Conditions: Brain Metastases Breast Cancer Metastatic Breast Cancer
Keywords: Breast Cancer Triple Negative Breast Cancer Brain Metastases Capecitabine Metastatic Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
This is a study to determine the safety and effectiveness of BKM120 plus capecitabine in breast cancer patients with brain metastases.

Both capecitabine and BMK120 have previously shown activity in patients with breast cancer. Like capecitabine, BMK120 is also effective in crossing the blood brain barrier making it a preferred candidate for its evaluation in patients with metastatic breast cancer (MBC).

Detailed description:
This is a Phase 2, multicenter, single-arm study to determine the safety and efficacy of BKM120 plus capecitabine in breast cancer patients with brain metastases. 40 patients will be included, who have either ER+/HER2-, HER2+ or triple negative breast cancer..

The Graded Prognostic Assessment (GPA) is a recently developed, validated prognostic score for patients with brain metastases. The Graded Prognostic Assessment will be utilized to evaluate efficacy in this clinical study.

Capecitabine is a prodrug which is enzymatically converted to 5-fluorouracil in its tumor target where it inhibits DNA synthesis and slows tumor growth. It is currently FDA approved for both colorectal and breast cancer. BMK120 is a pan phosphatidylinositol-3-kinase inhibitor being developed under IND# 102,823 by Novartis Corporation. As of September 2012 over 600 patients had been enrolled in fourteen separate Novartis sponsored monotherapy or combination therapy clinical studies of BMK120.

Phosphatidylinositol-3-kinase (PI3K) signaling regulates diverse cellular functions including cell proliferation, survival, translational regulation of protein synthesis, glucose metabolism, cell migration, and angiogenesis. PI3K signaling also serves a central role in the pathogenesis of numerous cancers.

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. Resistance to a variety of therapeutic interventions, including hormonal therapy, anti-HER2 therapies and chemotherapy can also be linked to constitutive activation of the PI3K pathway.

Preliminary data suggest that activation of the PI3K pathway is a predictor of a poor prognostic outcome in many cancer types. Thus, as a pan-PI3K inhibitor, BMK120 may provide a therapeutic benefit to patients with MBC. Both capecitabine and BMK120 have previously shown activity in patients with MBC. Like capecitabine, BMK120 is also effective in crossing the blood brain barrier making it a preferred candidate for its evaluation in patients with MBC.

Trastuzumab is a monoclonal antibody that targets the HER2 receptor which is overexpressed or amplified in approximately 20-25% of breast cancers. The clinical benefit of trastuzumab in women with metastatic breast cancer has been demonstrated in two pivotal studies.

Current clinical experience with BMK120 has shown that its most frequent adverse events (AEs) include fatigue, decreased appetite, diarrhea, hyperglycemia, nausea, rash and mood alteration disorders. Therefore patients will be closely monitored for fasting plasma glucose (FPG) HbA1c, and insulin C-peptide. Patients will also be frequently and routinely evaluated for mood disorders and disturbances. The remaining most frequent AEs will be detected by regular, frequent monitoring with symptomatic treatment to be provided as required.

Arms:
arm 1: BKM120 will be administered at a dose of 100 mg orally (PO) daily. Capecitabine will be administered at a dose of 1000 mg/m2 orally (PO) twice a day (rounded down to the nearest 500 mg pill) 14 days on and 7 days off.

For patients with HER2+ MBC only, standard every 3-weekly trastuzumab (6 mg/kg IV) will be added to the capecitabine/BKM120.

Interventions: intervention 1: BKM120 intervention 2: capecitabine intervention 3: Trastuzumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
Delta Clinical Research, LLC 
 
Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
[24JUN2016] 
 
1 
 
 
590-56+/0. 
Phase II Multicenter Single-arm Study of BKM120 plus Capecitabine 
for Breast Cancer Patients with Brain Metastases 
CBKM120ZUS39T 
Sponsor: Delta Clinical Research, LLC 11-025 
 
 
 
Study Investigators: 
Joyce O’Shaughnessy, MD 
Baylor Sammons Cancer Center 
3410 Worth Street 
Dallas, Texas  75246 
(214) 370-1796 
 
Morris D. Groves, MD, JD 
Texas Oncology 
901 W. 38th St., Suite 200 
Austin, TX 78705 
(512) 421-4100 
 
 
Date: 
 
 
 
 
 
 
October 5, 2013 
February 17, 2014 (Amendment #1) 
July 22, 2015 (Amendment #2) 
June 24, 2016 (Amendment #3) 
 
 
 
CONFIDENTIAL 
Information and data included in this protocol contain trade secrets and privileged or confidential information that is 
the property of Delta Clinical Research, LLC (“Delta”) and Novartis Corporation. No person is authorized to make 
it public without written permission of Delta, and Novartis Corporation. These restrictions on disclosure will apply 
equally to all future information supplied to you, which is indicated as privileged or confidential. This material may 
be disclosed to and used by your staff and associates as may be necessary to conduct this clinical study. 
 


Delta Clinical Research, LLC 
 
Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
[24JUN2016] 
 
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Table of Contents 
 
1 
Background ........................................................................................................................10 
1.1 
Disease Background ...............................................................................................10 
1.2 
PI3K Pathway and Mechanism of Action ..............................................................11 
1.2.1 
PI3K pathway activation in MBC .........................................................12 
1.3 
Study Treatments ...................................................................................................15 
1.3.1 
Buparlisib ..............................................................................................15 
1.3.2 
Capecitabine ..........................................................................................39 
1.3.3 
Buparlisib in combination with capecitabine ........................................39 
1.3.4 
Buparlisib in combination with trastuzumab .........................................40 
1.4 
Study Rationale ......................................................................................................40 
1.4.1 
Rationale for dose selection...................................................................40 
2 
Study objectives .................................................................................................................41 
3 
Exploratory Investigational Plan .......................................................................................41 
3.1 
Overall Study Design .............................................................................................41 
3.2 
Study Population ....................................................................................................45 
3.2.1 
Patient population ..................................................................................45 
3.2.2 
Registration procedures .........................................................................46 
3.2.3 
Inclusion and exclusion criteria .............................................................46 
4 
Treatments .........................................................................................................................51 
4.1 
Interruption or Discontinuation of Treatment ........................................................51 
4.1.2 
Known Undesirable Side Effects of Buparlisib .....................................64 
4.1.3 
Criteria for capecitabine dose modification ..........................................71 
4.1.4 
Trastuzumab – Cardiac Monitoring and Cardiomyopathy 
Management Guidelines ........................................................................72 
4.1.5 
Reasons off treatment ............................................................................72 
4.1.6 
Reasons for taking patients “off study” .................................................73 
4.2 
Treatments ..............................................................................................................73 
4.2.1 
Study treatment administration ..............................................................73 
4.2.2 
Dosing regimen .....................................................................................74 
4.2.3 
Concomitant therapy .............................................................................75 
Table 4-11 List of CYP450 Substrates to be used with caution ............................82 
4.3 
Visit Schedule and Assessments ............................................................................83 
4.3.1 
Visit schedule ........................................................................................83 
4.3.2 
Efficacy assessments .............................................................................89 
4.3.3 
Safety assessments.................................................................................90 


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Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
[24JUN2016] 
 
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4.3.4 
Treatment compliance ...........................................................................91 
4.3.5 
Adverse events.......................................................................................91 
4.3.6 
Serious adverse events ...........................................................................91 
4.3.7 
Instructions for rapid notification of serious adverse events .................92 
4.3.8 
Laboratory evaluations ..........................................................................94 
4.3.9 
Vital signs ..............................................................................................95 
4.3.10 
Physical examination .............................................................................95 
4.3.11 
Neuropsychiatric assessments ...............................................................95 
4.3.12 
ECG/EKG –ECHO/MUGA...................................................................95 
4.3.13 
Performance status.................................................................................95 
4.3.14 
Disease-related symptom assessment ....................................................96 
4.3.15 
Drug levels and pharmacokinetic assessments ......................................96 
5 
Data management ..............................................................................................................96 
5.1 
Data collection .......................................................................................................96 
6 
Statistical methods .............................................................................................................96 
6.1 
Populations for analysis .........................................................................................96 
6.1.1 
Analysis populations .............................................................................96 
6.1.2 
Patient characteristics ............................................................................96 
6.1.3 
Patient disposition .................................................................................97 
6.2 
Hypothesis and endpoints ......................................................................................97 
6.3 
Sample size and projected study duration ..............................................................97 
6.4 
Statistical methods .................................................................................................97 
6.4.1 
Primary efficacy analysis ......................................................................97 
6.4.2 
Secondary efficacy analysis ..................................................................98 
7 
Protocol and Data Development ........................................................................................98 
7.1 
Ethics ......................................................................................................................98 
7.1.1 
Institutional review board ......................................................................98 
7.1.2 
Patient informed consent .......................................................................99 
7.1.3 
Confidentiality of records ....................................................................100 
7.2 
Study Records ......................................................................................................100 
7.2.1 
Documentation ....................................................................................100 
7.2.2 
Electronic case report form procedures ...............................................100 
7.3 
Monitoring/Site Visits ..........................................................................................101 
7.4 
Modification of Protocol ......................................................................................101 
8 
References ........................................................................................................................102 
APPENDICES ........................................................................................................................108 
 
 


Delta Clinical Research, LLC 
 
Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
[24JUN2016] 
 
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List of Abbreviations 
 
AE  
 
 
Adverse Event 
ADME 
 
Absorption, Digestion, Metabolism, Excretion 
AKT   
 
See PKB (protein Kinase B) 
ALT   
 
Alanine aminotransferase/glutamic-pyruvic transaminase/GPT 
ANC   
 
Absolute Neutrophil Count 
ASCO  
 
American Society of Clinical Oncology 
AST   
 
Aspartateaminotransferase/glutamic-oxaloacetic transaminase/GOT 
BAL  
 
Bronchoalveolar lavage 
BC 
 
 
Breast Cancer 
BRCA1/2 
 
Breast Cancer 1/2  
BUN   
 
Blood Urea Nitrogen 
CBC   
 
Complete Blood Count 
CBR  
 
Clinical Benefit Rate 
C1D1  
 
Cycle 1 Day 1 
CK  
 
 
Creatine Kinase 
CK-MB  
 
Creatine Kinase - Muscle and Brain isoenzyme 
CNS 
 
 
Central Nervous System 
CR  
 
 
Complete Response 
CRD   
 
Clinical Research and Development 
CS  
 
 
Cowden Syndrome 
CT  
 
 
Computed Tomography 
CTI 
 
 
Clinical Trial Information 
CTCAE  
 
Common Terminology Criteria for Adverse Events 
CTMS  
 
Clinical Trial Management System 
CYP3A4 
 
Cytochrome P450 3A4 
CYP450 
 
Cytochrome P450 
DLco  
 
Diffusing capacity of the Lung for Carbon Monoxide 
DLT   
 
Dose Limiting Toxicity 
Delta  
 
Delta Clinical Research, LLC 
DSMB  
 
Drug Safety Monitoring Board 
DSTPlan 
 
Double Precision Study Planning (software) 


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ECG   
 
Electrocardiogram 
ECHO  
 
Echocardiogram 
ECOG  
 
Eastern Cooperative Group 
eCRF                     
electronic Case Report Form 
eDC 
 
 
electronic Data Capture 
EGFR   
 
Epidermal Growth Factor Receptor 
EOT 
 
 
End Of Treatment 
ER 
 
 
Estrogen Receptor 
18F-FDG  
 
[18F]-Fluorodeoxyglucose 
FFPE  
 
Formalin Fixed Paraffin Embedded 
FGF 
 
 
Fibroblast Growth Factor 
FISH  
 
Fluorescence In Situ Hybridization 
FNA  
 
Fine Needle Aspiration 
FOXO3a 
 
Forkhead Box O3 
FPG   
 
Fasting Plasma Glucose 
FSH 
 
 
Follicle Stimulating Hormone 
GABA  
 
Gamma-Amino Butyric Acid 
GAD-7 
 
Generalized Anxiety Disorder Scale 7 
GCP   
 
Good Clinical Practice 
GGT  
 
Gamma-Glutamyl Transferase 
GI  
 
 
Gastrointestinal 
GLP 
 
 
Good Laboratory Practice 
GPA  
 
Graded Prognostic Assessment 
GSK3 beta 
 
Glycogen Synthase Kinase-3 
HbA1c  
 
Hemoglobin A1c 
HDL   
 
High density lipoprotein 
HER2  
 
Human Epidermal Growth Factor Receptor 2 
hERG  
 
Human Ether-à-go-go Related Gene 
HIAA  
 
5-Hydroxyindoleacetic Acid 
HIV                     
Human Immunodeficiency Virus 
HLGT  
 
High Level Group Term 
HPF                         
High Power Field 
 


Delta Clinical Research, LLC 
 
Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
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ICH   
 
International Conference on Harmonization 
IC50  
 
Half-maximal Inhibitory Concentration 
IEC  
 
 
Independent Ethics Committee 
IGF-1  
 
Insulin-like Growth Factor-1 
IHC 
 
 
Immunohistochemistry 
 
 
 
INPP4B 
 
Inositol Polyphosphate 4-phosphatase type II 
INR 
 
 
International Normalized Ratio 
IRB  
 
 
Institutional Review Board 
LDL   
 
Low density lipoprotein 
LFT 
 
 
Liver Function Test 
LFU 
 
 
Lost to Follow Up 
LumA  
 
Luminal A 
LumB  
 
Luminal B 
LVEF   
 
Left Ventricular Ejection fraction 
MBC  
 
Metastatic Breast Cancer 
MDASI-BT 
 
M.D. Anderson Symptom Inventory – Brain Tumor 
MEFs  
 
Mouse Embryonic Fibroblasts 
MRI   
 
Magnetic Resonance Imaging 
MTD   
 
Maximum Tolerated Dose 
MTOR  
 
Mammalian Target of Rapamycin 
MTORC2 
 
mTOR Complex 2 
NE 
 
 
Non-evaluable 
NEC  
 
Not Elsewhere Classified 
MUGA  
 
Multiple Gated Acquisition Scan 
ORR  
 
Objective Response Rate 
OS 
 
 
Overall Survival 
PARP  
 
Poly (ADP-Ribose) Polymerase 
PD  
 
 
Pharmacodynamic 
PDFG  
 
Platelet Derived Growth Factor 
PET   
 
Positron Emission Tomography 
PgR 
 
 
Progesterone Receptor 
PHQ9  
 
Patient Health Questionnaire 9 
PI3K   
 
Phosphatidylinositol 3’-kinase 


Delta Clinical Research, LLC 
 
Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
[24JUN2016] 
 
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PIP3 
 
 
Phosphatidylinositol Phosphate 3 
PK  
 
 
Pharmacokinetic 
PKB   
 
Protein Kinase B (or AKT) 
PR 
 
 
Partial Response 
pS6 
 
 
Phosphorylated S6 Protein of the 40S Ribosomal Subunit 
PT  
 
 
Prothrombin Time 
PTEN   
 
Phosphatase and Tensin homolog 
PTT   
 
Partial Thromboplastin Time (also known as APTT) 
QTc   
 
QT interval (corrected) 
RAD001 
 
Everolimus 
RAS1  
 
Rat Sarcoma Gene 1 
RBC  
 
Red Blood Cells 
REB   
 
Research Ethics Board 
RECIST  
 
Response Evaluation Criteria In Solid Tumors 
S6K   
 
Protein Kinase S6 
SAE   
 
Serious adverse event 
SD 
 
 
Stable Disease 
SHIP2  
 
SH2-containing 5'-Inositol Phosphatase 2 
SI 
 
 
Study Investigator 
SOP   
 
Standard Operating Procedure 
Src 
 
 
Src Nonreceptor Tyrosine Kinase 
SRS 
 
 
Stereotactic Radiosurgery 
SUV   
 
Standardized Uptake Value 
TCGA  
 
The Cancer Genome Atlas 
TdP 
 
 
Torsades de Pointes 
TNBC  
 
Triple Negative Breast Cancer 
TR-FRET 
 
Time Resolved-Fluorescence Resonance Energy Transfer 
TSC1  
 
Tuberous Sclerosis Complex 1 
TTP   
 
Time to Progression 
ULN   
 
Upper Limit of Normal 
UPN  
 
Unique Patient Number 
VPs34  
 
Class III Phosphoinositide 3-Kinase Isoform 
WBC   
 
White Blood Count 


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Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
[24JUN2016] 
 
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WBRT  
 
Whole Brain Radiation Therapy 
WHO   
 
World Health Organization 
WOCBP 
 
Women of Child-Bearing Potential 
 
 
 


Delta Clinical Research, LLC 
 
Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
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Synopsis 
 
This is a Phase 2, multicenter, single-arm study to determine the safety and efficacy of buparlisib 
(BKM120) plus capecitabine in breast cancer patients with brain metastases.  42 patients will be 
included, who have either ER+/HER2-, HER2+ or triple negative breast cancer.    
The primary objective will be to determine the clinical benefit rate (CBR) defined as the 
proportion of patients with the best overall response of complete response (CR) or of partial 
response (PR) or of stable disease (SD) lasting at least 24 weeks.  The Graded Prognostic 
Assessment (GPA) is a recently developed, validated prognostic score for patients with brain 
metastases (Sperduto 2008, Sperduto 2012b).  The Graded Prognostic Assessment will be 
utilized to evaluate efficacy in this clinical study.  Secondary objectives include an assessment of 
objective response rate (ORR) in the CNS, the median time to progression (TTP) and the median 
overall survival (OS) as well as the usual requirement to characterize the safety and tolerability 
of the combined buparlisib plus capecitabine therapy.   
Capecitabine is a prodrug which is enzymatically converted to 5-fluorourocil in its tumor target 
where it inhibits DNA synthesis and slows tumor growth.  It is currently FDA approved for both 
colorectal and breast cancer.  Buparlisib is a pan phosphatidylinositol-3-kinase inhibitor being 
developed under IND# 102,823 by Novartis Corporation.  As of September 2012 over 600 
patients had been enrolled in fourteen separate Novartis sponsored monotherapy or combination 
therapy clinical studies of buparlisib which are summarized in Section 1.3.1.3.1.   
Phosphatdyinositol-3-kinase (PI3K) signaling regulates diverse cellular functions including cell 
proliferation, survival, translational regulation of protein synthesis, glucose metabolism, cell 
migration, and angiogenesis (Katso, et. al., 2001).  PI3K signaling also serves a central role in 
the pathogenesis of numerous cancers.  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 
hormonal therapyanti-HER2 therapies and chemotherapy can also be linked to constitutive 
activation of the PI3K pathway (McCubrey 2006).   
Preliminary data suggest that activation of the PI3K pathway is a predictor of a poor prognostic 
outcome in many cancer types.  Thus, as a pan-PI3K inhibitor, buparlisib may provide a 
therapeutic benefit to patients with MBC.  Both capecitabine and buparlisib have previously 
shown activity in patients with MBC.  Like capecitabine, buparlisib is also effective in crossing 
the blood brain barrier making it a preferred candidate for its evaluation in patients with MBC. 
Current clinical experience with buparlisib has shown that its most frequent adverse events 
(AEs) include fatigue, decreased appetite, diarrhea, hyperglycemia, nausea, rash and mood 
alteration disorders.  Therefore patients will be closely monitored for fasting plasma glucose 
(FPG) HbA1c, and insulin C-peptide.  Patients will also be frequently and routinely evaluated 
for mood disorders and disturbances.  The remaining most frequent AEs will be detected by 
regular, frequent monitoring with symptomatic treatment to be provided as required.   
  


