.67 (i.e. 33% reduction in risk of PFS event with 
BKM120 compared to the placebo arm)
and

Posterior probability (HR < 1) > 97.5% (PFS treatment benefit of BKM120 compared to the 
placebo).
The posterior probability in the second criterion will be derived from the Bayesian posterior 
distribution of the HR. Assuming an uninformative prior distribution, the distribution of the HR will 
be updated with all available data from the patients included in the FAS.
The distribution of PFS will be estimated using the Kaplan-Meier (K-M) method. The median PFS 
along with two-sided 95% confidence intervals (CIs) will be presented by treatment group
(Brookmeyer and Crowley 1982).. 
Additionally, the 25% and 75% percentiles will also be provided. The results will be plotted 
graphically (K-M plots) by treatment group. 
The PFS probabilities at 2, 4, 6 and 8 months, and the associated 95% Cis (Greenwood formula) will 
be summarized by treatment group. 
The median time to censoring will estimated  as a measure of lost to follow up using the KM method 
having the event and censor indicators reversed.( Schemper, M.; Smith, TL , 1996)
PFS events will be described according to the type of events (death, objective tumor progression) by 
treatment group and overall. 
In addition, a summary of reasons for PFS censoring will be provided by treatment group. 
The following categories will be used as appropriate (based on “End of Treatment Phase Completion”, 
“End of post-treatment follow-up Phase”, “Withdrawal of informed consent”, “Death”, “Anti-
neoplastic therapy since discontinuation of study treatment-medication” eCRF pages and based on the 
distance D2 defined in Section 2.4.4):


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
Ongoing without event 

Lost to follow-up

Withdrew consent

Adequate assessment no longer available  

New cancer therapy added.
If the distance between the last adequate tumor assessment date and the first of the following dates:
1. Analysis cut-off date
2. Start date of further anti-neoplastic therapy
3. Date of study treatment discontinuation due to consent withdrawal
4. Date of study treatment discontinuation due to loss to follow-up 
is smaller or equal to D2 then the censoring reason will be 
1. ‘Ongoing’, 
2. ‘New cancer therapy added’, 
3. ‘Withdrew consent’ 
4. ‘Lost to follow-up’, respectively.
However, if this distance is larger than D2 and there is no PFS event (see Section 2.4.4), then the 
censoring reason will always default to ‘Adequate assessment no longer available’. If the distance 
between the last adequate tumor assessment date and the PFS event date is larger than D2 then the 
patient will be censored and the censoring reason will be 'Event documented after two or more missing 
tumor assessments'.
3.8.1.3
Sensitivity and other supportive analyses of the primary endpoint PFS
Some sensitivity PFS analyses may be performed for the full population. No other inferential statistics 
will be provided.
As a supportive evidence, the primary PFS analyses performed based on the data cut-off date: 
31 Aug 2015 used for primary PFS analysis reporting effort will be repeated using data from 
central radiology assessments (Source 2 in Table 3-1) based on patients in FAS.
For central radiology, data from the two independent central readers will be listed together 
with the final (i.e. either of the 2 readers data if they agree or the adjudicated data between the 
two central readers if the 2 readers disagree) data. Differences in overall responses between 
local radiology (Source 1, Table 3-1) and central radiology (Source 2, Table 3-1) will be 
summarized.
The following sensitivity PFS analyses will be performed for the patients in FAS:

Comparison of PFS events type and timing of PFS event between local investigator’s 
assessment and central radiology assessment

Summary of the discordance on PFS events type and timing of PFS between local 
investigator’s assessment and central radiology assessment

Summary of missing/unknown tumor assessments as per central radiology review
(Section 3.8.1.3.3)


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3.8.1.3.1 Stratification as per eCRF
The Primary Analyses will be repeated using the stratification variables as per eCRF  instead of IRT if 
the efficacy criteria for primary analyses using the stratification factors based on IRT given in Section 
3.8.1.2 are met..
Patients with Prior Lines of therapy at recurrent/metastatic setting =1 and region = North America, will 
be considered Strata 1. Patients with Prior Lines of therapy at recurrent/metastatic setting =1 and 
region = Rest of the world, will be considered Strata 3. Patients with Prior Lines of therapy at 
recurrent/metastatic setting =2 and region = North America, will be considered Strata 2. Patients with 
Prior Lines of therapy at recurrent/metastatic setting =2 and region = Rest of the world, will be 
considered Strata 4.
3.8.1.3.2 Per-protocol set analysis
If the PoC is established for the primary endpoint of PFS, the primary analyses will be repeated in the 
PPS.
3.8.1.3.3 Missing/unknown tumor assessments (TAs)
The purpose of the below analyses is to gain an insight as to whether the TAs have been
carried out in accordance with the protocol and to understand if any meaningful discrepancies 
exist between the pattern of missing/unknown assessments between local and central reviews 
and between treatment arms with each of the two sources.
The following time windows (in weeks) will be constructed: [0, 7], [7, 13], [13, 19], etc. for 
each patient, where ‘0’ is the patient’s date of randomization. Every time-window (with the 
exception of the initial, broader one) is centered at the scheduled time of TA, i.e., around 
week 10, week 16 for second and third window, respectively, etc. A patient is considered ‘at 
risk’ of missing their TA for any one of these time-windows if the patient either:

was ‘on study’ for at least the first 2 weeks of the time-window (4 weeks for the first time 
window), i.e., if the patient is ongoing at the time of the scheduled TA, 
or

discontinued treatment due to documented disease progression within the specific time 
window.
For example, if a patient discontinued during Week 15, then she would have been ‘at risk’ of 
a missing/unknown TA for the [13, 19] week time-window. For the purpose of this analysis, 
‘unknown’ TAs (i.e., evaluations with an overall lesion response of ‘unknown’) will be 
considered to be missing. However, a clear distinction between ‘truly missing’ and ‘present 
but unknown’ needs to be done in the derived dataset to allow for both combined, i.e. missing 
and unknown treated the same, and separate analyses.
TAs performed after a documented disease progression will not be considered. In other words, 
the final time-window for which a patient would be at risk of a missing/unknown scan would 
be that during which the documented progression occurred.
For patients without documented progression, all TAs are considered up to the earliest of the 
following dates: death, the analysis cut-off, start of new antineoplastic therapy, 
discontinuation for either withdrawal of consent or loss to follow-up. 


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The results will be presented by treatment arm and separately for investigator/local and 
central radiology using the same cut-off date. Number of patients with at least one 
missing/unknown TA will be presented together with the following categories: number of 
patients with 1, 2, 3, 4, 5, >5 missing/unknown TAs.
Since the two treatment arms are expected to differ in the follow-up “tails” the following 
summaries will be displayed in addition: number of patients with at least one 
missing/unknown TA between the last adequate TA and PFS event or cut-off, number of 
patients with at least one missing TA after the study treatment discontinuation.
3.8.2
Secondary efficacy endpoints
All secondary efficacy analyses will be reported by treatment group based on the local investigator’s 
assessment of the tumor assessment data. Analyses will be based on the FAS unless otherwise 
specified.
Sensitivity analyses for tumor related endpoints will also be performed based on central radiology 
assessments.
3.8.2.1
Key Secondary efficacy endpoints 
The key secondary objective is to determine whether the treatment BKM120 plus paclitaxel provides 
an improvement in overall survival compared to treatment with placebo plus paclitaxel. The key 
secondary analysis will be done after approximately 112 deaths are documented in the clinical 
database.
Overall survival (OS) is defined as the time from date of randomization to date of death due to any 
cause. If a patient is not known to have died by the date of analysis cut-off, OS will be censored at the 
date of last contact (see Section 2.1.10).
All deaths occurring before the cut-off date will be counted in the overall survival analysis regardless 
of presence or absence of the Baseline tumor assessment. Data collected in the ‘Death’ eCRF page will 
be used.
The analyses for OS will be based on the FAS. 
OS will be compared between the two treatment groups. The HR for BKM120 + paclitaxel versus 
placebo + paclitaxel will be estimated by a stratified Cox proportional hazard model, using the 
randomization strata (i.e. prior lines of therapy and region (North America vs Rest of the world)). HR 
will be presented together with the 95% confidence interval. 
In order to guide the Phase III design for this indication, Proof of Concept (PoC) for Overall Survival 
is defined based on the following criteria: 

The estimated hazard ratio is equal or less than 0.77 (i.e. 23% reduction in risk of OS event with 
BKM120 compared to the comparator arm)
and

Posterior probability (HR < 1) > 90% (OS treatment benefit of BKM120 compared to the control).
The posterior probability of HR < 1 will be derived from the Bayesian posterior distribution of the HR 
for Overall Survival. Assuming an uninformative prior distribution, the distribution of the HR will be 
updated with all available data from the patients included in the FAS. The above proof of concept 
analysis for OS will only be done after approximately 112 deaths are documented in the clinical 


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database. All the other analyses of OS as described below may be done at the time of the Primary 
analysis of the study. The PoC for OS will be assessed irrespective of PFS PoC outcome. 
The distribution of OS will be summarized using the K-M method. The median OS along with two-
sided 95% CIs will be presented by treatment group. Additionally, the 25% and 75% percentiles will 
also be provided. The results will also be plotted graphically (K-M plots) by treatment group. 
The proportion of patients alive at 3.5, 7,  9, 11 and 13 months and the associated 95% CIs will be 
summarized by treatment group.
Number of deaths as well as the primary reason for death (study indication, other) will be displayed by 
treatment group. A listing of patients displaying the reason of death entered by the investigator will be 
provided.
In addition, censoring reasons (‘Alive’ or ‘Lost to follow-up’) will be described by treatment group. 
‘Lost-to-follow-up’ will be determined using the “End of Treatment Phase Completion”, “End of post-
treatment follow-up Phase”, and “Survival information” eCRF pages. Patients not known to have died 
will be censored for ‘Lost to follow-up’ if the time between their last contact date and the analysis cut-
off date is longer than 3 months and 2 weeks (104 days).
3.8.2.2
Overall response rate (ORR)
Overall response rate (ORR) is defined as the proportion of patients with confirmed best overall 
response of complete response (CR) or partial response (PR) based on the local investigator’s 
assessment according to RECIST 1.1 (see Appendix 6 of the CSP). However, patients with non-
measurable lesions only at Baseline will be included as ‘responders’ if they achieve a complete 
response. 
Proportions of patients with ORR will be presented by treatment group along with exact 95% CIs
(Clopper & Pearson, 1934). 
ORR will also be summarized using the data from central radiology assessments based on the 
data cut-off date used for primary PFS analysis reporting effort (Source 2 in Table 3-1). 
3.8.2.3
Duration of Overall Response and Time to Overall Response
Duration of Overall response (DoR) applies only to FAS responders, i.e., patients whose best overall 
response was CR or PR. This analysis will include only responders and therefore it might introduce a 
bias.
DoR is defined as the elapsed time between the date of first documented response (CR or PR, which 
has to be confirmed subsequently) based on the local investigator’s assessment according to RECIST 
1.1 (see Appendix 6 of the CSP) and the following date of event defined as the first radiologically 
documented disease progression or death due to study indication. 
DoR will be summarized for patients with a confirmed CR or PR using descriptive statistics. The 
aspects of censoring as discussed for PFS will also apply here. 
DoR will also be summarized for both local investigator and central radiology assessment 
based on the data cut-off date to be used for the final OS analysis reporting effort (Source 2 in 
Table 3-1).


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Discordance on Best Overall Response between local investigator’s assessment and central 
radiology assessment will be summarized by treatment arms based on the data cut-off date  
used for primary PFS analysis reporting effort.
Time to overall response (TTR) applies only to FAS responders, i.e., patients whose best overall 
response was CR or PR. This analysis will include only responders and therefore it might introduce a 
bias.
TTR is defined as the time from the date of randomization to the date of first documented response 
(CR or PR, which has to be confirmed subsequently) based on the local investigator’s assessment 
according to RECIST 1.1 (see Appendix 6 of the CSP). The date of event is defined as the date the 
response is first determined and not using the date the response is confirmed.Descriptive summary 
statistics will be reported on the confirmed responders subset only. 
Additionally, Kaplan-Meier plot for Duration of response and TTR based on local investigator 
assessment and central radiology assessment will be provided by treatment arms.
TTR will also be summarized using the data from central radiology assessments based on the 
data cut-off date: used for primary PFS analysis reporting effort (Source 2 in Table 3-1). 
Disease control rate (DCR) is defined as the proportion of patients with a best overall response of CR, 
PR or stable disease (SD), based on the investigator assessment (see RECIST Version 1.1 guidelines, 
Appendix 6 of CSP).
Proportions of patients with DCR will be presented by treatment group along with exact 95% CIs 
(Clopper & Pearson, 1934). DCR will also be summarized using the data from central radiology 
assessments based on the data cut-off date: used for primary PFS analysis reporting effort
(Source 2 in Table 3-1). 
At the time of Primary Analysis, many of the patients who responded were getting censored for 
duration of response. Thus for OS Analysis, Duration of response summaries based on local 
investigator assessment as well as central radiology assessment  is based on OS Cut-off to present 
more mature data, with reduced number of censoring.
3.8.2.4
Patient Reported Outcomes – Health Related Quality of Life
The EORTC QLQ-C30 questionnaire along with the head and neck cancer module (QLQ-HN35) will 
be used to collect data on patient’s QoL.  
The global health status/QoL scale and pain score of the QLQ-C30 and QLQ-HN35, respectively, are 
identified as the primary patient-reported outcome (PRO)  scales of interest. Physical functioning, 
emotional functioning and social functioning scale scores of the QLQ-C30 and the head and neck 
cancer symptom scales for swallowing, sense and speech of the QLQ-HN35 are identified as 
secondary patient-reported HRQoL variables of interest. The FAS population will be used for all PRO 
summaries of interest. 
Scoring and handling of missing QoL data from the EORTC QLQ-C30 and QLQ-HN35 will be in 
accordance to the EORTC scoring manual (Fayers 2001).  No imputation will be applied if the total or 
subscale scores are missing at a visit. For each domain and item (Table 3-2 and Table 3-3), a linear 
transformation is applied to standardize the score between 0 and 100.  Higher score values for a 
functional scale and global health status/QoL indicate higher functioning and health-related quality of 
life, respectively. Higher score values for symptoms scales indicate greater symptomatology or 
problems.


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Table 3-2
EORTC QLQ-C30 scales
Domain
(Sub)Scale
Item numbers
Global health status/QOL
Global health status/QOL
29, 30
Functional scales
Physical functioning
1 to 5
Role functioning
6, 7
Emotional functioning
21 to 24
Cognitive functioning
20, 25
Social functioning
26, 27
Symptom scales
Fatigue
10, 12, 18
Nausea and vomiting
14, 15
Pain
9, 19
Dyspnea
8
Insomnia
11
Appetite loss
13
Constipation
16
Diarrhea
17
Financial difficulties
28
Table 3-3
EORTC QLQ-HN35 scales
Domain
(Sub)Scale
Item numbers
Symptom scales
Pain
31-34
Swallowing
35-38
Senses problems
43,44
Speech problems
46,53,54
Trouble with social eating
49-52
Trouble with social contact
48,55-58
Less sexuality
59,60
Teeth
39
Opening mouth
40
Dry mouth
41
Sticky saliva
42
Coughing
45
Felt ill
47
Pain killers
61
Nutritional supplements
62
Feeding tube
63
Weight loss
64
Weight gain
65
Patient-reported HRQoL questionnaires (EORTC QLQ-C30 and QLQ-HN35) are planned to be 
administered at screening, every 6 weeks after randomization, and at the End of Treatment assessment. 
The following time-based intervals (Table 3-4) will be used to group the HRQOL data over time. 
Day x is defined as date of HRQOL administration – randomization date + 1.