Delta Clinical Research, LLC 
 
Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
[24JUN2016] 
 
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1 
Background 
1.1 
Disease Background 
Breast cancer (BC) is the most common form of malignant tumor in women worldwide, and 
incidence rates are as high as 99.4 per 100,000 women (World Health Organization 2011). 
Subtypes of BC are distinguished by expression of estrogen receptors (ER), progesterone 
receptors (PgR) and human epidermal growth factor receptor-2 (HER2), as well as by distinct 
gene expression profiles (Perou 2000; Sotiriou and Pusztai 2009). 
Patients with metastatic ER-negative breast cancer have a high risk of developing brain 
metastases. In one retrospective cohort study, 46% of patients with metastatic triple negative 
breast cancer (TNBC) were found to have central nervous system (CNS) metastases at some 
point before death, and 14% had a CNS metastasis at first metastatic presentation (Lin 2008). A 
second retrospective study reported a 25% incidence of CNS metastases in patients with TNBC 
(Kennecke 2010). Outside of surgery and radiation therapy there are no proven therapies which 
improve overall survival (OS) of patients with brain metastases. In patients with HER2+ MBC, 
retrospective studies have documented an incidence of CNS metastases of approximately 25% - 
40%, and this frequently occurs while systemic disease is still well controlled by effective 
HER2-targeted therapies (Lin 2007). A study of breast cancer patients in the British Columbia 
Cancer Agency reported a 15 year incidence rate of CNS metastases of 5% and 2% in estrogen 
receptor-positive Luminal B and Luminal A subtypes, respectively (Kennecke 2010).   However, 
patients with ER+ breast cancer brain metastases are more prevalent than patients with TNBC or 
HER2+ brain metastases because the majority of metastatic disease is ER+ HER2-negative 
(Sperduto 2012)  
The American Society of Therapeutic Radiation Oncology (ASTRO)’s guidelines regarding 
radiation therapy for breast cancer brain metastases have changed, in recent years now de-
emphasizing the role of whole brain radiation (WBRT) and expanding the role of stereotactic 
radiosurgery (SRS) (Tsao M, et al.,2012)    
In this new guideline, any number of brain metastases are appropriate for SRS provided they are 
not over 3cm in size and provided they can be treated in one radiation therapy session.   WBRT 
is administered only for the development of new metastases following SRS, and only if there are 
more than 3 new metastases.  If 1-3 new metastases following previous SRS, repeated SRS is 
preferred and WBRT is reserved for patients with more than 3 new metastases following WBRT.   
ASTRO has emphasized SRS over WBRT because of the considerable toxicity of WBRT and the 
lack of improved survival or other clinical outcomes with WBRT compared with SRS.  
Most systemic therapies are ineffective due to the impenetrability of the blood/brain barrier, the 
intrinsic resistance of CNS metastases, and expression of the P-glycoprotein efflux pump. In the 
published natural history studies, the median OS time for patients with triple negative (TN) brain 
metastases is approximately 4 months (Lin 2008; Anders 2007; Adamo 2007, Nam 2008; Eichler 
2008). Another retrospective study of outcomes in patients with breast cancer-associated CNS 
metastases by subtype reported mean OS times of 61.2 and 39.0 months for luminal A and 
luminal B estrogen receptor-positive cancers, respectively, and a mean OS of 20.3 months for 


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Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
[24JUN2016] 
 
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HER2+ cancers (Wiens 2014).   The Sperduto Graded Prognostic Assessment Tool further 
refines OS estimates based on age and performance status.  ER+ brain metastases in woman with 
symptoms and/or over age 60 is associated with OS rates less than 2 years (Sperduto 2008 and 
Appendix 1). 
The Graded Prognostic Assessment (GPA) is a recently developed, validated prognostic score 
for patients with brain metastases (Sperduto 2008). The GPA has been further refined and 
updated to create diagnosis-specific indices, including a breast cancer-specific GPA (Sperduto 
2012a; Sperduto 2012b; Barnholtz-Sloan 2012). GPA scores range from 4.0 (best prognosis) to 
0.0 (worst prognosis), based on weighted significant prognostic factors, and can be used to 
estimate survival for individual patients. The components for the breast cancer GPA are tumor 
subtype, Karnofsky performance score, and age.  A recent study that utilized the GPA showed 
that patients with TNBC and brain metastases had a median survival time of 6.4 months 
(Sperduto 2012b).  
Brain metastases in patients with TNBC are life-limiting metastases. Therapies which change the 
natural history of this condition are urgently needed. 
1.2 
PI3K Pathway and Mechanism of Action 
The phosphatidylinositol-3-kinase (PI3K) signaling regulates diverse cellular functions, 
including cell proliferation, survival, translational regulation of protein synthesis, glucose 
metabolism, cell migration, and angiogenesis (Katso, et al 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 subunit. The 
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 and 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 may 
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 (	 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) or  
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 PI3K pathway could be a critical therapeutic target for 
the treatment of patients with advanced solid malignancies who often have limited therapeutic 


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Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
[24JUN2016] 
 
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options beyond institutional standard of care. Hence, treatment with the pan-PI3K inhibitor  
buparlisib (BKM120) potentially addresses an unmet medical need in such patients.  
A schematic representation of these PI3K components is shown in Figure 1-1. 
Figure 1-1 
Schematic representation of the PI3K pathway 
 
 
1.2.1 
PI3K pathway activation in MBC 
The PI3K pathway can be alternatively activated through various receptor classes or cross-talk 
with other pathways. In TNBC, the PI3K pathway appears to be modulated by the EGFR. 
Preclinical models have demonstrated that EGFR signaling through the PI3K pathway leads to a 
higher level of Akt phosphorylation in TNBC cell lines (Umemura 2007; Marty 2008; reviewed 
by Moulder 2010). Interestingly, TNBC cell lines have also been associated with lower 
expression of PTEN, which correlates with increased activation of Akt and portends a favorable 
response to PI3K inhibition. Indeed, cell lines which are wild type for PIK3CA, but have lost 
PTEN expression can be sensitive to a PI3K inhibitor (O’Brien 2010). These agents, therefore, 
present an intriguing class of targeted anti-cancer therapy for patients with TNBC. The 
epidemiology data reported so far present significant variation (Stemke-Hale 2008; Humphrey 


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Study No. 11-025/CBKM120ZUS39T  
BKM120 for MBC with Brain Metastases 
 
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Gardner unpublished; Lopez-Knowles 2010; Hernandez-Aya and Gonzalez-Angulo 2011) (Table 
1.1), however, based on these numbers, approximately 48% of triple negative breast cancers 
should be PI3K pathway activated (either 	 mutated or PTEN loss).   
Up to 40% of HR+/HER2- cancers also exhibit activation of PI3K pathway, via PIK3CA 
mutation or PTEN loss (Stemke-Hale 2008; Humphrey Gardner unpublished; Lopez-Knowles 
2010; Hernandez-Aya and Gonzalez-Angulo 2011). Bidirectional crosstalk between the ER/PR 
and PI3K pathways has been shown to influence ER/PR levels and activity, including 
phosphorylation and genomic activation of the ER, while membrane ER signaling can activate 
PI3K/Akt (Hernandez-Aya and Gonzalez-Angulo 2011). Experimentally, PI3K pathway 
activation has been associated with de novo and acquired resistance to endocrine therapy 
(Campbell 2001) including AI resistance (Shoman 2005; Crowder, 2009; Miller, 2011). 
A substantial fraction of HER2-amplified breast cancers also demonstrate activation of the PI3K 
pathway, primarily through loss of PTEN (Table 1-1). Activation of this pathway, either by 
PIK3CA mutation or PTEN loss, has been associated with resistance to trastuzumab, and cell 
line research suggests that inhibition of the PI3K pathway is an important mechanism of action 
for trastuzumab (Hernandez-Aya and Gonzalez-Angulo 2011). Further, synergistic activity has 
been observed with combinations of trastuzumab and PI3K inhibitors in breast cancer cell line 
studies (Hernandez-Aya and Gonzalez-Angulo 2011). 
Genomic and phosphoproteomic analysis of human primary breast cancers in the TCGA showed 
strong activation of PI3K pathway signaling in the majority of basal breast cancers, as well as 
PIK3CA mutations in 45% of Luminal A cancers, 29% of luminal B cancers, and 39% of HER2-
enriched cancers (Cancer Genome Atlas Network 2012). 
Table 1-1 PI3K signaling pathway mutations and alterations in breast cancer [1; 2; 3; 4] 
 
Mutation 
Alteration 



	 Mutation 
[1] 
PTEN loss of 
expression 
All Breast 
Tumors 
10-40% 
~2% 
29-50% 
HR(+) HER2(-) 
7-40% 
2-4% 
19-29% 
Triple Negative 
6-9% 
0% 
15-66% 
HER2-amplified 
20-25% 
- 
30-40% 
([1] Stemke-Hale 2008, [2] Humphrey Gardner, Oncology Translational Laboratories, Novartis, unpublished [3] 
Lopez-Knowles 2010 [4] Hernandez-Aya and Gonzalez-Angulo, 2011. Ranges represent the minimum and 
maximum incidence reported in these trials. Trial incidence calculations were made using the midpoint of the range. 
 
 
A study of the PI3K pathway specifically in breast cancer brain metastases found activation of 
this pathway in the majority of cases, regardless of breast cancer subtype, although PTEN loss 
was most common in the TNBC subtype (37%, vs 17% in HR_/HER2- and 25% in HER2+) 
(Adamo 2011).  


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In addition to mutation of 	, and loss or mutation of 
, loss of the tumor suppressor 

 (inositol polyphosphate 4-phosphatase-II) is emerging as an important activator of PI3K 
signaling in triple-negative or basal-like breast cancers. Preclinical studies in breast cancer cell 
lines showed that inactivation of INPP4B leads to Akt activation, cell proliferation, and growth 
of tumor xenografts (Fedele 2010). Investigation of INPP4B protein expression in primary breast 
cancers found loss of expression most frequently in basal-like primary breast cancers (84%); 
INPP4B loss was also associated with high clinical grade and tumor size (Fedele 2010). The 
Cancer Genome Atlas study, which used a variety of genomic and proteomic methods of 
analysis, found that 	 mutations occurred in 7% of basal-like breast cancer, 
 
mutation or loss occurred in 35%, and loss of 
 occurred in 30% (Cancer Genome Atlas 
Network). In another study, DNA copy number aberration analysis combined with breast cancer 
intrinsic subtyping found loss of 
 in 40% - 47.5% of basal-like breast cancers, and loss of 

 in 22.5% - 34%, using two different datasets containing 40 and 61 patient samples, 
respectively (Weigman 2012). Finally, a recent study that used whole genome and transcriptome 
sequencing to analyze 14 metastatic TNBCs revealed that the PI3K/Akt/mTOR pathway was 
activated due to genomic changes in 5 cases, most frequently through loss of 
 or 
, 
as well as at the transcription level with decreased INPP4B or PTEN mRNA levels in nearly all 
patients (Craig 2013).  
Another pathway that has been associated with metastatic colonization of the central nervous 
system (CNS) in breast cancer is the HER3/neuregulin 1 axis which strongly activates the PI3K 
pathway. Neuregulin 1 (heregulin), a ligand for HER3, is abundant in brain tissue, and one study 
reported overexpression and activation of HER3 in brain metastases compared with matched 
primary breast cancer samples (Da Silva 2010). Within the HER family of receptors, activation 
of PI3K signaling is driven primarily through transphosphorylation of the kinase-inactive HER3 
receptor, which has also been implicated in resistance to HER2-targeted therapies in HER2+ 
breast cancers (Hsieh 2007). HER3 expression has also been associated with a poorer prognosis 
in both TNBC and HER2+ breast cancers (Bae 2013). In addition, signaling through HER3 has 
been implicated in resistance to the estrogen receptor downregulator fulvestrant in an ER+ breast 
cancer xenograft model system (Osipo 2007). 
These studies suggest that through a variety of mechanisms, activation of the PI3K signaling 
pathway is likely to occur in the vast majority of metastatic breast cancers, and thus rendering 
PI3K a promising therapeutic target. 
 
 
 
 
 
 


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1.3 
Study Treatments 
1.3.1 
Buparlisib 
NVP-BKM120 (BKM120; bupa
inhibitor that is a 2,6-dimorpho
extensively in non-clinical mode
1.3.1.1 
Preclinical studies 
Buparlisib activity against class 
mTOR related PI3K or PI4Kβ, w
PI3Ks and PI4Kβ) or a TR-FRE
below in Table 1.2. 
Table 1.2 Inhibitory activities
kinases 
Buparlisib significantly inhibits
E454K, E542K), p110β, p110δ 
inhibitor. Enzymatic characteriza
buparlisib is a mixed inhibitor 
Vmax). The cocrystal X-ray s
interacts with PI3K into the AT
selective (50-fold difference) tow
 
 
 
 
 
 
 
Study No. 11-025/C
ses 
15 
arlisib) is a potent and highly specific oral p
olino pyrimidine derivative. This compound h
ls and is currently being evaluated in clinical tri
 I PI3K (p110α, -β, -δ and -γ), Class III (Vps
was assessed using either a luciferase luminescen
ET assay (Class IV mTOR). The IC50 in these a
s (IC50) of buparlisib against other PI3K 
s p110α and the most common p110α muta
and p110γ. Buparlisib is classified as a pure p
ation of the inhibitory properties of the compou
of PI3Kα with a strong competitive compo
structure of buparlisib with PI3Kγ confirmed
TP catalytic cleft.  As shown in Table 1.3, b
ward p110α compared to other protein kinases. 
CBKM120ZUS39T  
[24JUN2016] 
pan-class I PI3K 
has been studied 
als. 
34), the class IV 
nce (class I or III 
assays is outlined 
or related 
 
ations (H1047R, 
pan-class I PI3K 
und revealed that 
nent (largest for 
d that buparlisib 
buparlisib is also 


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Table 1.3 Activity of buparlisib in the Novartis kinase panel 
 
Activity in mechanistically driven cell-based models 
The PI3K pathway regulates the activity of the mTORC1 complex, when cells are challenged 
through mitogenic stimuli. In order to assess in cells the potential impact of the buparlisib on the 
mTORC1 complex, the compound was tested in TSC1 null cells. These cells express a 
constitutively activated mTORC1 complex that uncouples the mTOR pathway from the PI3K 
upstream input (Kwiatkowski 2003). When exposed to TSC1 null MEFS, buparlisib reduced the 
S235/236P-RPS6 levels with an IC50 of 1785 nM, in agreement with the data obtained in the 
mTOR biochemical assay. In contrast, and as expected the allosteric mTORC1 inhibitor 
RAD001 displayed sub-nanomolar inhibitory activity in this assay. 
PI3K pathway inhibition potency and specificity in relevant cell-based disease models 
In contrast to molecules with a distinct mechanism of action (e.g., the BCR-Abl inhibitor 
STI571, mTORC1 allosteric inhibitor RAD001), buparlisib is able to decrease the 
phosphorylation status of various either direct (GSK3β, FKHRL1/FOXO3a) or indirect 
downstream Akt effectors (p70S6K, through mTOR) in the PTEN null U87MG cell line, as 
efficiently as prototypical PI3K inhibitors such as LY294002 and Wortmannin. 
In all cases, buparlisib showed specific PI3K pathway attenuation as demonstrated by specific 
attenuation of S473P-Akt levels without affecting the non-PI3K-driven read–outs such as 
activated receptors (EGFR, PDGFR), MAP kinases (ERK, JNK and p38) or Jak cytosolic 
tyrosine kinases responsible for Stat transcription factor phosphorylation. 