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Table 3-4
Time based intervals to group HRQOL
Visit
Time Interval 
Baseline 
Time period on or before the randomization date, i.e., 
≤ Study Day 1
Week 6 
Day 2 to Day 63
Weeks 12, 
18 etc. or 
EOT 
+/- 3 weeks centered around the planned 
assessment i.e. days 64, days 105 for Week 12
(3rd assessment) days 106, days 147 for Week 18
(4th assessment) days etc.
(week x -3*7+1 ; week x +3*7)
Time windows are applicable for descriptive summary of PRO data by visit. It is not applicable to time 
to deterioration analysis since all post-baseline assessments will be considered.
If more than one assessment is done within the same time window, the assessment performed closest 
to the target date will be used. For the baseline time window the target would be study day 1 (i.e., just 
before the patient starts randomized treatment phase); for the first post-baseline assessment the target 
would be study day 43 (week 6+1) and thereafter it would be every 6 weeks, corresponding to the 
planned assessment times of day 84 (week 12), day 126 (week 18), etc. If 2 assessments within a time 
window are equidistant from the target date then the assessment obtained prior to the target date will 
be considered. If the closest assessment to the target date has two questionnaires filled out on the same 
date , then the average of these assessments will be used for each subscale score.
The number of patients completing PRO assessments and the number of patients missing/expected to 
have completed PRO assessments as reported by the investigational sites will be summarized by each 
treatment group for each scheduled assessment time point in the FAS. 
Other exploratory analysis may be performed to better understand any missing data patterns identified 
for PRO assessments.
Descriptive statistics (N, mean, median, SD, Q1, Q3, minimum, maximum) will be used to summarize 
the individual item and scored sub-scale scores of PROdata at each scheduled assessment time point in 
the FAS for all the sub-scales defined in Table 3-2 and Table 3-3. Additionally, change from baseline 
in the sub-scale scores at the time of each assessment will be summarized. Patients with an evaluable 
baseline score and at least one evaluable post baseline score during the treatment period will be 
included in the change from baseline analyses. 
Time to deterioration in the global health status / quality of life scale, physical functioning, emotional 
functioning, social functioning, and head and neck cancer symptoms scales for pain, swallowing, 
senses, and speech will be assessed for the two treatment arms. The survival distributions will be 
presented descriptively using Kaplan-Meier curves for global health status / quality of life scale of 
EORTC-QLQ-C30 and head and neck cancer symptoms scales for pain, swallowing, senses, and 
speech. Time to deterioration in the physical functioning, emotional functioning, social functioning 
subscales of EORTC-QLQ-C30 will only be listed. Summary statistics from the Kaplan-Meier 
distributions will be determined, including the median time to deterioration and the proportions of 
patients without deterioration in PRO scales of interest at 3 and 6 months. Both point estimates and 95% 
confidence intervals will be presented.


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Definitive Deterioration in PRO (EORTC-QLQ-C30- global health status / quality of life scale) scales 
will be defined as a decrease in the subscale score by at least 10% compared to baseline, with no later 
increase above this threshold observed during the course of the study. A single measure reporting a 
decrease of at least 10% is considered evaluable only if it is the last observation available for the 
patient. 
Note: Definitive Deterioration in PRO scales (EORTC-QLQ-HN35) will be defined as an increase in 
the subscale score by at least 10% compared to baseline, with no later decrease above this threshold 
observed during the course of the study. A single measure reporting an increase of at least 10% is 
considered evaluable only if it is the last observation available for the patient. 
Time to deterioration is the number of days between the date of randomization and the date of the 
assessment at which definitive deterioration is seen. If a patient has not had an event prior to analysis 
cut-off or start of another anticancer therapy, time to deterioration will be censored at the date of the 
last PRO evaluation. Only assessments collected while the patient is on treatment and on or before the 
end of treatment visit will be included in the PRO time to definitive deterioration. If a definitive 
deterioration is observed after 2 or more missing assessments, this event will the patient is censored at 
the date of the last available assessment prior to the deterioration. For example, if a patient has an 
assessment at week 6, misses the following two assessments on weeks 12 and 18 and a definitive 
deterioration is observed on week 23, then the patient will be censored at week 6.
Death will be considered as deterioration of symptoms/PRO if it occurs close to the last available 
assessment, where “close” is defined as twice the planned period between two assessments. This 
avoids overestimating the time to definitive worsening in patients dying after an irregular assessment 
scheme. Patients who die after more than twice the planned period between two assessments since the 
last assessment are censored at the date of their last available questionnaire. For example, if the last 
assessment is at week 6 and the patient dies on week 16, the deterioration date will be week 16. On the 
other hand, if the last assessment is at week 6 and the patient dies on week 24, which is after more than 
twice the planned period between two assessments since the last assessment (week 6), then the patient 
will be censored at week 6. Patients receiving any further anti-neoplastic therapy (See Section 2.6.3) 
before definitive worsening will be censored at the date of their last assessment before starting this 
therapy. Patients that have not worsened as of the cutoff date for the analysis will be censored at the 
date of their last assessment before the cutoff.
Patients without baseline PRO or without any post-baseline PRO will be censored at the date of 
randomization with censoring reason being ‘No baseline score’ or ‘No post-baseline score’, 
respectively. If the time interval between the last assessment date and the earliest of the following 
dates is ≤ twice planned interval protocol assessments i.e. 98 days (2*6weeks  + 2*7 days)(Table 7-6 
of CSP) and there is no definitive deterioration:
1.
analysis cut-off date
2.
End of Treatment Date
3.
start date of further antineoplastic therapy
4.
date of consent withdrawal
5.
Visit date of study treatment discontinuation due to lost to follow-up  
then the censoring reason will be 
1.
Deterioration-free at the last assessment until cut-off, 
2.
Deterioration-free at the last assessment until EOT,


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3.
New anticancer therapy added, 
4.
Withdrew consent,
5.
Lost to follow-up.
If this time interval is larger than 98 days and there is no definitive deterioration event, then the 
censoring reason will always default to ‘Adequate assessment no longer available’. However, if 
definitive deterioration occurred more than 98 days since the last assessment then the censoring 
reason will be ‘event after >= 2 missing assessments’.
Patients receiving any further antineoplastic therapy before definitive worsening will be censored at 
the date of their last assessment before starting this therapy. Patients that have not worsened as of the 
cutoff date are censored at the date of their last assessment before the cutoff. 
3.8.3
Follow-up of the study
Summary information on the follow-up of patients is displayed in order to describe the maturity of 
data and quality of follow-up.  
Follow-up of the study will be summarized using the following methods to provide a comprehensive 
assessment of follow-up for patients in each treatment group in the FAS.
Summary of duration between randomization and cut-off date, and follow-up times for PFS/OS, which 
are defined as follows:

Randomization (recruitment) period = (Date of last patient randomized - Date of first patient 
randomized + 1)/30.4375 (months).

Duration between randomization and data cut-off date = (Cut-off date – Date of randomization + 
1)/30.4375 (months).