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1.3.1.2 
Preclinical Safety 
Please refer to the Investigator’s Brochure for additional information on the preclinical testing of 
buparlisib. 
1.3.1.2.1 Pharmacodynamics 
Buparlisib inhibits wild-type PI3K (IC50: 35 nM), with at least 50-fold selectivity towards this 
compared to activity against other protein kinases outside the PI3K family.  The compound is 
equipotent against somatic PI3K mutants (H1047R-, E542K-, and E545K-p110), and is active 
against the other three PI3K paralogs (PI3Kβ, -γ, -δ; IC50 108 to 348 nM range). Buparlisib does 
not significantly inhibit the related kinases mTOR or Vps34, nor does it inhibit (IC50 >10 µM) 
other receptors and ion channels profiled. 
Buparlisib reduces the phosphorylation of the direct downstream effector Akt in relevant tumor 
cell lines (e.g., IC50 93 nM for S473P-Akt in Rat1-p110 cells). This biological activity 
correlates with inhibition of various other downstream signaling components and with 
antiproliferative activity in a variety of tumor cell lines. 
Buparlisib demonstrates significant tumor growth inhibition in relevant tumor xenografts in mice 
and rats when administered orally, including models of breast cancer, lung cancer (A549, NCI-
H1975), colorectal cancer (HCT116, HCT-15), glioblastoma multiforme (U87MG), melanoma 
(A2058, A375), ovarian cancer (A2780), pancreatic cancer, prostate cancer (PC3M),  and renal 
cell cancer (RENCA, 786-0, Caki-1).   PK/PD analyses of tumor tissues shows a good 
correlation between exposure, PI3K pathway blockade (S473P-Akt levels), and anti-tumor 
activity. 
Antitumor activity of buparlisib in breast cancer 
Preclinical data in models of breast cancer are emerging that support buparlisib evaluation in 
clinical studies. In a series of 20 basal breast cancer cell lines, 4 lines carrying a loss of a 
phosphatase related to PTEN, INPP4B, displayed sensitivity to buparlisib (between 17 and 30% 
cell death) (Gerwinner 2009). The sensitivity to buparlisib has been confirmed in xenograft 
models where stasis and regressions have been observed in models mostly driven by loss of 
PTEN.  Treatment of TNBC cell lines and patient-derived TNBC xenografts with buparlisib has 
also been shown to increase DNA damage, downregulate BRCA1/2, and increase poly-ADP-
ribosylation (Ibrahim 2012). Likewise, in a BRCA1-related breast cancer mouse model, 
buparlisib delayed tumor doubling time, and reduced AKT phosphorylation, tumor proliferation, 
and angiogenesis (Juvekar 2012). 
Preclinical in vitro and in vivo models suggest that buparlisib has an inhibitory effect in breast 
cancer models (Maira et al 2012).. In a panel of 44 cell lines, buparlisib induced cell death in the 
majority of luminal breast cancer lines (12/18) as well as 4/20 basal-type cell lines. This was 
confirmed in xenograft models, where HER2+ and ER+ models displayed tumor control for up 
to 120 days (O’Brien et al 2011), and triple-negative primary tumor models displayed stasis or 
occasional regression. 


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Furthermore, AI resistance has been associated with activation of PI3K pathway (Crowder 2009, 
Miller 2011) and   response to buparlisib was also observed in ER-positives cell lines 
before and after long-term estrogen deprivation (Sanchez 2011). These cell lines included 
various mechanisms of PI3K pathway activation (i.e., PIK3CA mutation, HER2 amplification, or 
PTEN mutation. 
Finally, buparlisib was also shown to be efficacious in controlling brain metastasis in a 
preclinical model of human HER2⁺ breast cancer in Rag2⁻/⁻;Il2rg⁻/⁻ mice (Nanni 2012). 
This activity of buparlisib observed in pre-clinical models provides strong molecular evidence 
for the role of PI3K signaling in MBC and supports the exploration of buparlisib in this disease 
setting. 
1.3.1.2.2 Nonclinical pharmacokinetics and metabolism 
Buparlisib showed favorable pharmacokinetic properties in all animal species tested. The 
absorption of [14C]-buparlisib -related radioactivity was >84% in the rat. Oral bioavailability was 
moderate to high in rats, dogs, monkeys (42-100%). The estimated steady state plasma volume 
of distribution (Vss) was moderate in all species (3.0-3.5 L/kg). Buparlisib penetrates the blood 
brain barrier in rats with a tissue-to-plasma ratio about 2. Buparlisib is 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 CYP3A4 (estimated fraction 
metabolized >0.9). Direct phase II metabolism (glucuronidation) via UGT1A4 is also observed 
in human liver microsomes supplemented with UDPGA. All phase I metabolites identified in 
human hepatocytes and microsomes were also detected in animals. Buparlisib and identified 
metabolites have a low potential for covalent binding to protein.  
Buparlisib is 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 
does not show time-dependent inhibition of CYP450 enzymes. With respect to transporter-based 
drug-drug interactions, buparlisib is neither a substrate for MRP-2, OATP1A2, OATP1B1, 
OATP1B3, OATP2B1, P-gp nor an inhibitor for BCRP, MATE1, MATE2K, MRP2, OAT1, 
OAT3, OCT2, P-gp in the observed range of clinically relevant concentrations. 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 for the 100 mg qd dose 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 


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male rats after 13 weeks of daily dosing. There was a slight accumulation in female rats (<2 
fold). 
1.3.1.2.3 Safety pharmacology and toxicology 
Safety pharmacology studies in rats revealed no effects on neuronal (behavior) or respiratory 
functions. When using a microdialysis technique to investigate the effect of a single or 2-week 
repeated dosing of buparlisib in various brain regions of rats, a marked increase in extracellular 
levels of gamma-aminobutyric acid (GABA) were observed in the ventral hippocampus (vHPC) 
and median prefrontal cortex (mPFC), both under acute as well as repeated dosing conditions. In 
the same brain regions, smaller increases in levels of dopamine, serotonine and noradrenaline 
were observed in the vHPC, with a trend to decreased corticosterone. Cardiac safety studies, 
conducted  and  did not indicate a prominent electrophysiological risk. 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 the absence of an 
electrophysiological effect.  
Repeated-dose studies (up to 13 weeks of duration) were performed in rats and dogs. In rats, 
clinical pathology and histopathology findings showed a decrease in lymphocyte counts in the 
peripheral blood, decreases in germinal center development in different lymph nodes, and 
lymphocytolysis in the thymus. In dogs, similar findings were made. In both species, 
erythropoiesis was affected, as evidenced by reduced erythrocyte counts accompanied by bone 
marrow suppression observed in rats. 
The pancreas was 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 and in the 
exocrine pancreas. 
Male reproductive 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, plus cellular debris in epididymal tubules. Testicular toxicity did 
not fully reverse after the 4-week treatment-free period in rats, 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 reproductive 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. 
Buparlisib does not have sensitizing or irritative potential in the skin. 
No evidence for a direct DNA interaction was found in an Ames test and two chromosome 
aberration tests in vitro with buparlisib. However, a potential for genotoxicity was identified 
based on the observation of an aneugenic potential and was confirmed by fluo rescence in situ 
hybridization of centromeric sequences within micronuclei induced in human peripheral 
lymphocytes in vitro. In line with this result, buparlisib treatment resulted in an elevated 
frequency of micronucleated polychromatic erythrocytes in the bone marrow of rats. In 


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summary, evidence of a genotoxic potential with buparlisib has been seen in vitro and in vivo 
and is likely due to an aneugenic effect. 
In a rat embryofetal dose-range finding study, buparlisib treatment induced embryolethality and 
implantation loss, together with foetal pathology changes at doses that were only minimally 
maternally toxic. No phototoxic potential or any effect on wound healing has been identified 
with buparlisib in pre-clinical studies. 
In summary, the toxicity and safety pharmacology profile of buparlisib can be associated 
primarily to the expected pharmacodynamics activity of buparlisib. Main target organs for toxic 
effects were the hematopoietic and lymphopoietic systems and the reproductive tract.  Buparlisib 
is genotoxic via an aneugenic mechanism, and it interferes with insulin signaling and the 
associated metabolic disturbances. The compound may have an influence on central 
neurotransmitter levels, but this effect needs to be further evaluated. Overall, these findings are 
compatible with the treatment of advanced cancer and do not preclude the use in the foreseen 
indications. 
1.3.1.2.4 Pharmacodynamic biomarkers 
The preclinical  studies with xenograft tumors in mice indicate that detectable inhibition 
of AKT phosphorylation, which is an accurate readout of PI3K activity, and further suppression 
of downstream signaling (e.g., 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 suggested post-treatment induction of insulin insensitivity/resistance. Therefore, 
throughout the trial the circulating levels of several markers for glucose metabolism (e.g., 
glucose, insulin, C-peptide) will be assessed as an additional measure of PI3K signaling 
modulation. 
1.3.1.3 
Clinical experience 
1.3.1.3.1 Clinical experience with buparlisib 
As of 15 September 2013, approximately1469 patients and healthy volunteers have been enrolled 
into twenty-two clinical studies with buparlisib (as single agent or in combinations). The 
Novartis sponsored clinical studies were: 
 Phase 
I 
single 
agent 
studies 
[CBKM120X2101], 
[CBKM120X1101], 
and 
[CBKM120Z2102], 
[CBKM120C2110], 
[CBKM120C2104], 
[CBKM120C2106], 
[CBKM120C2111], and [CBKM120C2102]. 
 Phase II single agent studies [CBKM120C2201] and [CBKM120D2201] 
 Phase I combination studies [CBKM120B2101], [CBKM120X2107], [BKM120E2101], 
[CBEZ235A2118], 
[LDE225X2114], 
[CSTI571X2101], 
[CMEK162X2101], 
[CMEK162X2101], [CINC424A2104], and [CBEZ235D2101. 
 Phase II combination study [CBKM120F2202] 
 Phase III combination studies [CBKM120F2302] and [CBKM120F2303]. 
With regard to the current protocol, results presented below will focus on phase I single agent 
studies ([CBKM120X2101], [CBKM120X1101]), and phase I combinations in breast cancer 


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patients ([CBKM120X2107], [CBEZ235A2118]). Please refer to the current version of the IB for 
more detailed information. 
1.3.1.3.1.1 
Human safety and tolerability data  
Recruitment in study [CBKM120X2101] has been completed with forty (40) patients included in 
the dose escalation phase at 6 dose levels (all once daily) (12.5 mg (1 patient); 25 mg (2), 50 mg 
(5), 80 mg (11), 100 mg (17), 150 mg (4)). Dose limiting toxicities were hyperglycemia, skin 
rash, epigastric pain, mood disorder and joint pain. The MTD for buparlisib given as single 
agent, once daily was established at 100 mg/day (Bendell, 2012).  Forty-three additional patients 
were treated in the expansion cohort at 100 mg/day. At the cut-off date of July 4th 2011 (Graña 
2011), patient characteristics for the 82 patients analyzed were as follows: median age 55 years 
(range 30–78); ECOG performance status 0/1/2 for 35/46/1 patients, respectively. The safety 
experience for this single agent trial of buparlisib is described in Table 1-3: 
Table 1-3  Most frequent AEs (> 15%) related to study drug study CBKM120X2101 
(n=81): 
Event 
All grades 
Grade 3/4 
Fatigue/asthenia  
31(38.3%) 
3 (3.7%) 
Decreased appetite  
24 (29.6%) 
- 
Diarrhea  
24 (29.6%) 
3 (3.7%) 
Hyperglycemia  
24 (29.6%) 
4 (4.9%) 
Nausea  
24 (29.6%) 
- 
Rash  
22 (27.2%) 
4 (4.9%) 
Mood altered/emotional 
disorder/affective disorder  
17 (21.0%) 
4 (4.9%) 
Transaminases increased  
16 (19.8%) 
9 (11.1%) 
Anxiety  
14 (17.3%) 
1 (1.2%) 
Depression 
14 (17.3%) 
1 (1.2%) 
A second single agent trial, [CBKM120X1101] was a phase I dose escalation study in Japanese patients with 
advanced solid tumors who received dose levels ranging from 25 to 100mg/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 abnormalities in 6 patients including transaminase increase in 2 patients, G3 anemia in 2 patients, 
and hypokalemia in 2 patients. The recommended phase 2 dose (RP2D) for the Japanese study has been determined 
at 100 mg/day, as in the western population.  
 
The safety and efficacy of buparlisib combined with trastuzumab in patients with relapsing 
HER2-overexpressing BC who have previously failed trastuzumab are being explored in a phase 
Ib/II, multi-center study [CBKM120X2107]. The combination of buparlisib and trastuzumab was 
shown to be tolerable, and with one dose-limiting toxicity (G3 asthenia) the MTD for buparlisib 
was declared at 100 mg/day (Saura 2011). Among the 18 patients evaluated in the PhIb part, the 
following G3/G4 AEs were observed: asthenia, ALT elevation, hyperglycemia, mood alteration, 
affective disorder, hypersensitivity, photosensitivity reaction, and rash. These AEs were all 
short-lived and reversible with either dose interruption or modifications as needed. In the phase 


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II portion of the study, as of June 2012, 53 patients have been enrolled and received buparlisib at 
the recommended phase 2 dose (RP2D) of 100 mg/day in combination with trastuzumab (Pistilli 
ESMO 2012). Overall the treatment was well tolerated. Most common AEs (>15%) included 
gastro-intestinal toxicity (e.g. diarrhea, nausea, stomatitis), rash, fatigue, transaminase increase, 
hyperglycemia, depression and anorexia. No G4 AEs have been reported. Most common G3 
treatment related AEs included transaminase increase (~10%), rash (9%) and fatigue (6%), and 
were consistent with phase Ib findings with as well as single agent buparlisib. 
Details on liver toxicity, mood alterations, pneumonitis, hyperglycemia, skin rash and 
hypersensitivity as side effects of buparlisib are presented below.  
Liver Toxicity 
Liver toxicity has been analyzed based on a search of multiple MedDRA event terms (SMQ 
pertinent to hepatobiliary toxicity), and is presented in Table 1.5 Liver function test (LFT) 
alterations observed during ongoing and completed studies have been mostly reversible 
transaminase increases (ALT and/or AST), and have been rarely associated with signs or 
symptoms of impaired liver function. The increase in AST/ALT values typically occurred within 
the first 6 to 8 weeks of study treatment. 
The highest rates of transaminase increase have been observed on the Phase I Japanese and 
Chinese studies [CBKM120X1101] and [CBKM120Z2102] as well as in combination with 
fulvestrant in the randomized Phase 3 study [CBKM120F2302]. In contrast, the rate of 
transaminitis appeared to be lower in combination studies with taxanes (e.g. studies 
[CBKM120D2205], [CBKM120F2202] and [CBKM120H2201]) in which also steroids have 
been administered regularly as part of the standard premedication. In addition, transaminitis was 
infrequent in the lymphoma study [CBKM120Z2402]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1.5 Number (%) of patients with liver toxicity regardless of study treatment 
relationship, occurred at 100 mg / day in BKM120 studies - Safety Set 
 
 
Although transaminase increases are relatively common, only a few of the patients with LFT 
alterations had simultaneous observations indicative of impaired liver function (e.g. bilirubin 
increase or clinical symptoms). 
A search and review of potential drug-induced liver injury (DILI) cases in Novartis-sponsored 
trials with buparlisib using conservative biochemical criteria (e.g. AST/ALT >3.0x ULN and 
TBL>2.0xULN) has shown that most of these cases occurred in the context of disease 
progression in advanced cancer patients and/or were confounded by other causes. However, for 
some of the DILI candidates causal relationship with study treatment cannot be ruled out.  An 
aggregated safety findings report (ASFR) has been sent to all investigators/health authorities 
participating in buparlisib trials in May 2015 informing them about the liver toxicity findings. 


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As of 08-Sep 2015, in total 8 DILI cases consistent with Hy’s Law have been identified upon 
medical review across the buparlisib program. Six out of these cases occurred in combination 
with fulvestrant, one in combination with letrozole and one in combination with LDE225. 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. A summary of the 8 
cases is provided in below Table 1.6 Thus far, no fatal cases have been reported in the context of 
DILI.  
 
 


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Table 1.6 DILI cases consistent with Hy’s Law, as of 08-Sep-2015 
Study/ 
Subject number 
Summary 
CBKM120F2302 
- 
patient 5018001 
(fulvestrant + 
100 mg/d 
buparlisib) 
59 year-old female patient with breast cancer and no pre-study history of hepato-biliary 
conditions disorders. At study baseline, the patient had no known metastases in the liver. 
Under study medication the patient developed 34 fold increase of ALT and AST, 16 fold 
increase in total bilirubin and 2 fold increase in ALP. The patient was asymptomatic. Study 
treatment with BKM120 was permanently discontinued due to elevated liver function tests. 
The patient fully recovered. The investigator reported that the event was suspected to 
treatment with BKM120 and not suspected to fulvestrant 
CBKM120F2302 
– 
patient 2302002 
(fulvestrant + 
100 mg/d 
buparlisib) 
60 year-old female patient with metastatic breast cancer (bone metastasis), history of 
depression, osteoporosis, headaches, dyspnea, back-pain and elevated AST/ALP (Grade 1) 
and GGT (Grade 2) at baseline. On Day 43, the patient developed Grade 3 transaminitis 
which worsened to Grade 4 on Day 48; treatment with buparlisib/placebo was permanently 
discontinued due to this event. Bilirubin was increased to Grade 2 from Day 48 to 50. The 
patient received ciprofloxacin for infection (from Day 48 to 52), dexamethasone for 
transaminitis (from Day 50 to 63) and spironolactone for abdominal distention/ ascites (from 
Day 48 to 53). She further took 3 herbal preparations during 1 week prior to the event, and 
received zoledronic acid medication for bone metastasis. The patient recovered from the 
event. 
CBKM120F2302 
– 
patient 2700014 
(fulvestrant +100 
mg/d buparlisib) 
65 year-old-female patient with metastatic breast cancer (liver and bone metastasis), history 
of rheumatoid arthritis and elevated AST (Grade 1) at baseline. On Day 42 she developed 
Grade 1 transaminitis which worsened to Grade 4 on Day 64; study treatment was 
permanently discontinued due to this event. Bilirubin was increased to Grade 2 on Day 64. 
Patient decided to withdraw from the study and did not return for post treatment safety 
follow-up; consequently, outcome of the liver event remains unknown. She died 3 months 
after the end of treatment due to disease progression. 
CBKM120F2302 
– 
patient 3080012 
(fulvestrant + 
100 mg/d 
buparlisib) 
53 year-old female patient with metastatic breast (liver, lung, bone and lymph-node 
metastasis), history of hypothyroidism, migraine, nausea, mood alteration, hot flashes, 
weakness, constipation and fibromyalgia; normal baseline liver chemistries. On Day 15, she 
developed Grade 1 ALT increase that worsened to Grade 2 on Day 39 (buparlisib/placebo 
dose reduced to 80 mg/d), and to Grade 4 on Day 46 upon which study treatment was 
permanently discontinued. Bilirubin was increased to Grade 2 on Days 53 and 55. The patient 
was taking levothyroxine for hypothyroidism, metamizole and ibuprofen for pain and 
clodronate for bone metastasis (before and during the study). The patient further had 
concurrent disease progression by RECIST on Day 50 (new liver lesions). The patient 
recovered from the event. 
CBKM120F2302 
– 
patient 5037006 
(fulvestrant + 
100 mg/d 
buparlisib) 
54 year-old female patient with metastatic breast cancer (bone metastasis), history of 
vomiting/nausea, anemia, GERD, and elevated GGT (Grade 1) at baseline. On Day 43 she 
developed Grade 2 AST and Grade 1 ALT increase (treatment with buparlisib/placebo 
interrupted). Transaminitis worsened to Grade 4 on Day 50 upon which study treatment was 
permanently discontinued. Bilirubin was increased to Grade 2 from Day 50 to 56. The patient 
received 
ibuprofen 
for 
headache 
and 
fever 
(from 
Day 
49), 
prophylactic 
piperacillin/tacobactam/vancomycin (from Day 50 to 53) and zoledronic acid for bone 
metastasis. The patient recovered from the event. 
CLDE225X2114 
– 
patient 1514005 
(80 mg/d 
buparlisib + 400 
mg/d LDE225) 
71 year-old male patient with stage IV glioblastoma multiforme and no relevant medical 
history; normal baseline liver chemistries. On Day 44, he developed Grade 4 transaminitis 
and Grade 1 bilirubin increase upon which study treatment was permanently discontinued. 
Bilirubin briefly increased to Grade 2 on Day 57 based on local labs. Patient received 
paracetamol for pain, metoclopramide and ondansetron for nausea from Day 58 to 60; he was 
further on dexamethasone for seizure prophylaxis during the study. The patient recovered 
from the event. 
 


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In the randomized Phase 3 study [CBKM120F2302] in combination with fulvestrant, 13 vs 4 
patients in the buparlisib vs placebo arm reported AST/ALT >3x ULN and total bilirubin >2x 
ULN regardless of causality and temporal relationship. Based on medical review, 5 out of these 
cases were consistent with Hy’s law criteria, all of which were in the buparlisib arm.  These 5 
cases are part of the 8 total cases described above. 
 
 
 
 
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-X).  
 


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Patients with clinically significant liver test abnormalities should perform liver-directed medical 
history, physical examination and other tests as medically indicated to assess 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 BKM120/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 PK analysis is 
performed in the study. Record the date/time of the PK blood sample draw and the 
date/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.  
 
Patient demographics and other baseline characteristics  
Furthermore the following assessments will be performed to assess the eligibility of the patient:  


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 Viral hepatitis serology [e.g. HAAb, HBsAg, HBsAb HBcAb, HCV RNA or HDV RNA 
(where needed), HEAb, CMVAb, EBcAb] and other tests (see Section 6.2.4.X 
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.X.X.X Viral hepatitis 
serology and other tests for hepatotoxicity follow-up)  
 
Assessment types  
Laboratory evaluations  
Hepatotoxicity follow-up testing will be performed when needed (refer to Section 6.2.4.X 
Management of hepatotoxicity (ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) in 
patients receiving BKM120/placebo).  
 
Table 1-7 Clinical laboratory parameters collection plan Test Category 
Test Category 
Test Name 
*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.  
* Hepatotoxicity follow-up testing/procedures will be performed locally (refer to Section 6.2.4.X 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.X.X.X Viral hepatitis serology and other tests for hepatotoxicity follow-up). 
 
 
Viral hepatitis serology and other tests for hepatotoxicity follow-up  
Viral hepatitis serologic tests are performed confirm patient’s eligibility when needed per clinical 
judgment and specific patient’s clinical circumstances.  
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 6.2.4.X 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)  


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 Herpes Simplex Virus  
Liver toxicity has been analyzed based on a search of multiple MedDRA event terms and is 
presented in Table 1-6. Liver function test (LFT) alterations observed during ongoing and 
completed studies have been mostly transaminase enzyme increases (ALT and/or AST). Data 
suggest a higher rate of grade 3/4 liver enzyme elevations in Japanese patients (44.4%) in the 
[CBKM120X1101] study, however, the number of patients (9 patients) treated at 100mg in this 
study was limited. 
 
 
Table 1-8  Number (%) of patients with Liver toxicity, regardless of study drug   
relationship, by preferred term and treatment – occurred at 100 mg/day in 
ongoing buparlisib studies          
 
 
 
 
Although transaminase increases are relatively common, only a few of the patients with LFT 
alterations had other simultaneous observations related to impaired liver function (e.g., bilirubin 
increase or clinical symptoms). Based on these findings, conservative inclusion criteria and 
guidelines to monitor and to follow patients with LFT alterations (including dose and schedule 
modifications) are currently implemented in study protocols investigating buparlisib. 
 
Please refer to the respective inclusion/exclusion criteria. 
Mood disorders 
Recently, a number of publications demonstrated that the modulation of AKT/GSK3 signaling 
pathway by neurotransmitters is important for the regulation of behavior (Beaulieu 2009). 
Preclinical studies conducted in rats to investigate the effect of buparlisib on different 
neurotransmitters have shown that repeated administration of buparlisib resulted in an enhanced 


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decrease in glutamate, dopamine, serotonin and epinephrine as well as in an enhanced increase in 
GABA and HIAA. 
Psychiatric side effects events have been reported in patients treated with buparlisib and are 
currently under investigation. The current data does not allow the identification of any sign or 
symptom which could predict patient susceptibility to buparlisib induced psychiatric disorders.  
A broad range of AEs including (but not limited to) depression, anxiety, mood alteration, 
confusion, affective disorders, insomnia, hallucination, panic disorders, irritability or difficulties 
to concentrate have been reported. 
Considering the initial symptoms reported during the first-in-man [CBKM120X2101] study, 
mood disorders have been analyzed based on HLGT 'Mood disorders and disturbances NEC' or 
HLGT 'Personality disorders disturbances in behavior' or HLGT “Psychiatric and behavioral 
symptoms NEC” or HLGT “suicidal and behaviors NEC”. The frequency of mood disorders thus 
defined, regardless of study drug relationship, ranged from 6.3% in [CBKM120B2101] study to 
50.0% in dose escalation part of [CBKM120X2107] study, however, the majority of events were 
of grade 1 or 2 severity (Table 1-7). 
 
Table 1-7  Number (%) of patients with Mood disorders, regardless of study drug 
relationship, by preferred term and treatment occurred at 100 mg/day in 
ongoing buparlisib studies 
 
 
Therefore, patients must be regularly and closely monitored for signs and symptoms of 
neuropsychiatric disorders with particular attention to changes in mood and personality. To 
support the identification and the assessment of psychiatric disorders, two self-assessment 
questionnaires, the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 
(GAD-7), are part of the protocol. Any AEs (symptom/diagnosis) should be accurately reported 
using CTCAE toxicity/grading. A consultation with a psychiatrist is strongly recommended for 
any psychiatric adverse event grade ≥ 1. Protocol guidelines further disqualify patients with an 


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active and/or history of major psychiatric disorder.  Please refer to the respective 
inclusion/exclusion criteria. 
Lung Toxicity/ Pneumonitis 
Lung changes compatible with pneumonitis have not been observed in the preclinical setting.  
Among the current studies, pneumonitis was reported in five cases and interstitial lung disease in 
one further case. One case of pneumonitis had a fatal outcome in a complex clinical context, 
combining progression of lung metastases and possible infection with pneumocystis carinii or 
cytomegalovirus. Apart from this fatal case, the conditions were resolved or improving at the 
latest report (except one non-suspected SAE which was unchanged). 
The currently available data still do not enable a clear assessment about the causal relationship of 
pneumonitis with buparlisib treatment. Newly appearing or significant changes in pulmonary 
symptoms (which cannot be explained by the underlying disease), should be carefully followed 
with appropriate management as per institutional guidelines and the guidelines provided in the 
protocol. 
Please refer to Table 4-5 for a more detailed guideline on the diagnosis and management of 
Pneumonitis.   
Hyperglycemia events 
The PI3K/AKT pathway plays a significant role in regulating glucose metabolism, particularly 
by regulating glucose transport into adipocytes and muscle tissue. Therefore, hyperglycemia is 
considered as an “on target” effect of buparlisib. Regular monitoring of FPG, HbA1c, and insulin 
C-peptide is implemented in buparlisib protocols to evaluate this pharmacodynamics effect. 
Transient increases of plasma glucose levels have been reported commonly in patients treated 
with buparlisib. Hyperglycemia observed at 100 mg/day, regardless of study drug relationship, in 
ongoing buparlisib studies are summarized in Table 1-8. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1-8  
Number (%) of patients with Hyperglycemia (narrow search), regardless of 
study drug relationship, by preferred term and treatment occurred at 100 
mg/day in ongoing buparlisib studies 
 
 
The highest rate of hyperglycemia (57.1%) was reported in [CBKM120C2201], a Phase II study 
conducted in patients with advanced endometrial carcinoma, as this was the only study among 
those listed allowing the enrollment of patients with controlled diabetes mellitus. However, so 
far, there were only two patients that experienced a grade 4 hyperglycemia, and they both were 
treated at the highest dose level (150mg/day) in [CBKM120X2101] study. In order to mitigate 
the potential risk of developing uncontrolled hyperglycemia, only patients with normal 
glycaemia defined as fasting plasma glucose (FPG) ≤ 120 mg/dL are eligible for study entry. 
Patients who have a poorly controlled diabetes mellitus defined as (HbA1c >8%) are excluded. 
In addition, detailed guidelines to monitor patients are recommended including: regular 
monitoring of FPG to early identify hyperglycemia and prevent acute/sub-acute complications, 
caution warranted for patients with history of DM, or taking corticosteroids, or with other severe 
medical conditions (e.g., infections). Hyperglycemia management guidance also includes: 
dietetic measures and appropriate anti-diabetic medications as per investigator’s decision and/or 
local guidelines, consider oral anti-diabetics such as metformin as first-line treatment for 
sustained and more severe hyperglycemia (other drugs as appropriate), if sulfonylurea or insulin 
are initiated, patients should be instructed on how to recognize (and treat) hypoglycemia, for 
patients with history of DM, management should be based on prior anti-DM treatment. 
Detailed guidelines to monitor and manage patients who develop hyperglycemia are provided in 
Table 4-1.  
Skin rash and hypersensitivity 
Skin rash is commonly observed in patients treated with buparlisib. The rate of skin rash and 
other related event terms ranged from 18.4% to 41.4% in single agent studies with a 


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representative number of patients treated with 100mg of buparlisib. In one study with nine 
evaluable patients, seven patients (77.8%) reported such events (Table 1-9). 
Studies of buparlisib in combination with other agents tended to report slightly higher 
frequencies (e.g. combination with MEK inhibitor). The skin rashes seen have no typical location 
or distribution pattern, are mainly papulo-macular (only a minority are acneiform) and are 
frequently associated with pruritus. Events have been reversible after treatment interruption and/ 
or dose reduction. Effective medications have included antihistamines, topical corticosteroids 
and/or low-dose systemic corticosteroids (the latter should be used with caution due to the 
increased risk of hyperglycemia). There have been few cases reported of allergic reactions and 
DRESS (drug rash with eosinophilia and system symptoms), but these have not been of acute 
onset or of a severe nature. 
 
Complementary information collected suggests that sun exposure may exacerbate the condition 
and should be avoided; however, genuine photosensitivity reaction has not been confirmed and 
no phototoxic potential has been seen pre-clinically. Patients are advised (e.g., in the written 
patient information) to avoid sun exposure, or take measures to protect themselves from intense 
sunlight, during study treatment. 
 
 
Table 1-9 Number (%) of patients with Hypersensitivity, rash, regardless of study drug 
relationship, by preferred term and treatment occurred at 100 mg/day in ongoing 
buparlisib studies 
 
 
Guidelines for the treatment of buparlisib induced hyperglycemia 
Hyperglycemia is a common site effect of PI3K and also mTOR inhibitors. Hyperglycemia often 
occurs during the first weeks after treatment start and is dose-dependent. Transient increase of 
glucose levels have been observed in some patients. Regular monitoring of FPG to early identify 
hyperglycemia and prevent acute/sub-acute complications is important. Caution is warranted for 


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patients with history of DM, or taking corticosteroids, or with other severe medical conditions 
(e.g. infections), or patients who show potential acute signs such as poly-noctiuria, polidypsia, 
confusion, etc.  Hyperglycemia management guidance includes patient education and dietetic 
measures/life-style changes as well as appropriate anti-diabetic medications as per investigator’s 
decision and/or local guidelines.  
Oral anti-diabetics such as metformin should be considered as first-line treatment for sustained 
and more severe hyperglycemia (other drugs as appropriate). Provided hyperglycemia is 
asymptomatic and there are no acute complications, sufficient time should be given to install 
optimal management (e.g. uptitrate metformin, addition of a second oral anti-diabetic agent to be 
considered as needed, etc.). Patients initiated on sulfonylurea or insulin should be instructed on 
how to recognize (and treat) hypoglycemia. Patients with history of DM, management should 
take prior anti-DM treatments into account. Note that some oral anti-diabetic drugs are CYP2C9 
substrates and should be used with caution; others are CYP3A inducers or inhibitors and may be 
prohibited (see Appendix 1 and Appendix 2 for more details). Patients who develop Grade 3 or 4 
or symptomatic hyperglycemia should be managed urgently as per standard clinical practice, 
with the goal of stabilizing glycemic control within 24 hours. More guidance on dose reductions 
and interruptions is provided in Table 3 above.  
Guidelines for the treatment of study drug 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. 
 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®), or as per local practice. 
 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. 
Guidelines for the treatment of buparlisib 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). 


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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 in case of treatment related diarrhea should follow the guidelines 
presented above for other non-hematological adverse events. 
Guidelines for the treatment of buparlisib 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 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 Patient self-rating mood questionnaires. 
If question 9 in the PHQ-9 has a positive response (as indicated by selecting "1", "2", or "3"), 
omit treatment with buparlisib and refer the patient for psychiatric consultation for optimal 
management regardless of the total questionnaire score or CTCAE grading to 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 (e.g., Day 15 of Cycle 1, Day 1 and Day 15 of Cycles 2, 
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. 
Guidelines for the treatment of study drug 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 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 comedication 
and treatment interruption if needed. Photographs of a skin rash event as well as skin biopsy are 
recommended, if possible. 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. 