Follow-up time = (Date of event or censoring – Date of randomization + 1)/30.4375 (months) 
regardless of censoring. Date of event or censoring is the same as the one defined for the main 
analyses.
Gap analysis: Summary of gap time (months) for PFS/OS follow-up as compared to cut-off date. Gap 
time for PFS/OS is defined as follows:

For patients who are censored regardless of follow-up status 
Gap time = (Analysis cut-off date – censoring date)/30.4375 
3.9
Safety evaluation
The assessment of safety will be based mainly on the frequency of on-treatment adverse events and on 
the number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. ECG, 
mood disorders, and vital signs) will be considered as appropriate.  
Risks identified in the Safety Profiling Plan (SPP) will mainly be analysed by frequency of events, 
further exploratory analyses may be performed as appropriate. The latest version of the SPP available 
at the time of the analyses will be used.


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The safety summary tables include only on-treatment assessments (refer to Section 2.1.9 for 
definition). All safety assessments are listed and those collected outside of the on-treatment window 
are flagged.  
All safety outputs will use the Safety set, unless otherwise specified.
3.9.1
Adverse events data
3.9.1.1
Dictionary Coding of AEs
Adverse events will be coded according to the MedDRA dictionary and will be reported by primary 
SOC and PT, and by Standardized MedDRA Queries (SMQs) and Novartis MedDRA Queries (NMQs) 
for safety topics of interest.
The MedDRA dictionary version used for reporting the study will be the version used for coding the 
study and will be specified in the CSR. The latest version available at the time of the analyses will be 
used.
3.9.1.2
Grading of AEs
Adverse events will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects of 
cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding to mild, 
moderate, severe, life threatening, and death. This grading system inherently places a value on the 
importance of an event although there is not necessarily proportionality among grades (a grade 2 is not 
twice as bad as a grade 1).
If CTCAE grading is not available for an adverse event, Grades 1 – 4 corresponding to the severity of 
mild, moderate, severe, and life-threatening will be used. CTCAE Grade 5 (death) is not be used in 
this study; rather, death information will be collected in the “death” eCRF page.
3.9.1.3
General rules for AE reporting
Treatment-emergent adverse events (TEAE) are events that occurred on treatment or events present 
prior to the study treatment start but increased in severity based on preferred term when the patient is 
on-treatment. 
All deaths including those that occurred on-treatment and post treatment, will be listed, post treatment 
deaths will be flagged. In addition to the on-treatment deaths and additional summary of all deaths 
(on-treatment + post-treatment) by treatment will be provided. 
All AEs summary tables will present only TEAEs. The number (%) of patients reporting any AE will 
be summarized by primary SOC, PT and treatment group. The most common AEs reported (≥ 10% in 
either group for each preferred term) will be presented in descending frequency according to its 
incidence in BKM120 + paclitaxel treatment group starting from the most common event.
Additional summaries will be provided by maximum toxicity grade and relationship to study treatment.
If a patient reported more than one AE with the same PT, the AE with the maximum toxicity grade 
will be presented. If a patient reported more than one AE within the same primary SOC, the patient 
will be counted only once with the maximum toxicity grade at the primary SOC level, where 
applicable. 


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Summaries will be provided for study treatment related adverse events, death, serious adverse event, 
other significant adverse events leading to discontinuation and adverse events leading to dose 
adjustment.  Adverse event tables presented by maximum CTCAE grade will provide the following 
information: (1) maximum individual grade, (2) maximum G3/G4 and (3) Any grade. 
Note: For in-text tables, adverse event tables presented by maximum CTCAE grade will provide the 
following information: Any grade and maximum G3/G4. 
3.9.1.4
AE Summaries
The following AE summaries will be produced by treatment group for all patients in Safety 
set:

On-treatment deaths, by PT (This indicates the number of deaths due to study indication and 
those due to AE)

Deaths by primary SOC, PT. (All deaths (on-treatment + post treatment) are included)

SAEs, regardless of study treatment relationship, by primary SOC, PT and maximum 
CTCAE grade

SAEs suspected to be related to the study treatment, by primary SOC, PT and maximum 
CTCAE grade

Most frequent SAEs (at least 2%), regardless of study treatment relationship, by primary 
SOC and PT

Most frequent SAEs (at least 2%), suspected of study treatment relationship, by primary SOC and 
PT 

AEs, regardless of study treatment relationship by primary SOC, PT and maximum 
CTCAE grade

AEs suspected to be related to the study treatment by primary SOC, PT and maximum 
CTCAE grade

Most frequent AEs (at least 10%), regardless of study treatment relationship by PT and
maximum CTCAE grade (All grades and Grade 3/4)

Most frequent AEs (at least 10%), suspected to be related to the study treatment by, PT
and maximum CTCAE grade(All grades and Grade 3/4)

AEs leading to study drug permanent discontinuation, regardless of study treatment 
relationship, by primary SOC, PT and maximum CTCAE grade

Most frequent AEs (at least 2%) leading to study drug permanent discontinuation, 
regardless of study treatment relationship, by primary SOC , PT and maximum CTCAE 
grade

AEs leading to study drug dose adjustment, regardless of study treatment relationship, by 
primary SOC, PT and maximum CTCAE grade

AEs leading to study drug temporary interruption, regardless of study treatment 
relationship, by primary SOC, PT and maximum CTCAE grade


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
AEs requiring additional therapy, regardless of study treatment relationship, by primary 
SOC, PT and maximum CTCAE grade 

Non-serious AEs, regardless of study treatment relationship by primary SOC, PT, maximum 
CTCAE grade Note: Required for reporting trial results to CT.GOV
Deaths and other SAEs will also be listed for patients who were screening failures and those 
who were randomized but not treated.
3.9.1.5
Specific Safety Event Categories
Specific Safety Event Categories (SEC) consist of adverse events for which there is a specific clinical 
interest in connection with BKM120 treatment (i.e. where BKM120 may influence a common 
mechanism of action responsible for triggering them) or adverse events which are similar in nature 
(although not identical).
General considerations for adverse events described in Section 3.9.1 are applicable to SECs. Each of 
these SECs uses MedDRA terms (SMQ, NMQ, 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. The 
MedDRA preferred terms used to define the SECs are defined in the program Case Retrieval Strategy 
(CRS) document and will be summarized. The latest version of the CRS document available at the 
time of the analyses will be used. 
The following SECs will be reported:

Mood disorders

Hyperglycemia

Hypersensitivity, rash (including DRESS, photosensitivity)

Liver toxicity

Posterior Reversible Encephalopahty Syndrom(PRES)

Asthenia, Fatigue 

Nausea, Vomiting, Diarrhea

Pneumonitis 
Additional SECs may be reported if there are any updates to the CRS at the time of the analyses. 
Standard data of analysis for all SECs will be conducted as follows:

The number (%) of patients will be reported by SEC risk, maximum CTCAE grade and by 
treatment group.

The number (%) of patients will be reported by SEC risk, by MedDRA category, by preferred term, 
maximum CTCAE grade and by treatment group. 

All AEs of patients having at least one AE in that SEC will be listed.

For particular SECs (hyperglycemia, Hypersensitivity/rash, mood disorder for BKM120), 
depending on the number of events, the time to first occurrence of any grade event (or any grade ≥ 
2) will be summarized using Kaplan-Meir method. Median time to onset and 95% CI will be 
summarized. Kaplan-Meier plots will be generated. 