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Recommended therapies for skin toxicity events (refer to Table 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), for mild and moderate rashes. 
 Topical steroids of high potency (trunk/extremities): fluocinonide 0.05%; clobetasol 
0.05% cream or spray (< 8 weeks continuously), for mild and moderate rashes. 
 Oral antihistamines (sedating, evening): diphenhydramine 25 to 50mg t.i.d; hydroxizine 
25mg tid or q.i.d;  
 Oral antihistamines (non-sedating, day time): fexofenadine 180mg q.d. 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 
 In case of mild acneiform rashes topical antibiotics: clindamycin 1% to 2%; erythromycin 
1% to 2% (gel or solution formulation can be used, ointments cannot be used); 
metronidazole 1%; silver sulphadiazine. 
 For more severe acneiform rashes oral antibiotics: doxycycline 100mg b.i.d.; minocycline 
100mg b.i.d.; oxytetracycline 500mg b.i.d. for 6 weeks can be considered. If infection 
suspected (yellow crusts, purulent discharge, painful skin/nares), then switch to broad 
spectrum/gram negative antibiotics; consider skin swab for bacterial culture. 
 Topical antipruritics (pramoxine 1%, doxepin 5% cream) applied twice daily 
 For severe pruritus GABA Agonists: Gabapentin 300mg every 8 hours, or pregabalin 50 
to 75 mg every 8 hours (to adjust of renal impairment) can be considered. Dose should be 
adjusted 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% b.i.d.  
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. 
Guidelines for the management of Posterior Reversible Encephalopathy Syndrome (PRES) 
There have been rare reports of PRES occurring under treatment with buparlisib. Signs and 
symptoms may include severe headache, confusion or seizures, altered consciousness, visual 
disturbances, with or without associated high blood pressure. Patients are instructed in the 
written patient information to inform their treating physician if they suspect such an event. Take 
appropriate measures in such cases to assess the signs and symptoms. If PRES is suspected based 
on the signs and symptoms, buparlisib should be interrupted and a brain MRI should be 
performed to confirm the diagnosis. 
1.3.1.3.1.2 
Human pharmacokinetic and metabolism data 
Preliminary clinical pharmacokinetic data of buparlisib after single and multiple daily dosing are 
available from the first-in-human trial [CBKM120X2101]. Buparlisib was administered as a 


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capsule (doses ranging between 12.5 and 150 mg) and full pharmacokinetic profiles were 
collected on Day 1, Day 8 and Day 28 of Cycle 1.  
Buparlisib was rapidly absorbed, with the median time to reach the peak plasma concentration 
(Tmax) ranging from 1.0 to 1.75 hours after administration. Tmax was independent of dose and 
was not altered after multiple oral doses. Variability in systemic drug exposure was moderate at 
all dose levels. At 100 mg the variability in systemic drug exposure and Cmax (CV %) at steady-
state was moderate, about 36% and 25%, respectively. 
During once daily dosing, plasma buparlisib concentrations were found to accumulate in 
reaching steady-state. After one week of oral daily dosing (day 8), both Cmax and AUC0-24h 
were approximately 3-fold higher than after a single dose (day 1). The mean accumulation ratio 
(Racc) of buparlisib at 100 mg was 2.7 and 3.3 on days 8 and 28, respectively, indicating the 
absence of significant drug accumulation after day 8.  
The decay in buparlisib plasma concentration over time was bi-exponential, with an apparent 
long terminal half-life. The mean T1/2,acc (effective half-life, obtained from drug accumulation) 
calculated from exposure data at day 28 ranged between 38 and 49 hours across all dose levels. 
T1/2,acc was found to be independent of dose. Based on the effective half-life, steady state 
buparlisib plasma levels can be expected to be reached after 1 week of daily dosing. 
Furthermore, the preliminary PK data within the Japanese population [CBKM120X1101] show 
no significant differences in Cmax or AUC0-24h compared with the PK data for the Caucasian 
population [CBKM120X2101]. A preliminary population PK analysis, including data from 
studies [CBKM120X2101] and [CBKM120X1101] confirmed these findings (Novartis internal 
data). 
In study [CBKM120X2107] a daily dosing regimen of buparlisib was tested in combination with 
weekly infusions of trastuzumab in patients with relapsed HER2-overexpressing breast cancer. 
Preliminary pharmacokinetic data indicated that the systemic drug exposure (Cmax and AUC) of 
oral buparlisib in combination with trastuzumab was similar to that for the single agent data. 
Trastuzumab trough levels were consistent with those previously reported to be therapeutic (i.e., 
generally greater than 20 µg/ml). 
In the current study, corticosteroids and other CYP3A4 inducers will be prohibited in order to 
maintain buparlisib exposure in the expected range. In addition, anti-acids will be dosed at least 
one hour after buparlisib administration to avoid a decrease of pH during the absorption phase of 
buparlisib and thus avoid any possible solubility limitations.
1.3.1.3.1.3 
Clinical efficacy data 
Sixty six patients were evaluable for response in study [CBKM120X2101] where all patients in 
the expansion cohort were required to have mutated and/or amplified PIK3CA and/or mutated 
PTEN or null/low PTEN protein expression: partial tumor responses (PR) were observed in 3 
patients, one of which was a RECIST v1.0 confirmed PR in a patient with triple negative breast 
cancer and the other 2 patients’ responses were not confirmed (1 patient with metastatic breast 
cancer and 1 patient with parotid carcinoma) (Graña 2011). 
The first patient was a 61 year-old female with poorly differentiated ductal metastatic breast 
cancer assessed as triple negative (ER-, PgR-, HER2-), PI3KCA wild type, PTEN IHC positive. 
Since 2006 she received many previous anticancer agents (cyclophosphamide, doxorubicin, 


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gemcitabine, docetaxel, paclitaxel, vinorelbine, capecitabine, etoposide, anastrozole). As 
progressive disease developed (bulky lymph node involvement and local breast relapse), she was 
enrolled (April 2009) in the Phase I study of buparlisib in the 100 mg/day cohort. A metabolic 
response (61% decrease in SUV) was observed after 2 cycles, followed by a RECIST partial 
response (66% tumor shrinkage) after 4 cycles. This patient continues to receive treatment 
beyond 32 cycles.  
The second patient was a 52 year-old female with moderately differentiated ductal metastatic 
breast cancer, assessed as ER positive, HER2 negative, PI3KCA mutated (E545K & H1047Y), 
PTEN IHC positive. She had been previously treated with several antineoplastic agents. When 
she received buparlisib at 100 mg/day (January 2010), she had measurable metastases in the 
brain, lung and liver. At the second radiological assessment after receiving 4 cycles of buparlisib 
treatment, a 45% reduction of the sum of the lesions was recorded. The TTP for this patient was 
24 weeks.  
The third patient was a 45 year-old man with grade 4 parotid gland ductal carcinoma, PI3KCA 
wild type, PTEN IHC positive. He had been previously treated with doxorubicin and adriamycin. 
After disease progression was observed on this regimen he was enrolled in the 100mg/day cohort 
(July 2010) in the [CBKM120X2101] study. At the first radiological assessment after receiving 2 
cycles of buparlisib treatment, a 33% reduction of the sum of the lesions was recorded. The TTP 
for this patient was 16 weeks. 
As of the data cut-off 04July2011, preliminary analysis shows forty-five percent of patients (30 
of 66 evaluable) had stable disease as their best response, with 20 patients (30%) having a 
disease stabilization of 3 months or longer. A trend towards better activity (long-term 
stabilizations) has been observed at the higher dose cohorts, also expressed in metabolic FDG-
PET response. However, considering the impact of a PI3K inhibitor on glucose metabolism, 
further data are needed to understand whether the current FDG-PET assessment data can be used 
as a predictive factor for efficacy. 
With regard to pharmacodynamic markers observed in study [CBKM120X2101], down 
regulation of pS6 in skin by 30-80% was demonstrated in 28 out of the 38 evaluable patients at 
100 and 150 mg/d with more than a 25% FDG-PET signal decrease in patients at doses greater 
than the MTD.  
With regards to the PI3K pathway activation, two of the three responders described above had a 
cancer with a PIK3CA mutation. Moreover, 18 patients had a stable disease lasting for 16 weeks 
or longer, including 8 patients who had tumors with an activated PI3K pathway. These data are 
promising and continued exploration of the activity of buparlisib in patients with activated PI3K 
pathway is warranted.  
More specifically, in [CBKM120X2101], 25.3% (21/83) of patients had metastatic breast cancer. 
At the cut-off date of July 4th, 2011, twenty breast cancer patients were evaluable for objective 
tumor response by RECIST 1.0. Two breast cancer patients (11%), described above exhibited 
partial responses. For these 2 patients, the treatment duration was 27+ (ongoing) and 5 months, 
respectively. An additional 8 breast cancer patients (40%) had stable disease. Median 
progression-free survival was 60 days and the 6-month PFS rate was 33% (Rodon 2011). 
Other than [CBKM120X2101], two trials are ongoing in breast cancer patients with preliminary 
data available: 


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 In [CBKM120X2107], buparlisib is combined with trastuzumab in metastatic breast 
cancer patients with trastuzumab resistance. As of September 30, 2011, out of 17 
patients enrolled, 2 PR and 8 SD were observed in the dose escalation portion of this 
study, with a disease control rate (CR+PR+SD) of 59%. (Saura 2011). 
 Buparlisib has been combined with letrozole in ER+ post-menopausal breast cancer 
patients (Mayer 2011). Out of the 20 patients enrolled, 12 were evaluable for 
efficacy; 1 PR, and 7 SD were observed. Over 50% of patients had >25% reduction in 
their peak SUV at the 2-week FDG-PET scan. 
 
Please refer to the Investigator’s Brochure for additional information on the available 
clinical experience with buparlisib. 
1.3.2 
Capecitabine 
Capecitabine is a prodrug that is enzymatically converted to 5-fluorouracil in the tumor where it 
inhibits DNA synthesis and slows growth of tumor tissue (Xeloda package insert). Capecitabine 
is approved in both colorectal and breast cancer. Capecitabine demonstrated single-agent activity 
in subjects with MBC with an ORR of about 20% in subjects whose disease had progressed 
during or following anthracycline and taxane-based therapy (Xeloda package insert).  
Capecitabine is also indicated as a combination treatment with docetaxel in early-line treatment 
for MBC and in combination with ixabepilone or lapatinib as second-line treatment after failure 
of prior anthracycline and taxane-containing chemotherapy (Xeloda package insert). 
The recommended, approved dose of capecitabine is 1250 mg/m2 daily BID for 14 days, 
followed by 7 days without treatment (Xeloda package insert). This dose/schedule necessitates 
dose interruptions or reductions in approximately 30% of patients, and in clinical trials, 
approximately 17% of patients discontinued the drug due to toxicities (primarily hand-foot 
syndrome, diarrhea and stomatitis) (Mackean 1998; O’Shaughnessy 2001).  
There have been isolated case reports of responses to single agent capecitabine in patients with 
breast cancer-related CNS metastases (Ekenel 2007; Hikino 2006; Rogers 2004; Wang 2001; 
Fabi 2006; Tham 2006).  In addition, in a phase II trial of patients with HER2+ MBC with CNS 
metastases, the combination of capecitabine plus lapatinib was associated with a higher objective 
response rate (20%) compared with 6% observed with lapatinib alone (Lin 2009). Further, this 
combination produced a 66% partial CNS response rate in patients with previously untreated 
HER2+ CNS metastases in the phase II LANDSCAPE trial (Bachelot 2013). 
1.3.3 
Buparlisib in combination with capecitabine 
Investigators at the University of North Carolina and Duke are conducting a phase I study of 
capecitabine plus buparlisibin patients with MBC.  Although the study is not yet completed, 16 
patients have been enrolled as of January 3, 2013.  Based on assessment of toxicities in cycle 
1, the investigators believe that the recommended phase II dose from this study will likely be 
capecitabine 1000 mg/m2 PO BID 14 days on and 7 days off plus buparlisib 100 mg PO 
QD. Additional patients are being enrolled to this dose level presently.   Dose limiting toxicities 
(DLT) to date have included one patient each with psychosis, photosensitivity "sunburned" rash, 
fatigue, and mucositis.  Several patients who did not have a cycle 1 DLT, and whose disease had 
not progressed, withdrew from study therapy due to capecitabine-related toxicities including 


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diarrhea and hand foot syndrome, which occurred after cycle 1.  Several patients needed a dose 
reduction of capecitabine in cycles 2-5, and dose reductions of buparlisib to 80 mg PO QD were 
required in some patients due to grade 2 psychiatric or cognitive side effects. Evidence of 
antitumor activity has been observed in triple negative and ER+ MBC patients.  Overall, 
administration of the combination of capecitabine and buparlisib is feasible with doses of the two 
agents that are their single agent MTDs. Toxicities observed to date have been generally 
manageable with dose reduction although some patients have withdrawn from study therapy due 
to cumulative toxicity (Claire Dees, MD. personal communication).  
1.3.4 
Buparlisib in combination with trastuzumab 
 
A phase Ib/II trial by Pistilli et al ESMO 2012 combining trastuzumab plus buparlisib (100mg 
QD) showed acceptable safety in 52+ pts with basically no overlapping toxicities (Pistilli 2012).  
Of note, 5 patients had brain metastasis at study entry and 2 had SD still ongoing at the time of 
the abstract; 2 others had SD for 90 and 106 days and the fifth was not evaluable.  
 
1.4 
Study Rationale 
CNS metastases occur with high frequency in patients with metastatic MBC, developing in 
approximately one-fourth to one-half of patients. Currently there are no effective systemic 
therapies that have been shown to improve OS for patients with MBC with brain metastases. (see 
Section 1.1.1) Thus, there is an urgent unmet need for more effective treatments for this patient 
population.  
Dysregulation of the PI3K signaling pathway occurs in the majority of MBCs, through a variety 
of mechanisms including mutation of PIK3CA or PTEN, or loss of PTEN or INPP4B, as well as 
through activation by upstream receptor activation. PTEN loss and activation of PI3K signaling 
has also been documented specifically in MBC brain metastases, making inhibition of this 
pathway an attractive therapeutic strategy for investigation. (see section 1.2.1) 
Capecitabine and buparlisib have both individually demonstrated the ability to penetrate the 
blood-brain barrier, and have shown activity in MBC, making this a rational combination to 
evaluate for the treatment of MBC brain metastases. In addition, this combination is currently 
being evaluated in a phase I study in MBC, including patients with MBC, with  evidence of 
activity as well as tolerability. (see Section 1.3.3) 
Given this background, we have decided to proceed with a phase II study to test the combination 
of capecitabine plus buparlisib in metastatic breast cancer with HER2+ or ER+/HER2- or triple 
negative brain metastases. The purpose of this study is to evaluate the effect of buparlisib plus 
capecitabine on clinical benefit rate in this patient population. 
1.4.1 
Rationale for dose selection 
 
Buparlisib will be administered at a dose of 100 mg orally (PO) daily, the MTD/RP2D 
determined in single agent ([CBKM120X2101] and [CBMK120X1101]) and combination 
([CBKM120X2107], 
[CBEZ235A2118] 
and 
[CBKM120XUS13T]) 
studies 
(Buparlisib 
Investigator Brochure). This dose has also shown preliminary tolerability in combination with 
capecitabine in the ongoing phase I study in MBC. Capecitabine will be administered at a dose 


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of 1000 mg/m2 PO BID (rounded down to the nearest 500 mg pill) 14 days on and 7 days off, 
based on the recommended phase II dose determined in the phase I study of capecitabine plus 
buparlisib in MBC (Claire Dees, MD. personal communication). 
2 
Study objectives 
Primary Objectives 
 To determine the clinical benefit rate (CBR) based on local investigator assessment 
associated with buparlisib once daily plus capecitabine (1000 mg/m2 PO BID 14 days 
on/7 days off) in patients with metastatic breast cancer with a  brain metastasis at 
least 5mm in size following whole brain radiation therapy (WBRT)  or stereotactic 
radiosurgery (SRS) or both. The target lesion that is at least 5mm in size must not 
have undergone treatment with SRS and may represent residual disease following 
SRS or WBRT, or may represent progression of disease following SRS or WBRT.  
Clinical benefit rate is defined as the proportion of patients with best overall response 
of complete response (CR) or partial response (PR) or stable disease (SD) in the CNS 
lasting at least 24 weeks based on local investigator assessment.  
Secondary Objectives 
 To assess ORR in the CNS based on local investigator assessment associated with 
buparlisib plus capecitabine. 
 To assess median time to progression (TTP) associated with buparlisib plus 
capecitabine. 
 To determine median overall survival (OS) associated with buparlisib plus 
capecitabine. 
 To determine if buparlisib plus capecitabine prolongs OS compared with expected 
survival of patients with brain metastases, estimated using the breast-GPA (See 
Appendix 1). 
 To characterize the safety and tolerability of buparlisib plus capecitabine, with or 
without trastuzumab. 
 To assess median time to deterioration of neurologic function. 
 To monitor changes in symptom occurrence using the M.D. Anderson Symptom 
Inventory-Brain Tumor Module (MDASI-BT), and to provide results of PHQ-9 
Depression Scale. 
 To investigate whether there is a correlation between PI3K pathway-related 
biomarkers and clinical response. 
3 
Exploratory Investigational Plan 
3.1 
Overall Study Design 
This is a Phase 2, multicenter, single-arm study to determine the efficacy and safety of buparlisib 
plus capecitabine in approximately 42 patients with metastatic breast cancer with measurable 
brain metastases at least 5mm in size following WBRT or SRS or both.   The target lesion that is 
at least 5mm in size must not have undergone treatment with SRS and may represent residual 


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disease following SRS or WBRT, or may represent progression of disease following SRS or 
WBRT. 
 
This study will consist of 2 phases: a Screening Phase where the informed consent will be 
collected and eligibility criteria will be assessed followed by a Treatment Phase that includes 
end-of-treatment follow-up assessments. The Screening Phase will include assessments before 
the first dose of study drugs (Cycle 1/Day 1) to establish eligibility and baseline values. The 
Treatment Phase will commence for each subject with the first dose of buparlisib plus 
capecitabine, with or without trastuzumab, and continue through the end of treatment. After 
discontinuing all study treatment, the patient will be followed for a mandatory 30-day safety 
follow-up, efficacy (tumor assessments, if applicable) follow-up and survival follow-up.  
During the treatment phase:  
 Patients with HER2- MBC will receive buparlisib orally (PO) at a dose of 100 mg 
daily continuously in combination with capecitabine 1000 mg/m2 PO BID 14 days 
on/7 days off.   
 For patients with HER2+ MBC, standard every 3-weekly trastuzumab (6 mg/kg IV) 
will be added to the capecitabine/buparlisib.   
Patients will receive treatment until disease progression, unacceptable toxicity, death, or 
discontinuation from the study treatment for any other reason. Patients will be followed for 
survival regardless of treatment discontinuation for any reason for up 2 years from date of 
registration (except if consent is withdrawn or patient is lost to follow-up).  
Note: Information from procedures that may have been previously performed as part of the 
patient’s routine disease care (prior to enrolling in the trial) is allowed to be used to satisfy 
inclusion criteria as long as the procedures were performed within 28 days of registration. 
 
Screening phase 
All patients will undergo screening assessments to determine study eligibility. Within 28 days 
before initiation of treatment, the patient will provide a signed informed consent form prior to 
any study related activities. All screening evaluations must be performed during the screening 
period (day −28 to day −1). Receptor status may be obtained anytime before enrollment on 
study. Collection and shipment of tumor sample (new biopsy or archived tissue) to designated 
lab (check the CTI) should occur as soon as possible and no later than Day −1. Check Table 4-12 
for details of tests to be done at screening. 
Screening procedures are to be performed within 28 days of the start of study treatment. 
Receptor status may be obtained any time before enrollment on study. Baseline values for those 
assessments (e.g., physical examination, ECOG performance status, weight, vital signs, 
hematology, biochemistry and fasting plasma glucose) may be used for Cycle 1 assessments as 
long as they are performed within 2 weeks prior to the patient receiving their first dose of the of 
study drug. 
 


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Treatment phase 
Once inclusion and exclusion eligibility criteria have been confirmed, study treatment will be 
initiated. Patients will receive buparlisib orally (PO) at a dose of 100 mg daily continuously in 
combination with capecitabine 1000 mg/m2 PO BID 14 days on/7 days off, then repeat the cycle. 
Patients with HER2+ MBC will also receive trastuzumab by IV administration every 3 weeks.   
Capecitabine needs to be rounded down to the nearest 500 mg pill.  Buparlisib and capecitabine 
dose modifications will be allowed (see Section 4-1). Safety will be monitored as outlined in 
Section 4-3. 
Cycle treatment and evaluations will be performed during therapy at the start of each cycle, 
unless otherwise specified. Cycle 2 and subsequent cycles, has a window of +/-3 business days 
(after the scheduled time) for treatment administration and cycle assessments (e.g., the physical 
examination, performance status (ECOG), weight, vital signs, and labs) during the study 
treatment. Any delay within this window is NOT a deviation. 
Patients will receive treatment until disease progression (assessed by RECIST 1.1), unacceptable 
toxicity, death or discontinuation from treatment for any other reasons. Efficacy and safety 
monitoring will continue as per the visit schedule (Table 4-12). Tumor assessments will be 
performed every 8 weeks after treatment initiation date until clinical or radiological progression. 
Disease progression in the brain and other sites should always be documented radiologically, 
adding an earlier than planned imaging time point for tumor assessments as clinically indicated. 
Note: Cycle 1 only, the baseline values for those assessments (e.g., the physical examination, 
performance status (ECOG), weight, vital signs hematology, biochemistry, and fasting plasma 
glucose,) that are to be done for screening may be used for Cycle 1 assessments as long as they 
are completed within 2 weeks prior to the patient receiving their first dose of study drug. If more 
than 2 weeks have elapsed since the baseline assessment, the assessment must be repeated.  
Assessments need to be put in the order in which they appear in eCRF.  Treatment must begin 
within 5 working days after patient registration to the study, not including weekends or holidays. 
End of Treatment Phase 
After the end of the treatment visits, all patients will be followed up for safety up to 30 days after 
the last dose of study treatment (buparlisib plus capecitabine).  There is window of +/- 7 business 
days for end of treatment assessments.  Any delay within this window is NOT a deviation.  End 
of treatment will continue as per the visit schedule (Table 4-12). 
Follow up phase 
After the end of the treatment visits, all patients will be followed up for safety up to 30 days after 
the last dose of study treatment (buparlisib plus capecitabine).   
All patients who discontinue from study treatment due to disease progression must have their 
progression clearly documented according to the criteria specified in RECIST 1.1. 


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If a patient did not discontinue study treatment due to disease progression, death, adverse event, 
start of new anti-neoplastic therapies, lost to follow-up, or withdrawal of consent for efficacy 
follow-up then tumor assessments should continue to be performed every 8 weeks until the start 
of new anti-cancer therapy, disease progression, death, lost to follow-up or withdrawal of 
consent for efficacy follow-up. 
All patients will be followed for survival every 2 months from last date of treatment regardless of 
treatment discontinuation reason (except if consent is withdrawn or patient is lost to follow-up) 
until death or for up to 2 years from date of registration. Survival information can be obtained via 
phone and information will be documented in source document. 
There is window of +/- 7 business days for end of treatment assessments.  Any delay within this 
window is NOT a deviation.  For details on required assessments, please refer to Table 4-12. 
 
 


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Figure 3-1 Study design 
Patients with metastatic breast cancer with a brain metastasis at least 5mm in size who have  been treated with WBRT
Screening
From day -28 to day -1
Treatment
BKM120 + Capecitabine
+ trastuzumab if HER2+
~ 40 Patients
End of treatment (EoT)
EoT1 due to disease 
progression
Other reason for EoT2
Safety follow-up
(up to 30 days after EoT)
Safety follow-up
(up to 30 days after EoT)
Efficacy follow-up tumor assessments
Every 8 weeks
Survival follow-up: every 2 months (or
more frequently if necessary)
Survival follow-up: every 2 months (or
more frequently if necessary)
1 End of treatment (EoT) is due to disease progression, start of new cancer therapy, lost to follow-up or withdrawal of consent for efficacy 
follow-up
2 EoT is for reasons other than disease progression, lost to follow-up or withdrawal of consent for efficacy follow-up or started new anti-
cancer treatment
SCREENING
TREATMENT
FOLLOW UP
 
 
 
Definition of 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. The end of study will be declared depending on the results of the primary 
analysis.  
 
 
3.2 
Study Population 
3.2.1 
Patient population 
The primary analysis patient population consists of patients with MBC with a non-progressing 
brain metastasis that is at least 5mm in size and who have undergone treatment with WBRT or 
SRS or both at any time for their brain metastases and who do not have evidence of impending 
visceral crisis outside of brain.  The target lesion that is at least 5mm in size must not have 
undergone treatment with SRS and may represent residual disease following SRS or WBRT, or 
may represent progression of disease following SRS or WBRT. Evidence of progression of 
disease following WBRT or SRS is allowed but is not required.  Patients may be symptomatic as 
long as ECOG performance status is ≤2. There is no limit on the number of chemotherapy 
regimens previously received and prior treatment with capecitabine is allowed.   The patients 


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must not have active cardiac disease, or clinically significant GI disease that impairs GI function. 
The patients must provide tumor tissue (archival or new biopsy) for the analysis of PI3K 
pathway-related biomarkers unless previously discussed with the study principal investigator. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered enrollment in the study.  Eligible patients must 
have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
criteria. 
The patients are not permitted to participate in additional parallel investigational drug or device 
studies.  
3.2.2 
Registration procedures 
Written documentation of full IRB and FDA approval must be on file before a patient can be 
registered. The registration process begins when the coordinator has obtained a signed informed 
consent. Please enter patient demographics into the Clinical Trial Management System (CTMS); 
this is the Web-based intranet system for the delivery of trial information between Delta and 
used across all sites. A UPN will be assigned to the patient at that time. Entering a patient into 
CTMS does not signify that you have registered the patient in the study. If you have any 
difficulty with CTMS please contact the Clinical Trial Manager. 
Once the patient has an UPN number, the coordinator can go to their Patient Report and select 
the patient that they want to register.  Located to the left of the patient’s UPN will be the letters 
“Reg” in blue.  The coordinator will click on the blue “Reg” to open up that patient’s 
information.  Each page that needs to be completed will be in yellow.  The site will answer the 
questions on the Inclusions and Exclusions.  Once all questions on each page are answered, that 
page will turn green.  Once all the pages turn green, click on the “verify data” tab, then click the 
“register” tab.  The register page will open, “click to register”.  An ID number will be directly 
assigned. For any difficulties with entering the data, please contact the Project Manager of the 
study. 
 
Treatment must begin within 5 working days after the patient’s registration on the study, 
not including weekends or holidays. 
 
3.2.3 
Inclusion and exclusion criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. Results of all baseline evaluations, which assure that all 
inclusion and exclusion criteria have been satisfied, must be documented on the checklist and 
signed by the treating physician. In addition, the patient must be thoroughly informed about all 
aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent. The written informed consent must be obtained 
from the patient prior to enrollment. Patients eligible for enrollment in the treatment phase of this 
study must meet all of the following criteria: 
 
 


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Inclusion criteria  
1. Age ≥ 18 years 
2. Female 
3. Histologically and/or cytologically confirmed diagnosis of inoperable breast cancer 
4. ER+/HER2- OR HER2+ OR triple-negative breast cancer, assessed as ER-, PgR-, and 
HER2-negative by local laboratory testing; HER2 negative status (based on most recently 
analyzed biopsy) is defined as IHC status of 0, 1+ or 2+ (if IHC 2+, a negative FISH test is 
required, i.e.,  HER2 FISH ratio < 2.0 with an average HER2 copy number <4.0 signals/cell);  
ER-negative and PR-negative status is defined as ER and PgR <1% nuclei positive by IHC 
(per ASCO guidelines). HER2-positive status is defined as 3+ staining in ≥10% of cells  by 
immunohistochemistry or a HER2/CEP17 ratio ≥2 or an average of ≥6 HER2 gene copies per 
cell by in situ hybridization (ISH) according to the 2013 ASCO/CAP guidelines 
5. At least one CNS lesion that is at least 5mm in size in at least one dimension in the setting of 
prior WBRT or SRS or both: 
 Prior WBRT or SRS or both is required and may have been administered at any time in 
patient’s treatment history.  Patients must have completed WBRT at least 3 weeks prior 
to study entry and a minimum of a 5 days window is required following SRS before 
beginning study therapy.  
 The target lesion that is at least 5mm in size must not have undergone treatment with SRS 
and may represent residual disease following SRS or WBRT, or may represent 
progression of disease following SRS or WBRT or both. 
6. ECOG performance status  2   
7. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 
109/L, Hb >9 g/dL  
8. Total calcium (corrected for serum albumin) within normal limits (biphosphonate use 
for malignant hypercalcemia control is not allowed) 
9. Magnesium ≥ the lower limit of normal  
10. Potassium within normal limits for the institution 
11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal 
range (or ≤  3.0 x upper limit of normal (ULN) if liver metastases are present) 
12. Serum bilirubin within normal range (or ≤  1.5 x ULN if liver metastases are present; or 
total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with  
known Gilbert Syndrome) 
13. Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min 
14. Serum amylase ≤ ULN 
15. Serum lipase ≤ ULN 
16. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) 
17. Negative serum pregnancy test within 72 hours before starting study treatment in 
women with childbearing potential 
18. INR ≤ 2 
19. Life expectancy > 12 weeks 
20. Available tissue (blocks and/or slides) samples unless discussed in advance with study 
principal investigator 


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21. Patient is able to swallow and retain oral medication 
22. Signed most recent patient informed consent form 
23. Signed Patient HIPAA Authorization Form  
Exclusion criteria   
Patients eligible for enrollment into the treatment phase of this study must not meet any of 
the following criteria: 
1. Patient received prior treatment with a PI3K inhibitor.  
2. Patient with known hypersensitivity to buparlisib, capecitabine, or their excipients. 
3. Patient has evidence of impending herniation on baseline brain imaging. 
4. Patient has evidence of diffuse leptomeningeal disease on brain MRI or by previously 
documented CSF. 
5. Patients has acute or chronic liver, renal disease or pancreatitis (liver metastases are 
allowed) 
6. Patients has a mood disorder as judged by the Investigator or a psychiatrist, or as a 
result of patient’s mood assessment questionnaire (PHQ-9 and/or GAD-7):  
 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 (immediate risk of doing 
harm to 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. 
  ≥ CTCAE grade 3 anxiety  
 Meets the cut-off score of ≥ 12 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 
mood scale, respectively, or selects a positive response of “1, 2, or 3” to 
question number 9 regarding potential for suicidal thoughts in the PHQ-9 
(independent of the total score of the PHQ-9)  
7. Patients has diarrhea ≥ CTCAE grade 2 
8. Patients with uncontrolled hypertension defined as systolic blood pressure 170 or 
greater or diastolic blood pressure over 100. 
9. Patient has active cardiac disease including any of the following:  
 Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple 
Gated acquisition (MUGA) scan or echocardiogram (ECHO)  
 QTc > 480 msec on screening ECG (using the QTcF formula) 
 Angina pectoris that requires the use of anti-anginal medication 
 Ventricular arrhythmias except for benign premature ventricular contractions 
 Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled 
with medication 
 Conduction abnormality requiring a pacemaker 
 Valvular disease with document compromise in cardiac function  
 Symptomatic pericarditis 


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10. Patient has a history of cardiac dysfunction including any of the following: 
 Myocardial infarction within the last 6 months, documented by persistent 
elevated cardiac enzymes or persistent regional wall abnormalities on 
assessment of LVEF function 
 History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
 Documented cardiomyopathy 
11. Patient has poorly controlled  diabetes mellitus or steroid-induced diabetes mellitus 
12. Patient has other concurrent severe and/or uncontrolled concomitant medical conditions 
(e.g., active or uncontrolled infection) that could cause unacceptable safety risks or 
compromise compliance with the protocol 
 Significant symptomatic deterioration of lung function.  If clinically indicated, 
pulmonary function tests including measures of predicted lung volumes, DLco, 
O2 saturation at rest on room air should be considered to exclude pneumonitis 
or pulmonary infiltrates.  
13. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of buparlisib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or small bowel resection). Patients with unresolved 
diarrhea will be excluded as previously indicated 
14. Patient was treated with any hematopoietic colony-stimulating growth factors (e.g., G-
CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or darbepoetin 
therapy, if initiated at least 2 weeks prior to enrollment, may be continued 
15. Patient is currently receiving treatment with medication with a known risk to prolong 
the QT interval or inducing Torsades de Pointes and the treatment cannot either be 
discontinued or switched to a different medication prior to starting study drug.  Please 
refer to Table 3-2 or a list of prohibited QT prolonging drugs with risk of Torsades de 
Pointes.   
16. Patients receiving chronic treatment with steroids or another immunosuppressive agent. 
Patients must have been off all corticosteroids (except for physiologic doses of 
hydrocortisone as replacement therapy) for at least 2 weeks prior to study entry. 
 Note: Single doses, or topical applications (e.g. rash), inhaled sprays (e.g. 
obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are 
allowed.   
17. Patient has taken herbal medications and certain fruits within 7 days prior to starting 
study drug. 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.  Fruits include the CYP3A inhibitors Seville oranges, grapefruit, 
pummelos, or exotic citrus fruits. Regular orange juice is permitted.  
18. Patient is currently treated with drugs known to be moderate and strong inhibitors or 
inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched 
to a different medication prior to starting study drug.  Please refer to Table 4-8 for a list 
of prohibited inhibitors and inducers of CYP3A (Please note that co-treatment with 
weak inhibitors of CYP3A is allowed). 


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19. Patient received chemotherapy or targeted anticancer therapy ≤ 3  weeks (6 weeks for 
nitrosourea, antibodies or mitomycin-C) prior to starting study drug, and have related 
side effects must recover to a grade 1 or less before starting the trial  
20. Patient received any continuous or intermittent small molecule therapeutics (excluding 
monoclonal antibodies) with ≤ 5 effective half lives prior to starting study drug or who 
have not recovered from side effects of such therapy 
21. Patient received wide field radiotherapy ≤ 4 weeks or limited field radiation for 
palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side 
effects of such therapy 
22. Patient underwent major surgery ≤ 2 weeks prior to starting study drug or who have not 
recovered from side effects of such therapy.  
23. Patient is currently taking therapeutic doses of warfarin sodium or any other coumadin-
derivative anticoagulant.  
24. Patient is pregnant or breast feeding or is of reproductive potential and not employing 
an effective method of birth control.  
 Note: Double barrier contraceptives must be used through the trial by both sexes. 
Oral, implantable, or injectable contraceptives may be affected by cytochrome 
P450 interactions, and are therefore not considered effective for this study. Women 
of child-bearing potential, defined as sexually mature women who have not 
undergone a hysterectomy or who have not been naturally postmenopausal for at 
least 12 consecutive months (i.e., who has had menses any time in the preceding 12 
consecutive months), must have a negative serum pregnancy test ≤ 72 hours prior 
to initiating treatment. 
 Note: 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 six months 
of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [: and 
estradiol < 20 pg/mL] 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. 
 Note: Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, must use highly effective contraception during 
treatment for 4 weeks (5 T1/2) after stopping treatment. The highly effective 
contraception is defined as either: 
1. True 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. Sterilization:  have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago.  In case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment. 