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The version of MedDRA version and NMQ dictionary date of the Case Retrieval Sheet used for the 
analyses will be described in a footnote. The Case Retrieval Sheet used for the analyses will be listed. 
3.9.1.6
Time to onset of CTCAE Grade 2 or worse SEC
Time to onset of CTCAE Grade 2 or worse SEC is defined as the time from the start of treatment to 
the start date of the first incidence of CTCAE Grade 2 or worse SEC i.e. time in days is calculated as 
(start date of first occurrence of Grade 2 or worse SEC) – (date of first dose of study treatment) +1. A 
patient will be censored for time to onset of Grade 2 or worse occurrence if the patient:

does not experience any post-baseline Grade 2 or worse SEC

dies without experiencing Grade 2 or worse SEC 

receives a new anti-neoplastic therapy without experiencing Grade 2 or worse SEC or before the 
Grade 2 or worse SEC has occurred 

discontinues from the study treatment without experiencing Grade 2 or worse SEC (up to 30 days 
after last date of study treatment administration)

is still ongoing at the analysis cut-off date without experiencing Grade 2 or worse SEC,
In the absence of grade 2 or worse SEC ,the censoring date will be the earliest date from the 
following dates: last date of administration of study treatment + 30 days, analysis cut-off date, new 
anti- neoplastic therapy start date, death date and last contact date.
3.9.2
Laboratory data
3.9.2.1
Grading of laboratory data
Laboratory data grades of severity will be derived according to the Common Terminology Criteria for 
Adverse Events (CTCAE) v4.03. CTCAE grade is applied to the converted measurement in SI units.  
A severity grade of 0 will be assigned when the value is within normal limits. In the case when a local 
laboratory normal range overlaps into the higher (i.e. non-zero) CTCAE grade, the CTCAE grade will 
be taken.
For laboratory tests for which grades of severity are not defined by CTCAE, results will be graded by 
the low/normal/high classifications based on laboratory normal ranges.
Laboratory values with missing units or normal range may not be able to be graded or included in 
laboratory tables.
In cases of multiple laboratory measurements for gradable parameters taken on the same last 
assessment date:

The lowest absolute grade should be considered for baseline.

For duplicate laboratory measurements with same grade but different values taken at the last 
assessment date on or before the start date of  treatment, the baseline will be chosen as the values 
closest to the ULN if the duplicate values are at a grade > 0 and farthest from ULN if the 
duplicates are at grade 0 . This rule will apply for any lab parameter where increasing value 
implies increasing grade  eg. Total Bilirubin, AST, ALT etc. For labs where decreasing values 


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imply increasing grade e.g. Platelets, WBC etc,  the same rule will be applied with respect to the 
LLN. Details are provided in RAP M8.
If several records have the same absolute grade, but in different directions, 2 baselines should be 
created, the record with grade below 0 should be the baseline of the 'Hypo' parameter, and the other 
record should be the baseline for the 'Hyper' parameters.
For non-gradable labs with duplicate laboratory measurements taken at the last assessment date on or 
before the start date of study treatment:

If both within normal range: take the value which is closest to the average of ULN and LLN.

If one within normal range and the other outside: take the one within normal range.

If both outside normal range: take the one closest to the normal range.
In some cases these duplicate labs may come from different labs with different LNRs. More details on 
the derivation of the Baseline in such cases are described in the RAP M8.
Laboratory values with missing units or normal range may not be able to be graded or included in 
laboratory tables.
A severity grade of 0 will be assigned when the value is within normal limits. In the case when a 
local/central laboratory normal range overlaps into the higher (i.e. non-zero) CTCAE grade, the 
CTCAE grade will be taken.
3.9.2.2
Laboratory data summary
The summary of on-treatment laboratory evaluations will be presented for two groups of laboratory 
tests (hematology and biochemistry) from local laboratories. 
All lab parameters planned in the protocol will be summarized:

Hematology: absolute lymphocytes, absolute neutrophils, absolute eosinophils, absolute basophils, 
absolute monocytes, hemoglobin, hematocrit, WBC, RBC and platelet counts

Biochemistry: AST, ALT, alkaline phosphatase, phosphate, chloride, direct and total bilirubin, 
creatinine, creatinine clearance, potassium (hyper and hypo), corrected calcium (hyper and hypo), 
fasting glucose (hyper and hypo), lipase, GGT, albumin, amylase, total cholesterol, HDL-C, LDL-
C, triglycerides, magnesium (hyper & hypo), sodium (hyper & hypo), urea or blood urea nitrogen 
(BUN), uric acid, LDH, total protein 
The following summaries will be produced for the laboratory data (by laboratory parameter):

Number and percentage of patients with worst post-baseline CTC grade (regardless of the baseline 
status). Each patient will be counted only for the worst grade observed on-treatment.

Shift tables to compare baseline to the worst post-baseline value will be produced for hematology 
and biochemistry laboratory parameters using:

CTCAE grades for laboratory parameters where CTCAE grades are defined

The classifications relative to the laboratory reference ranges (low/normal/high) for laboratory 
parameters where CTCAE grades are not defined
The laboratory assessments collected outside the on-treatment period will be flagged in the listings. 
The following listings will be produced for the laboratory data:


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
Listing of patients with laboratory values outside the laboratory reference ranges with values 
flagged to show the corresponding CTCAE grades and the classifications relative to the 
laboratory reference ranges

By-patient listing of other laboratory data (collected if clinically indicated) such as urinalysis, 
coagulation and Serum hCG for pregnancy test .

Listing of patients with notable laboratory abnormalities (i.e. newly occurring CTC grade 3 or 
4 laboratory toxicities).
3.9.2.3
Liver function parameters
Liver function parameters of interest for BKM120 are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP).
The following summaries will be produced:

The number (%) of patients with worst post-baseline values in the following categories will be 
summarized:

ALT or AST > 3xULN 

ALT or AST > 5xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

ALP > 1.5xULN

TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN*
ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN*    
Note: *Potential Hy’s Law events (candidates) are defined as those patients with AST or ALT > 
3xULN and TBL > 2xULN and ALP < 2xULN at any visit during the on-treatment period... 
Note :The counts patients with ALT or AST > 3xULN, 5xULN, 10xULN etc are cumulative i.e. 
patient having a ALT or AST > 10x ULN would also be counted for ALT or AST > 5xULN and ALT 
or AST > 3xULN.Same rule applies for TBL increase as well.
A figure displaying time course of hepatic function tests (ALT, AST, TBL, ALP) in patients with Hy’s 
law will be displayed in the safety set.
Additional categories may be added to the above list based on any updates to the internal guidelines on 
collection, analysis, and presentation of liver safety data.
3.9.3
Patient self-reported Mood assessments
As a safety measure for BKM120 studies, mood assessment includes two patient self-rating mood 
questionnaires: GAD-7 Anxiety scale and PHQ-9 Depression scale. 
The primary variable for the analyses of mood will be the total scores of the two scales. Analysis will 
be performed based on the Safety set. 


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For each scale, total score will be derived by adding column scores. Categorization will be performed 
as described in Table 3-5
to assess severity. 
Table 3-5
Toxicity grading based on mood questionnaire scores
PHQ-9 (depression)
GAD-7 (anxiety)
Score
Severity
Score
Severity
0-4
None
0-4
None
5-9
Mild
5-9
Mild
10-19
Moderate
10-14
Moderate
20-27
Severe
≥ 15
Severe
If the questionnaire is fully completed at screening and partially completed at Cycle 1 Day 1, the 
partially completed questionnaire will be considered as the baseline and then the total score will be 
missing at baseline in the analyses.
In case of missing answer to at least one item, the total score value will be missing except if available 
answers translate into a severe score (e.g. 20 for PHQ-9 and 20 for GAD-7).  As an example: if a 
patient partially completes the PHQ-9 questionnaire and indicates a response of “nearly every day” 
(3x7) for questions 1 to 7 and leaves questions 8 and 9 unanswered, then the total score is unknown 
but would be 21. As a result, it is reasonable to categorize the severity grading as “severe”. 
Number (%) of patients will be described at each time point according to PHQ-9 total score categories 
(0-4, 5-9, 10-19, 20-27). Similar analysis will be performed to report answer to question 9 (suicide) of 
PHQ-9 questionnaire. 
Shift tables (from Baseline to worst total score) based on the classification (0-4, 5-9, 10-19, 20-27) 
will be produced for PHQ-9 total score. Bar charts will be provided. Number (%) of patients will be 
described at each time point according to GAD-7 total score categories (0-4, 5-9, 10-14, ≥15). Shift 
tables (from Baseline to worst total score) based on the classification (0-4, 5-9, 10-14, ≥15) will be 
produced. Bar charts will be provided. 
Completion status will be analyzed using a ratio of the number of completely responded assessments 
(i.e., no missing answer or no missing evaluation) and the number of planned assessments. 
3.9.4
Vital signs
The number (%) of patients with clinically notable changes in vital signs from baseline will be 
presented. Clinically notable vital sign results are defined in Table 3-6
.
The following listing will be produced by treatment group:

Patients with clinically notable vital sign abnormalities
Table 3-6
Clinically notable changes in vital signs
Vital Sign (unit)
Clinically notable criteria
Weight (kg)
decrease > 7% from Baseline
increase > 7% from Baseline
Systolic blood pressure (mmHg)
≤ 90 and decrease from Baseline of >20
≥ 180 and increase from Baseline of >20
Diastolic blood pressure (mmHg)
≤ 50 and decrease from Baseline of > 15


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Vital Sign (unit)
Clinically notable criteria
Weight (kg)
decrease > 7% from Baseline
increase > 7% from Baseline
≥ 105 and increase from Baseline of > 15
Heart Rate (bpm)
≤ 50 and decrease from Baseline of > 15
≥ 120 and increase from Baseline of > 15
3.9.5
Performance Status
Performance status is assessed to attempt to quantify the impact of disease on daily life activities of 
patients. 
If more than one assessment is done within the same time window, the assessment performed closest 
to the target date will be used. For the baseline time window the target would be the study reference 
start date. If 2 assessments within a time window are equidistant from the target date (or if the closest 
assessment to the target date has two ECOG filled out on the same date), then the worst E COG PS 
value will be used.
The performance status will be listed or summarized by time windows as defined in the study protocol
and treatment arm using numbers (%) of patients in each score category. All the analyses for 
Performance Status will be performed on the FAS. 
ECOG PS scale is used to assess physical health of patients, ranging from 0 (most active) to 5 (least 
active).
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 End of 
Treatment assessment. 
The following time-based intervals (Table 3-7) will be used to group the ECOG P.S. data over time. 
Day x is defined as date of ECOG P.S.Asessment – randomization date + 1.
Table 3-7
Time based intervals to group ECOG P.S.
Visit
Time Interval 
Baseline 
Time period on or before the randomization date 
Cycle 1
Day 2 to Day 14
Cycle 2
Day 15 to Day 42
Cycle 3,4,..
Or EOT
+/- 2 weeks centered around the planned 
assessment i.e. Day 43, Day 70 for Cycle 3, Day 
71 to Day 98 for Cycle 4 and so on…
(cycle x: (x-1)*28 -2*7+1 ; (x-1)*28 +2*7)
Time windows are applicable for descriptive summary of ECOG P.S. data by visit. It is not applicable 
to time to deterioration analysis since all post-baseline assessments will be considered.


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If more than one assessment is done within the same time window, the assessment performed closest 
to the target date will be used. For the baseline time window the target would be study day 1 (i.e., just 
before the patient starts randomized treatment phase); for the Cycle 1 ECOG P.S. the target would be 
study day 2 (C1D1+1) and thereafter it would be every 4 weeks, corresponding to the planned 
assessment times of day 29 (Cycle 2), day 57 (Cycle 3), etc. If 2 assessments within a time window 
are equidistant from the target date then the assessment obtained prior to the target date will be 
considered. If the closest assessment to the target date has two assessments filled out on the same date, 
then the worst of these assessments will be used.
Time to definitive worsening of performance status may also be analyzed.
Time to definitive deterioration of the ECOG PS is the number of days between the date of 
randomization and the date of the assessment at which definitive deterioration is seen. The ECOG PS 
deterioration is considered definitive if there is an increase in the performance status by at least one 
category relative to the baseline and no later improvement compared to the predefined threshold is 
observed within the course of the study following the time point when the deterioration was observed.
Baseline (see Section 2.1.8) is the last available assessment on or before date of randomization. If a 
patient has 2 ECOG PS values at the same date, the worst ECOG PS value will be taken as ‘baseline’.
Example : If the ECOG PS is 1 at baseline and then 1 , 2 , 1 , 2 , 3 at D28, D57, D83, D115, and D150 
respectively, then the time to definitive worsening is D115.
Example : if the ECOG PS is 1 at baseline and then 1 , 1 , 2 at D28, D57, and D83 respectively, with 
no assessment of the ECOG PS after D83 then the time to definitive worsening is 83 days.
If a definitive deterioration is observed after two or more missing assessments, patient is censored at 
the date of their last available ECOG PS assessment prior to the deterioration.
Example : If a patient has an assessment at week 6, misses the following two assessments on weeks 
10 and 14 and a definitive deterioration is observed on week 15, then the event will be censored at
week 6.
In addition, death is considered as a worsening of performance status if it occurs close to the last 
available assessment, where “close” is defined as twice the planned (i.e. protocol scheduled) period 
between two assessments. This avoids overestimating the time to definitive worsening in patients 
dying after an irregular assessment scheme. Patients who die after more than twice the planned p eriod 
between two assessments are censored at the date of their last available assessment of the performance 
status. 
Example: If the last assessment is at week 6 and the patient dies on week 10, the definitive 
deterioration date will be week 10. On the other hand, if the last assessment is at week 6 and the 
patient dies on week 16, which is after more than twice the planned period between two assessments 
since the last assessment (week 6), then the patient will be censored at week 6.
Patients receiving any further anti-neoplastic therapy before definitive worsening will be censored at 
the date of their last assessment before starting this therapy. Patients that have not worsened as of the 
cutoff date will be censored at the date of their last assessment before the cutoff.
Patients without baseline ECOG PS or without any post-baseline ECOG PS will be censored at the 
date of randomization with censoring reason being ‘No baseline score’ or ‘No post-baseline score’, 
respectively. However, patients without post-baseline ECOG PS* who die within D2 days after date of 


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randomization (which correspond to the first two planned  assessments) will be counted as having a 
definitive deterioration of the ECOG PS at the date of death. For more details of censoring reasons 
for time to deterioration of ECOG PS , please refer to Section 3.8.2.4
Note: This is a protocol deviation as this is an inclusion criterion from the study protocol. The variable 
D2 corresponds to twice the protocol defined ECOG assessment interval plus twice the time window 
around each assessment. In this study, D2= 2*4*7+2*3=62 days.
Kaplan-Meier estimates will be constructed for each treatment arm. Median for each treatment group 
will be obtained along with 95% confidence intervals. 
ECOG PS scale is used to assess physical health of patients, ranging from 0 (most active) to 5 (least 
active):
Table 3-8
ECOG Performance Status
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than  50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
A definitive deterioration will be considered for ECOG when there is an increase in the 
ECOG score by a margin of one unit or higher. The time to definitive deterioration of ECOG 
scores by treatment will be summarized using the Kaplan Meier method. 
3.9.6
Cardiac assessments
The summaries will include only assessments on treatment. All assessments will be listed and those 
collected outside of the treatment window will be flagged.
3.9.6.1
ECG parameters
ECG data from local assessment will be summarized. 
As recommended in the FDA guidance on Clinical Evaluation of QT/QTc interval prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs, the number (%) of patients having notable 
ECG interval values will be summarized by treatment group as follows:
Table 3-9
Clinically notable ECG values
ECG parameter (unit)
Clinically notable criteria
QT (ms), QTcF (ms)
New > 450 ms 
New > 480 ms 
New > 500 ms