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3. Male partner sterilization (with the appropriate post-vasectomy documentation 
of the absence of sperm in the ejaculate). For female subjects on the study, the 
vasectomized male partner should be the sole partner for that patient. 
4. Use of a combination of any two of the following (a+b): 
a) Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
b) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/vaginal 
suppository 
 Note: Oral contraception, injected or implanted hormonal methods are not 
allowed as buparlisib potentially decreases the effectiveness of hormonal 
contraceptives. 
25. Patient has known diagnosis of human immunodeficiency virus (HIV) infection  
26. Patient has history of another malignancy within 5 years, except cured basal cell 
carcinoma of the skin or excised carcinoma in situ of the cervix 
27. Patient is unable or unwilling to abide by the study protocol or cooperate fully with the 
investigator 
28. Patient is concurrently using other approved or investigational antineoplastic agent. 
29. Patient taking or needing enzyme-inducing anti-epileptic medication. 
30. Patients with an acute viral hepatitis or a history of chronic or active HBV or HCV 
infection  
 
4 
Treatments 
4.1 
Interruption or Discontinuation of Treatment 
 
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 
or capecitabine administration must be recorded on the eCRF. If administration of buparlisib 
must be interrupted because of unacceptable toxicity, drug dosing will be interrupted or modified 
according to rules described in Table 4-0 and Table 4-1. Toxicity will be assessed using the NIH-
NCI Common Terminology Criteria for Adverse Events, version 4.0. (CTCAEv4.0), 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf). 
The 
dose of buparlisib does not need to be reduced for toxicities that the physician believes are due to 
capecitabine.  
 
Capecitabine dose modification guidelines are described in Section 4.1.3. Please refer to the local 
approved prescribing information. Any planned variance from these guidelines in the view of 
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. The dose of capecitabine does not need to be reduced for toxicities 
that the physician believes are due to buparlisib.  
 


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Trastuzumab dose modifications will be per physician’s discretion and standard of care..  
 
If the administration of buparlisib or capecitabine is interrupted for reasons other than toxicity, 
then treatment with the respective study drug may be resumed at the same dose. The same 
applies if the patient experiences an unacceptable toxicity not specifically described, provided 
this toxicity resolved to ≤ CTCAE grade 1, unless otherwise specified. 
 
If one or both study drugs are being withheld 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 4-12. If administration of buparlisib or capecitabine dosing is held for more 
than 21 days, then this withheld study drug should be permanently discontinued. Patients who 
permanently discontinue one of the withheld study drugs for any reason other than disease 
progression may continue the other study drug as part of the trial therapy at the investigator’s 
discretion. 
 
Table 4-0   Buparlisib dose level modification guidelines 
Dose level 
Dose and schedule 
* 0 
100 mg daily   
-1 
80 mg daily 
-2 
60 mg daily 
* Starting Dose  
 
 
 
 


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Table 4-1 Criteria for interruption and re-initiation of Buparlisib treatment 
Recommended Dose Modifications for Buparlisib
Worst toxicity (CTCAE 
Grade)** 
Recommended Dose Modifications 
No toxicity 
Maintain dose level 
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, fever ≥ 
38.5°C) 
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 


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Recommended Dose Modifications for Buparlisib
Worst toxicity (CTCAE 
Grade)** 
Recommended Dose Modifications 
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 study 
treatment 
Grade 4 (> 10.0 x ULN) 
Omit dose and discontinue patient from study treatment 
AST or ALT 
Grade 1 (> ULN - 3.0 x ULN) 
 
Maintain dose level with LFTs* monitored as per 
protocol 
Grade 2 (> 3.0 - 5.0 x ULN) 
without bilirubin elevation to > 2.0 
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 (> 5.0 - 20.0 x ULN) 
without bilirubin elevation to > 2.0 
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 4 (> 20.0 x ULN) without 
bilirubin elevation to > 2.0 x ULN 
Omit dose until resolved to ≤ Grade 1 , then  1 dose 
level 
AST or ALT and concurrent 
Bilirubin 
 
AST or ALT > 3.0 x ULN and 
total bilirubin > 2.0 x ULN 
Discontinue study treatment permanently. 
* 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. 
 
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. 
 
 


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Recommended Dose Modifications for Buparlisib 
Worst 
toxicity 
(CTCAE 
Grade)** 
Recommended Dose Modifications 
ENDOCRINE/METABOLIC 
Fasting Plasma Glucose (FPG) 
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 every at least 2 weeks 
Grade 2 (>160 – 250 mg/dL) [> 
8.9 - 13.9 mmol/L] 
 If signs or symptoms of hyperglycemia (for example, 
mental status changes, excessive thirst, polyuria) 
manage as for Grade 3 hyperglycemia (see below). 
 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 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, 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: 


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Recommended Dose Modifications for Buparlisib 
Worst 
toxicity 
(CTCAE 
Grade)** 
Recommended Dose Modifications 
 administer intravenous hydration and intervention 
for electrolyte/ketoacidosis/hyperosmolar 
disturbances as clinically appropriate 
 continue to omit buparlisib 
 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 and reduce 1 dose level 
 If FPG remains greater than Grade 1 severity for 
more than 7 days, then discontinue patient from 
buparlisib 
 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 
hyperglycemia (for example, mental status changes, 
excessive thirst, polyuria), or presence of blood or urine 
ketones, omit buparlisib and following guidance for 
management of Grade 3 fasting plasma glucose (FPG) 
Grade 4 (> 500 mg/dL) [≥ 27.8 
mmol/L] 
 Immediately omit buparlisib, 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 buparlisib 
 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 


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Recommended Dose Modifications for Buparlisib 
Worst 
toxicity 
(CTCAE 
Grade)** 
Recommended Dose Modifications 
 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 buparlisib and following guidance 
for management of Grade 4 fasting plasma glucose 
(FPG). 


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Recommended Dose Modifications for Buparlisib 
Worst 
toxicity 
(CTCAE 
Grade)** 
Recommended Dose Modifications 
CARDIAC 
Cardiac – Left Ventricular 
systolic dysfunction 
 
Asymptomatic,  
resting ejection fraction 50 – 
40%; 
or 10-20% drop from baseline 
Maintain dose level 
 
 
Repeat LVEF within 4 weeks or as clinically appropriate 
Symptomatic,  
responsive to intervention,  
ejection fraction 39 – 20% 
or > 20% drop from baseline 
 Omit dose until resolved to ≤ Grade 1, then  1 dose 
level 
 LVEF measurement to be repeated, if not resolved to 
≤ Grade 1 within 3 weeks, permanently discontinue 
patient from buparlisib 
Refractory or poorly controlled,  
ejection fraction < 20% 
Omit dose and discontinue patient from buparlisib 
Cardiac – QTc prolongation 
 
QTcF > 500 ms (≥ Grade 3)  
or > 60 ms change from baseline 
on at least two separate ECGs 
First Occurrence: 
 omit buparlisib  
 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 
 If QTcF remains > 500 ms, repeat ECG as clinically 
indicated, but at least once a day until the QTcF 
returns to < 480 ms. 
 Once QTcF prolongation has resolved, buparlisib 
may be restarted at a one lower dose level  
Second Occurrence: 
 discontinue patient from buparlisib 
 
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 
Omit dose and discontinue patient from buparlisib 
 
 


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Recommended Dose Modifications for Buparlisib 
Worst toxicity (CTCAE 
Grade)** 
Recommended Dose Modifications 
OTHER 
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 
Grade 4 
Omit dose and discontinue patient from buparlisib 
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 
Omit dose and discontinue patient from study 
Note: Omit dose for ≥ Grade 3 vomiting or Grade 3 
nausea only if the vomiting or nausea cannot be 
controlled with optimal antiemetic 
Pneumonitis 
See Table 4.6 
** Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 























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Mood alteration/Psychiatric Disorders 
* Note: For all grades, if question 9 on the PHQ-9 has a positive response (as indicated by selecting "1", "2", 
or "3"), omit study drug and refer patient for psychiatric consult regardless of the total questionnaire score 
or CTCAE grading to confirm if study drug should be interrupted or permanently discontinued. 
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 (e.g. as per local guidelines and/or 
psychiatric/expert consultation) 
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 (e.g. as per local guidelines and/or 
psychiatric/expert consultation) 
 
● First event:  if the condition resolved to Grade ≤ 1 or 
to baseline status, continue to co-medicate and then 
maintain the 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  1 dose level 
Grade 4* 
Permanently discontinue patient from buparlisib 
● Psychiatric consultation is required  
● Introduce optimal management (e.g. as per local 
guidelines) 





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Skin toxicity 
Rash (maculo-papular) 
Grade 1 
(<10% body surface area BSA; 
no associated erythema or 
pruritus) 
Maintain dose level. Consider to initiate appropriate 
skin toxicity therapy, e.g. with topical corticosteroids 
b.i.d. and oral antihistamines 
Grade 1 
Maintain dose level. Consider to initiate appropriate 
skin toxicity therapy with antihistamines and topical 
corticosteroids 
Grade 2 
(10 to 30% BSA and associated 
with erythema or pruritus; 
limited instrumental activities of 
daily living (ADL)) 
Tolerable Grade 2: 
 Initiate/intensify appropriate skin toxicity therapy, 
e.g. with topical steroids b.i.d. and oral 
antihistamines. 
 Maintain dose level. 
Intolerable Grade 2: 
 Omit dose and initiate/intensify appropriate skin 
toxicity therapy, e.g. with topical steroids b.i.d., 
oral antihistamines and oral steroids. 
 First occurrence: 
 If resolved to grade ≤ 1 in ≤ 2 weeks, maintain 
dose level. 
 If resolved grade ≤ 1 in more than 2 weeks, ↓ 1 
dose level. 
 Consider continuing skin toxicity therapy up to 2 
weeks after re-introduction of BKM120/placebo. In 
case of flare after cessation of skin toxicity therapy, 
consider prompt re-implementation. 
Second occurrence: omit dose and follow treatment 
guidance above, 
 Once resolved to grade ≤ 1,  1 dose level 
Grade 3 
(Macules or papules covering 
>30%BSA with or without 
symptoms) 
 Omit dose and initiate/intensify appropriate skin 
toxicity therapy, e.g. with topical steroids b.i.d., 
oral antihistamines and oral steroids. 
 Once resolved to grade ≤ 1,  1 dose level. 
 Consider continuing skin toxicity therapy up to 2 
weeks after re-introduction of BKM120/placebo. In 
case of flare after cessation of skin toxicity therapy, 
consider prompt re-implementation 
Grade 4 
(including other skin toxicity 
than maculo-papular rash) 
Permanently discontinue patient from 
BKM120/placebo 


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Acneiform rash 
Grade 1 
(<10% body surface area BSA; 
no associated erythema or 
pruritus) 
Maintain dose level. Consider to initiate appropriate 
treatment, e.g. with topical steroids (moderate potency) 
and topical antibiotics b.i.d. 
Grade 2 
(10 to 30% BSA and associated 
with erythema or pruritus; 
limited instrumental activities of 
daily living (ADL)) 
Tolerable Grade 2: 
 Same management as Grade 1. 
Intolerable Grade 2: 
 Omit dose and initiate/intensify appropriate skin 
toxicity therapy, e.g. with oral antibiotics for 6 
weeks; stop topical antibiotics if being used and 
start with topical steroids of moderate potency. 
 If resolved to grade ≤ 1 in ≤ 2 weeks, maintain 
dose level. 
 If resolved grade ≤ 1 in more than 2 weeks, ↓ 1 
dose level. 
Second occurrence: omit dose and follow treatment 
guidance above 
 Once resolved to grade ≤ 1,  1 dose level 
Grade 3 
(>30% BSA And associated with 
pruritus; limiting self ADL) 
 Omit dose and initiate/intensify appropriate skin 
toxicity therapy, e.g. with oral antibiotics for 6 
weeks potency. 
 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. 
 Once resolved to grade ≤ 1,  1 dose level. 
Grade 4 
(Papules and/or pustules covering 
any % BSA, associated with 
symptoms or not but associated 
with extensive superinfection) 
Permanently discontinue patient from 
BKM120/placebo 
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 for additional follow up for selected 
toxicities 
Other non- hematological adverse events 


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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 
	 Omit dose for ≥ Grade 3 vomiting or Grade 3 
nausea only if the vomiting or nausea cannot be 
controlled with optimal antiemetic 
 
Stomatitis/Oral mucositis 
Grade 1 / Tolerable Grade 2 
Maintain dose level. 
Non-alcoholic or salt water mouth wash (see also 
section for additional follow up for selected toxicities) 
Intolerable Grade 2 or Grade 3 
First occurrence: hold until resolved to grade ≤ 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 resolved to grade ≤ G1 
and  1 dose level. 
Grade 4 
Permanently discontinue patient from buparlisib. 
** Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
These changes must be recorded on the Dosage Administration section of the patient record. 


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4.1.1.3 
Monitoring of buparlisib suspected toxicities   
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed as outlined in Table 3-1, at least 
once a week for 4 weeks, and subsequently at 4-week intervals, until resolution or 
stabilization of the event, whichever comes first. If a patient requires a dose delay of > 21 
days from the intended day of the next scheduled dose, then the patient should be 
discontinued from the study. If the patient requires more than 2 dose reductions, the patient 
should be discontinued from the study (i.e., patients cannot be treated below dose level -2). 
All patients must be followed for adverse events and serious adverse events for 30 days 
following the last dose of buparlisib. All SAEs must be reported to Delta as detailed in 
Section 4.3.7. 
 
4.1.2 
Known Undesirable Side Effects of Buparlisib 
4.1.2.3 
Neuropsychiatric events  
 
In an ongoing Phase Ia study of buparlisib in patients with solid tumors (CBKM120X2101), 
neuro-psychiatric adverse events, including reversible and generally mild to moderate mood 
alterations, described as anxiety, agitation with crying episodes and depression have been 
reported in patients treated with buparlisib. (Buparlisib Investigators Brochure) In this study, 
three out of five patients with moderate to severe mood alterations had a history of depression 
and/or anxiety. All patients with a documented medical history of depression/anxiety also 
developed mood alterations while treated with buparlisib at the 100 mg dose level, thus 
reflecting a potential risk group of patients.  
 
In order to lower the risk of experiencing significant mood alterations within the proposed 
study, cancer patients with an active or history of major depressive episode, bipolar disorder, 
obsessive-compulsive disorder, schizophrenia, a history of suicide attempt or ideation, or 
homicide/homicidal ideation as judged by the investigator and/or based on recent psychiatric 
assessment will not qualify for study participation. Patients with corresponding symptoms 
CTCAE Grade ≥ 2 should immediately be examined by a psychiatrist and closely followed 
medically. Medical treatment with mood stabilizers (2nd generation antipsychotics) such as 
olanzapine and quetiapine may be applied as per investigator’s discretion and following 
consultation with a psychiatrist.  
4.1.2.3.1 Management of mood alteration 
Patient self-rating mood questionnaires PHQ-9 (depression) and GAD-7 (anxiety) will be 
administered by the study nurse or CRC and will be used: 
• 
to support assessment of eligibility at Screening 
• 
to monitor for newly occurring or worsening mood alterations during the study. 
 
The following grading system will be used for this study (Table 4-2): 
 


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Table 4-2 Toxicity grading based on mood questionnaire scores 
PHQ-9 
GAD-7 
Score 
Severity 
CTCAE 
grading 
Score 
Severity 
CTCAE 
grading 
0-4 
None 
Normal 
0-4 
None 
Normal  
5-9 
Mild 
Grade 1 
5-9 
Mild  
Grade 1 
10-19 
Moderate 
Grade 2 
10-14 
Moderate 
Grade 2 
20-27 
Severe 
Grade 3 
≥ 15 
Severe 
Grade 3 
 
At Screening, a patient as judged by the investigator or who meets the cut-off score of ≥ 12 in 
the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, or who selects a 
positive response of ‘1, 2, or 3’ to question number 9 regarding suicidal thoughts or ideation 
will be excluded from the study.  
 
During the study, patients who meet the cut-off score of ≥ 10 (≥ CTCAE grade 2 mood 
alteration) in either questionnaire or who indicate a positive response by selecting ‘1, 2, or 3’ 
to question number 9 on the PHQ-9 (Table 4-4) must see a psychiatrist for diagnosis and 
determination of most appropriate medical treatment. For anxiety, this applies only if status 
has worsened from baseline. Patients who experience ≥ grade 2 mood alteration will be 
followed twice weekly by the patient self-rating mood scale and will be seen weekly by the 
psychiatrist until resolved ≤ grade 1 or baseline (for anxiety). Questionnaire responses will be 
checked at weekly visits until resolution to Grade 1 or baseline (for anxiety).  
 
 


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Table 4-3 GAD-7 anxiety scale 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4-4 PHQ-9 depression scale 
 
4.1.2.4 
Hyperglycemia 
In preclinical studies, insulin/glucose homeostasis was impacted in various species (mice, rats, 
dogs), as expected from the mode of action of buparlisib (Buparlisib Investigators Brochure). 
In both rats and dogs, at the doses used in the 4-week studies, these effects were minimal. 
However, in mice treated at high doses (30 or 60 mg/kg/day) a clear induction of insulin 
resistance/insensitivity was observed, without clear influence of the dose or the time point of 
testing. Histopathologic changes were seen in animal pancreas and liver samples which are in 
concordance with this activity.  
Grade 4 Hyperglycemia was also observed in an ongoing Phase Ia study of buparlisib in 
patients with solid tumors (CBKM120X2101). Therefore, no patients with uncontrolled 
diabetes mellitus will be enrolled in this study. In all patients, fasting plasma glucose will 
obtained at screening and will be monitored throughout the trial. For the treatment of glucose 
disturbances occurring under buparlisib treatment investigators are advised to adhere to the 
protocol guidelines outlined in Table 4-1. 
4.1.2.4.1 Management of Hyperglycemia 
In addition to the dose modification and hyperglycemia treatment guidelines in Table 4-1: 


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 Under the supervision of an endocrinologist, an insulin regimen should be initiated 
according to institutional standard of care or the Treat-To-Target Algorithm for 
Lantus®(Riddle, Rosenstock, and Gerich 2003).   
 For any hyperglycemia ≥ grade 1, the patient should continue to follow dietary 
guidelines provided by the American Diabetes Association (American Diabetes 
Association 2004). 
 For each patient, a maximum of 2 dose reductions will be allowed after which the 
patient should be discontinued from the study. In addition, a patient must discontinue 
treatment with buparlisib, if after treatment is resumed at a lower dose, hyperglycemia 
recurs at a worse severity. 
 For each patient, once a dose level reduction has occurred, the dose level may not be 
re-escalated in that patient during future treatment cycles with buparlisib. 
 Based upon the results of preliminary clinical data and actual laboratory values (e.g., 
glucose, insulin) generated, the treatment recommendations for study drug induced 
hyperglycemia may be modified as needed.  
 