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ECG parameter (unit)
Clinically notable criteria
Increase from Baseline > 30 ms
Increase from Baseline > 60 ms 
PR duration (ms)
Increase > 25% from Baseline and to PR duration > 200 
QRS duration (ms)
Increase > 25% from Baseline and to QRS duration > 110 
Heart Rate (bpm)
≤ 50 and decrease from Baseline of ≥ 25%
≥ 120 and increase from Baseline of ≥ 25%
A newly occurring ECG abnormality is defined as an abnormal post-baseline ECG finding that is not 
present at Baseline. Baseline is defined as the last ECG measurements taken at
The percentage of patients having notable ECG interval values will be summarized by treatment and 
based on the total number of patients in the Safety set.  
The following listing will be produced by treatment group:

Patients with clinically notable ECG abnormalities
3.9.6.2
Cardiac imaging (MUGA / ECHO)
Shift tables comparing baseline to worst post-baseline cardiac imaging overall interpretation (MUGA 
or ECHO) will be provided. Percentages will be based on all patients in the Safety setNote: If there is 
any change in the methodology used throughout the study compared to Baseline, the post-baseline 
values will be discarded in the tables presenting comparisons to Baseline.
Descriptive statistics of the left ventricular ejection fraction (LVEF) at Baseline, worst post-baseline
and change from Baseline to worst post-baseline value will be provided. 
The following listing will be produced by treatment group:

Patients with newly occurring clinically significant abnormality
3.10
Subgroup analyses
3.10.1
Efficacy
PFS and OS will be summarized for each level of the stratification factor: Number of prior lines of 
therapy (1 vs 2) and region of investigator site (North America vs Rest of the world) . Similar analysis 
for PFS,OS and ORR will performed in the subgroups of 
i.
PI3K pathway status (activated vs. non-activated) based on archival tumor.
iii.
PIK3CA status (Wildtype vs Mutant) based on archival tumor and ctDNA(at screening).


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For each of the subgroups, the following analyses will be performed:

Hazard ratio with 95% C.I and Median with 95% CI of Kaplan-Meier survival estimates for PFS
and OS 

ORR will be presented by treatment group along with exact 95% CIs (Clopper & Pearson, 1934). 
3.11
Pharmacokinetic Analysis 
FPAS will be used in the non-compartmental analysis and PAS will be used in the population PK and 
exposure response analysis.
The plasma samples from all patients will be assayed for BKM120 concentrations by Novartis or its 
designee using methods described in the Laboratory manual. Values below the assay LLOQ are 
assigned a value of zero in the BA source dataset. Therefore such values will be treated as zero in 
summary statistics and listings except for the geometric mean and geometric CV% for which they are 
treated as missing. Missing values will be labeled accordingly. All concentrations below the LLOQ or 
missing data will be labeled as such in the concentration data listings.
3.11.1
Non compartmental analysis
The aim of this PK analysis is to have a preliminary PK assessment of BKM120 exposure when 
administered in combination with paclitaxel in this specific population. Descriptive graphical plots of 
geometric mean and arithmetic mean (SD) BKM120 plasma concentration – time profiles at cycle 1 
Day 15 will be generated. Additionally graphical plots of individual BKM120 plasma concentration –
time profiles may be generated. Further graphical exploratory analyses may be carried out if deemed 
appropriate. 
The following PK parameters of BKM120 : 

AUClast : The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1)

AUCtau : The area under the plasma concentration-time curve from time zero to the end of 
the dosing interval, tau (mass x time x volume-1)

Cmax : The maximum (peak) observed plasma drug concentration after single dose 
administration (mass x volume-1)

Tmax : The time to reach maximum (peak) plasma drug concentration after single dose 
administration (time)

CL/F : Apparent total body clearance of drug from the plasma after oral administration
(volume x time-1)

Rsqadj : Square of the correlation coefficient associated with λz


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will be summarized using descriptive statistics presenting n(number of observations), arithmetic mean, 
SD, coefficient of variation CV (%), geometric mean, geometric CV%, median, minimum and 
maximum. For Tmax only median, minimum and maximum will be provided. For Rsqadj and λz only 
listings will be provided. Calculation of AUCtau will be based on the value of tau = 24 hours.
Calculation of PK parameters will include up to last measurable concentration Tlast, as outlined in the 
Novartis Internal Guidance Standardization of pharmacokinetic parameters. Similarly summary 
statistics will be provided for concentration by scheduled time point including both n(number of values 
to be reported) and m(number of non-zero values to be reported) in addition to the summary statistics 
listed above.
The derived PK parameters will be presented with PK data collected in other trials with 
[CBEZ235A2118] or without paclitaxel [CBKM120A2101]. This analysis aims to further characterize 
BKM120 exposure in this specific population but no formal analysis will be conducted.
3.12
Biomarkers 
The analysis of biomarker data collected at baseline will include basic descriptive statistics by 
treatment group and subgroup analyses with respect to key efficacy endpoints – PFS, OS and 
ORR for the FAS population as detailed in section 3.10.1.
For all markers with post-baseline data, baseline values/levels will be listed by patient and 
treatment group. 
There may be circumstances when a decision is made to stop a sample collection, or not perform or 
discontinue the analysis of blood/archival tumor due to either practical or strategic reasons (e.g. issues 
related to the quality and or quantity of samples, or issues related to the assay that preclude the 
analysis of samples). Under such circumstances, the number of samples may be inadequate to perform 
a rigorous data analysis and the available data will only be listed.
3.12.1.1
Outline of Data analysis
The number/proportion (%) of patients with molecular alterations from the screening archival or fresh 
biopsy tumor sample will be summarized overall and by treatment group. Molecular alterations 
identified using Next Generation Sequencing technology is planned to be summarized for only those 
genes found to be altered in at least 5 % of patients, as well as key genes, such as PIK3CA, PTEN, 
AKT and HPV even if they do not achieve this minimum. 
 
 
  
For analyses based on PI3K activation status (as per PIK3CA mutation, PTEN expression, see 
Sections 3.5.3 and 3.10.1.
 
 
 
Molecular alterations in ctDNA measured from the blood samples at screening will also be 
summarized and listed. It is planned to compare alterations identified in ctDNA at screening to those 
obtained in archival tumor samples.


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With the collection of optional post-baseline fresh tumor biopsy samples, proteomic and genomic 
analysis results may be summarized.  Otherwise, data may only be listed if there is sufficient sample 
size. Additional post hoc analyses of these data may occur and will be documented as  part of separate 
biomarker report.

Biomarker Status
The type of PI3K pathway activation status will be described (PIK3CA mutation, PTEN low 
expression). Biomarker assessment characteristics (archival tumor, fresh tumor, and their sources) will 
also be described. 
Pi3K Activation status will be defined as following:
Overall Mutation Load
Mutational load will be defined as the number of nonsynonymous alterations 
(mutations and short insertions/deletions) per patient. To exclude germline alterations 
from mutational load, alterations with an allelic fraction (AF; fraction of sequencing 
reads supporting the alteration) consistent with germline alterations (0.45 ≤AF < 0.55 
or AF ≥0.9) which are also of unknown functional significance will not be included. In 
addition, copy number alterations will be excluded in calculating mutational 
load.
 
 
PIK3CA Mutation
PTEN Loss of 
Expression
Pi3K Activation 
Status
Yes (mutant)
Yes
Yes
Yes (mutant)
No   
Yes
Yes (mutant)
Missing
Yes
Yes (mutant)
Unknown
Yes
No
Yes
Yes
No
No
No
No
Missing
Missing
No
Unknown
Unknown
Missing
Yes
Yes
Missing
No
Missing
Missing
Missing
Missing
Missing 
Unknown
Missing
Unknown
Yes
Yes
Unknown
No
Unknown
Unknown
Missing
Missing
Unknown
Unknown
Unknown


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TP53 disruptive/non-disruptive classification
TP53 alterations will be classified as disruptive versus non-disruptive based on the functional 
impact of the alteration on protein effect (Poeta et al, NEJM , 2007). Nonsense, frameshift and splice 
site acceptor/donor TP53 alterations will be classified as disruptive.  In addition, nonconservative 
alterations (change in polarity/charge of amino acid) located inside the key DNA-binding domain
(codons 163-195 or 236-251) will be classified as disruptive. All other TP53 alterations will be 
classified as non-disruptive.  The classification of amino acids by polarity and charge can be found in 
the supplementary appendix of Poeta et al (NEJM, 2007).  Patients will be classified into disruptive, 
non-disruptive and non-altered groups according to the following criteria:
TP53 alteration
TP53 category
1+ TP53 disruptive alterations
Disruptive
1+ TP53 non-disruptive alterations and 0 disruptive alterations
Non-disruptive
0 disruptive and 0 non-disruptive alterations
Non-altered
3.12.1.2
Data handling principles
PTEN loss of expression i.e PTEN Null / Low is < 10% tumor cells expressing PTEN at 1+ level (and
no cell expressing PTEN at 2+ or 3+ levels).
3.13
Interim safety review analyses
A DMC will be established to monitor and review the interim safety data on an ongoing basis. The 
first safety review of the patients will occur 3 – 6 months after FPFV and thereafter the safety review 
will occur every 3 – 6 months.  In addition to these periodic safety reviews the DMC will also receive 
and review the baseline biomarker data of patients related to their PI3K activation status. The analysis 
plan for interim safety and biomarker review is detailed in DMC RAP module 3.
4
General statistical methodology
4.1
Baseline comparability
Appropriate descriptive summary statistics of baseline variables (see Section 3.5) will be provided as 
in-text tables in the core CSR and also in the post-text tables. The summaries will be grouped by 
treatment group, but no p-values will be provided.
4.2
Center pooling
All study centers will be combined for the analysis unless otherwise specified. No center effect will be 
assessed due to expected small size of centers.


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4.3
One-sided vs. two-sided test
Not Applicable.
4.4
Time-to-event analyses
The following sections present a general methodology used to analyze time-to-event variables (e.g. 
progression-free survival, overall survival, duration of response).
4.4.1
Analysis of time-to-event data with ties
The STRATA statement in LIFETEST procedure will be used analyze time to event data with ties. 
The PHREG procedure in SAS with option TIES=EXACT will be used to fit the Cox proportional 
hazards model.
4.4.2
Kaplan-Meier estimates
The survival function in each treatment group will be estimated using the K-M (product-limit) method 
as implemented in PROC LIFETEST. Median survival for each treatment group will be obtained along 
with 95% CIs calculated from PROC LIFETEST output. K-M estimates with 95% CIs at specific time 
points will be summarized. The K-M graphs as well as the statistics (median, hazard ratio etc.) 
displayed on the graph will be obtained from the SAS software.
General SAS code is:
PROC LIFETEST data=dataset; 
TIME survtime*censor(1);
STRATA stratum1 stratum2....<stratums> /group=trt;
RUN;
/* stratum1 to stratums represent the stratification variables assigned at randomization (to be included 
for stratified analysis only);
survtime represents variable containing event/censor times;
censor represents censoring variable (1=censored, 0=event);
trt represents treatment group variable; */
4.4.3
Hazard ratio
The HR as a measure of treatment effect will be derived from the Cox proportional hazards model 
using SAS procedure PHREG with TIES=EXACT option in the MODEL statement. The stratified 
unadjusted Cox model will be used (where the baseline hazard function is allowed to vary across strata) 
for the primary analysis, i.e. the MODEL statement will include only the treatment group variable as a 
covariate and the STRATA statement will include stratification variable(s). The strata information will 
be based on the data obtained from IRT that was utilized for randomization.
General SAS code for the stratified Cox model:
PROC PHREG data=dataset;
MODEL survtime*censor(1)=trt / TIES=EXACT;
STRATA stratum1 stratum2....<stratums>;
RUN;


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/* survtime represents variable containing event/censor times;
censor represents censoring variable (1=censored, 0=event);
trt represents treatment group variable;
stratum1 to stratums represent the stratification variables assigned at randomization (to be included 
for stratified analysis only) */
4.5
Bayesian methodology for the PFS and OS analyses
PFS and OS analysis will be performed in the full population using Bayesian methodology. 
The PoC criteria for these two endpoints (described in Section 3.8.1.2) will be considered based on HR 
from a stratified unadjusted Cox proportional hazards regression model and Bayesian approaches to 
declare PoC for PFS and OS respectively.
Posterior distribution of logarithm of hazard ratio for PFS 
Let  θ  denote  the  natural  logarithm  of  hazard  ratio  (HR)  in  terms  of  the  PFS  of BKM120 +
paclitaxel  arm  vs.  placebo + paclitaxel  arm, and θ < 0 indicates efficacy in favor of BKM120 +
paclitaxel. 
Assume that θ follows a Normal prior distribution 
θ ~ N(θ0,4/ n0), 
where θ0 is the specified prior mean and n0 is the number of events worth  of  prior  information.  
Let  ym denote  the  log(HR)  of  PFS estimated from the current study based on m observed events, 
then ym ~ N(θ,4/m). 
Therefore the posterior distribution of θ is
θ ~ N(φym +(1-φ) θ0 ,4/(m+n0 )) 
where φ = m/(m+ n0 ).
A non-informative prior (HR=1 and n0=0) is used to derive the posterior distribution of θ given above; 
i.e,
θ ~ N(ym ,4/m)
Posterior distribution of logarithm of hazard ratio for OS 
The posterior distribution for the logarithm of hazard ratio for OS will be estimated in the same way 
described above for PFS using the overall survival data.
4.6
Confidence intervals for response rate and disease control rate
Response rate and disease control rate will be summarized as percentages with 95% confidence 
intervals. As a standard, an exact binomial confidence interval (implemented using SAS procedure 
FREQ with EXACT statement for one-way tables) will be calculated (Clopper & Pearson, 1934).
5
References
Brookmeyer R, Crowley J (1982) A confidence interval for the median survival time. Biometrics, 38: 
29-41.


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Clopper, C.; Pearson, E.S. (1934).  The use of confidence or fiducial limits illustrated in the case of the 
binomial.  Biometrika; 26, 404-413.
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall.
CPMP/EWP/2863/99 (2003). Points to Consider on Adjustment for Baseline Covariates 
FDA (2007). Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, US Department of Health and Human Services.
FDA (2005), Guidance for industry E4 Clinical Evaluation of QT/QTc interval prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs,
International Conference on Harmonization. E9: Statistical Principles for Clinical Trials.
Schemper, M.; Smith, TL (1996). A Note on Quantifying Follow-up in Studies of Failure Time. 
Controlled Clinical Trials; 17:343-346
M. Luana Poeta, M.D, et al. (2007) TP53 Mutations and Survival in Squamous-Cell Carcinoma of the 
Head and Neck. N Engl J Med. 2007 December 20; 357(25): 2552–2561.