4.1.2.5 
Cardiac events 
Cardiac safety studies, conducted in vitro and in vivo, did not indicate a prominent 
electrophysiological risk. The only effect considered relevant was a trend towards an increase 
in systolic and diastolic blood pressure, observed in two dog telemetry studies. As a 
precaution in the first-in-man study with buparlisib no patients with a severe or unstable 
cardiac disease or cardiac disease requiring continuous treatment, and no patients with 
uncontrolled hypertension will be enrolled in early clinical studies. In addition, HER2 positive 
patients will be assessed for cardiac diseases before start of treatment, while HER2 positive 
patients enrolled in the trial will undergo regular cardiac monitoring throughout the conduct 
of the trial. For the treatment of acute cardiac events occurring under buparlisib treatment 
investigators are advised to adhere to the protocol guidelines. Vital signs, including pulse rate 
and blood pressure, will be closely followed during the early clinical studies. 
4.1.2.5.1 Management of Cardiac events  
At the screening visit a 12-lead electrocardiogram (ECG), will be performed to assess 
eligibility. Repeat ECGs will be performed at screening and as clinically indicated.  
At the screening visit an echocardiogram or MUGA (ECHO/MUGA) for HER2 positive 
patients only will be performed to assess eligibility. Cardiac imaging will be repeated at 4 
months and then every 4 months thereafter for HER2 positive patients only.  End of 
Treatment ECHO/MUGA not required.  There is window of +/- 7 business days for an 
ECHO/MUGA.  Any delay within this window is NOT a deviation as per the visit schedule 
(Table 4-12). 


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4.1.2.5.2 Management of Pneumonitis  
Pneumonitis is a known side effect of rapamycin analogues. Based on the literature, the class 
of PI3K inhibitors has not previously been associated with the development of Pneumonitis. 
Clinically significant Pneumonitis is typically accompanied by non-specific symptoms 
including dyspnea, nonproductive cough, fatigue, and fever. Diagnosis is generally suspected 
in individuals who develop these symptoms or in asymptomatic individuals in whom a routine 
chest CT scan reveals a new ground glass or alveolar infiltrate.  
 
In ongoing clinical trials with buparlisib in the single agent setting two cases of Pneumonitis 
occurred. In the study BKM120X2101 one patient experienced Pneumonitis (grade 2) eight 
weeks after the first dose of buparlisib at 100mg which resolved in 7 days after antibiotic 
therapy and discontinuation of the study treatment due to fatigue. In the Japanese study 
BKM120X1101 one case of Pneumonitis occurred in a patient (given 100 mg) one month 
after the start of study medication with buparlisib. The patient experienced Pneumonitis with 
fatal outcome which was concomitant to progression of underlying malignancy including the 
progression of existing and the appearance of new lesions in combination with increasing 
pleural effusion (please see current Buparlisib Investigators Brochure for more details). 
 
All patients participating in clinical trials administering buparlisib will be routinely asked 
about the occurrence of adverse events which could include new or changed pulmonary 
symptoms (consistent with lung abnormalities). CT scans and pulmonary function test 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 the 
dose modifications) in Table 4-5 should be followed. Consultation with a pulmonologist is 
highly recommended for any Pneumonitis case identified during the study. 
 


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Table 4-5 Management of pneumonitis 
Worst 
Grade 
Pneumonitis 
Required Investigations 
Management 
of 
Pneumonitis 
Buparlisib  
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 
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 dose by 1 
dose level (see Table 4-0) 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 
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. 
 


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4.1.2.5.3 Management of Liver Toxicities  
Monitoring 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/ bilirubin values. 
 
Monitoring Cycle 3 and more: monthly or more frequently if clinically indicated. In case of 
any occurrence of ALT/ AST/ 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/ 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). 
4.1.3 
Criteria for capecitabine dose modification 
A capecitabine dose reduction will be administered as described in Table 4-6. For grade ≥2 
capecitabine-related toxicities (hand/foot syndrome, mucositis, diarrhea), capecitabine 
treatment should be delayed until resolution to grade 0 or 1, then resumed at the next lower 
dose level. For each patient, a maximum of 2 dose reductions will be allowed after which the 
patient will be discontinued from treatment with capecitabine. The dose of capecitabine does 
not need to be reduced for toxicities that the physician believes are due to buparlisib.  Initial 
dosing, as well as delays and/or dose reductions will be recorded on the patient diary and the 
EDC. 
Table 4-6 
Dose modification steps for Capecitabine 
Capecitabine dose levels 
Dose* and schedule 
Starting dose level 
1000** mg/m2 BID days 1-14 of 21 
day cycle 
Dose level -1 
750** mg/m2 BID days 1-14 of 21 day 
cycle  
Dose level -2 
750** mg/m2 mg BID days 1-7 of 14 
day cycle 
* Dose reduction should be based on worst preceding toxicity 
** Rounded down to nearest 500 mg pill 
 


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4.1.4 
Trastuzumab – Cardiac Monitoring and Cardiomyopathy Management 
Guidelines 
 
Trastuzumab dose modifications will be per physician’s discretion and standard of care. 
Left ventricular ejection fraction (LVEF) should be assessed prior to initiation of trastuzumab 
and at regular intervals during treatment. Withhold trastuzumab and capecitabine/buparlisib 
dosing for at least 4 weeks for either of the following: 
 
• 
≥ 16% absolute decrease in LVEF from pre-treatment values 
• 
LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from 
pretreatment values. 
 
Trastuzumab plus capecitabine/buparlisib may be resumed if, within 4−8 weeks, the LVEF 
returns to normal limits and the absolute decrease from baseline is ≤ 15%. Permanently 
discontinue trastuzumab and capecitabine/buparlisib for a persistent (> 8 weeks) LVEF 
decline or for suspension of trastuzumab dosing on more than 3 occasions for 
cardiomyopathy. If trastuzumab is stopped for toxicity other than cardiac toxicity, 
capecitabine/buparlisib may be continued until PD or intolerable toxicity. 
 
4.1.5 
Reasons off treatment 
Patients will be taken off treatment if any of the following occur: 
1. Disease progression  
2. Intolerable toxicity  
Note: If any patient goes off study treatment due to any adverse event, regardless 
of grade, the reason for off treatment will be documented as an “Adverse event” 
in eDC; the toxicity (regardless of grade) must be documented in the toxicity 
section of eDC with the action code entered that is appropriate for discontinuation 
of study treatment. 
3. Physician decision. An intercurrent illness, which would in the judgment of the 
Investigator affect assessments of clinical status to a significant degree or require 
discontinuation of study treatment, non protocol therapy, or non-compliance. 
4. Becomes pregnant 
5. Patient refuses to continue treatment (patient will continue to be followed for survival) 
6. Normal completion of treatment portion of the protocol 
 
The date of and reason for discontinuation must be noted on the Change of Status page of the 
eCRF. Every effort should be made to complete the appropriate assessments. 
 


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4.1.6 
Reasons for taking patients “off study” 
Patients will be considered “off study” if any of the following occur:  
1. Termination of the study by Delta and/or the Sponsor decision 
2. Withdrawal of consent (patient will not be contacted and no further information will 
be collected)  
Note: If the patient withdraws consent, then no additional data will be collected 
without his/her explicit consent; all data collected prior to withdrawal of consent may 
be used in the data analysis. The only exception to the collection of data after 
withdrawal of consent is collection of date of death and cause of death (if available) 
when the endpoint of the study is mortality. 
3. Lost to follow-up (3 attempts should be documented in the patient’s source document 
before the site considers the patient as LFU.) 
4. Death 
5. Discontinuation of the patient when determined by the Study Investigator that 
continuation of the patient on study is no longer in the best medical interest of the 
patient.   
The appropriate information must be completed on the Change of Status page of the eCRF. 
4.2 
Treatments 
4.2.1 
Study treatment administration 
Buparlisib 
The study drug buparlisib will be self-administered (by the patients themselves). The 
investigator will instruct the patient to take the study drug exactly as specified in the protocol. 
Buparlisib will be administered on a continuous once daily dosing schedule. Patients should 
be instructed to take the dose of buparlisib daily in the morning, one hour after a light 
breakfast (morning meal) at approximately the same time each day. Buparlisib should be 
taken with an 8 oz glass of water consumed over as short a time as possible. Patients should 
swallow the capsules whole and not chew them.  Patients should not crush the capsule. 
Patients should continue to fast for 2 hours after the administration of each buparlisib dose. 
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 as an adverse event.   
If the patient forgets to take her/his dose until AFTER 6:00 PM, then the dose should be 
withheld that day and buparlisib should be restarted the following day.  


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Patients must avoid consumption of St. John’s Wort, Seville oranges, grapefruit or grapefruit 
juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to the first dose 
of study medication and during the entire study treatment period due to potential CYP3A4 
interaction with the study medication. Patients must avoid concomitant intake of strong and 
moderate CYP3A4/5 inhibitors and inducers. See Table 4-8. Orange juice is allowed. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded. If a patient requires a buparlisib dose delay of > 21 days from the previous 
dose, the patient must be discontinued from treatment completely and will only require a 28 
day follow up visit for study completion. 
Medication labels will comply with US legal requirements and will be printed in English. 
They will supply no information about the patient. The storage conditions for study drug will 
be described on the medication label. 
Capecitabine 
Capecitabine will be supplied according to local practice. Capecitabine is commercially 
available as film-coated tablets (500 mg) for oral administration. Capecitabine will be dosed 
1000 mg/m2 PO BID 14 days on/7 days off (dose rounded down to nearest 500 mg pill). 
Capecitabine will be stored in accordance with labeled storage conditions at 25°C (77°F), with 
excursions permitted from 15 to 30°C (59 to 86°F) [controlled room temperature].  
The appropriate number of capecitabine tablets (500 mg) to make up a 14-day course will be 
prescribed to subjects to be self-administered at home. Capecitabine will not be supplied on 
this trial but will be obtained by prescription as a standard of care drug.  
Treatment will be administered on an outpatient basis. Tablets should be taken with water, at 
approximately 12-hour intervals, within 30 minutes after breakfast and dinner. As stated in the 
labeling for Xeloda® (capecitabine), care should be exercised when capecitabine is 
coadministered with CYP2C9 substrates.  
Full details for capecitabine can be found in its Package Insert. 
Trastuzumab 
Patients with HER2+ MBC will receive trastuzumab 6 mg/kg IV every 3 weeks along with 
capecitabine and buparlisib as detailed above.   Patients who require a loading disease may 
receive 8 mg/kg IV trastuzumab for their first dose. Trastuzumab dose modifications will be 
per physician’s discretion and standard of care. 
4.2.2 
Dosing regimen  
All eligible patients will receive buparlisib 100 mg administered orally once daily on a 
continuous dosing schedule starting on Cycle 1 Day 1 in combination with capecitabine      
1000 mg/m2 PO BID Days 1-14 of a 21 day cycle.  (Table 4-7)   Patients with HER2+ MBC 
will also receive trastuzumab every 3 weeks.  Patients who require a loading disease may 


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receive 8mg/kg IV trastuzumab for their first dose.  Patients will then receive trastuzumab 
6mg/kg IV every 3 weeks along with capecitabine and buparlisib.   
A complete cycle of treatment is defined as 21 days of once daily continuous treatment of 
buparlisib in combination with capecitabine twice daily on Days 1-14. 
The suggested timing is for patients to eat a light breakfast followed by the morning dose of 
capecitabine within 30 minutes. Buparlisib should be taken 1 hour after the light breakfast, 
after which the patient should fast for 2 hours (water allowed). The evening dose of 
capecitabine should be taken within 30 minutes following dinner. An oral medication diary 
will be provided (Appendix 5). 
 
Table 4-7 Buparlisib and Capecitabine (and Trastuzumab for HER2+ MBC) Dose and 
treatment schedule 
Study drugs 
Pharmaceutical form 
and route of 
administration 
Doseb 
Frequency and/or Regimen 
Buparlisib
Capsules for oral use
100 mg 
(2x 50mg 
capsulesa)
Daily 
Capecitabine
Film-coated tablets for 
oral use 
1000 
mg/m2 
BIDc 
Days 1-14 followed by 7 days 
off
Trastuzumab 
IV 
6 mg/kgd 
Every 3 weeks 
a In case of patient supply difficulties, any combination of buparlisib 50 mg or 10 mg capsules may be taken to 
constitute a dose of 100 mg/day (or dose reduction level). 
b Dose reduction levels for buparlisib will be administered accordingly. For example, buparlisib 80 mg should 
preferentially be administered as 1x50mg size capsule, and 3x10 mg size capsule. 
c Capecitabine dose should be rounded down to the nearest 500 mg pill. 
d  A loading dose of 8 mg/kg of trastuzumab may be administered with the first cycle if required. 
 
4.2.3 
Concomitant therapy 
All medications taken within 4 weeks prior to the administration of buparlisib and all 
concomitant therapy administration during the study with reasons for therapy should be 
recorded. All prior chemotherapy; biologic, immunologic or radiation therapy; and surgery 
within 4 weeks prior to the administration of study drug, will be recorded.      
Patients on chronic medications that can be given concomitantly with buparlisib should be 
maintained on the same dose and dose schedule throughout the study period, as medically 
feasible. The investigator should instruct the patient to notify the study site about any new 
medications he/she takes after the start of the study drug. All medications (other than study 


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drug) and significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient starts treatment with study drug, and any changes in dosing 
should be recorded. 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted with the following exceptions described in Section 4.2.3.1.  
4.2.3.1  Drugs that are prohibited 
 Other investigational therapies must not be used while the patient is on the study. 
 Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) 
other than the study treatments must not be given to patients while the patient is 
on the study. If such agents are required for a patient then the patient must be 
discontinued from the study. 
 In  metabolism studies suggest that oxidative metabolism of buparlisib is 
predominantly mediated by CYP3A4 (fm>0.9), with only minor contributions of 
CYP1A1. As buparlisib is a sensitive CYP3A4 substrate, co-administration of 
buparlisib with any strong and moderate CYP3A4 inhibitors and CYP3A4 
inducers is prohibited.  Refer to Table 4-8 for a list of prohibited drugs.  Please 
note this list may not be comprehensive. 
 Based on in vitro studies, co-administration of buparlisib with CYP3A4 inducers 
is predicted to decrease the systemic exposure to buparlisib, thereby increasing 
the risk of exposing the patient to subtherapeutic drug levels.  Refer to Table 4-8 
for a list of prohibited CYP3A inducers.  Please note that this list may not be 
comprehensive. Therapeutic doses of warfarin sodium (Coumadin®) or any 
other coumadin-derivative anticoagulants are not permitted. 
 If a patient requires the concomitant use of any medication included in Table 4-9 
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 Torsades des de Pointes), study treatment administration must be 
interrupted as long as the patient requires therapy with the QT prolonging agent. 
 Herbal preparations/medications are not allowed throughout the study.  These 
herbal medications include, but are not limited to St. John’s wort, Kava, ephedra 
(ma huang), ginko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng.  Patients should stop using these herbal medications 7 
days prior to first dose of study drug. 
 Hormonal contraceptives may be affected by cytochrome P450 interactions, and 
are therefore not considered effective in this study. 


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Table 4-8  List of prohibited CYP3A Inhibitors and Inducers  
Strong CYP3A 
inhibitors 
Moderate CYP3A 
inhibitors 
Strong CYP3A 
inducers 
Moderate CYP3A 
inducers 
clarithromycin 
aprepitant 
avasimibe 
bosentan 
conivaptan 
atazanavir 
carbamazepine 
efavirenz 
grapefruit juice 
cimetidine 
Phenobarbital 
(barbiturates) 
etravirine 
indinavir 
ciprofloxacin 
phenytoin 
modafenil 
itraconazole 
darunavir 
rifabutin 
nafcillin 
ketoconazole 
diltiazem 
rifampin  
ritonavir 
lopinavir 
erythromycin 
St. John's Wort  
talviraline 
mibefradil 
fluconazole 
 
tipranavir 
nefazodone 
tofisopam 
 
 
nelfinavir 
verapamil 
 
 
posaconazole 
amprenavir 
 
 
ritonavir 
fosamprenavir 
 
 
saquinavir 
elvitegravir 
 
 
telithromycin 
tipranavir 
 
 
troleandomycin 
 
 
 
voriconazole 
 
 
 
This database of CYP inhibitors was compiled from the Indiana University School of 
Medicine’s “Clinically Relevant” Table and from the University of Washington’s Drug 
Interaction Database based on  studies. Strong inhibitors are predicted to increase 
buparlisib AUC > 5-fold, and moderate inhibitors are predicted to increase buparlisib AUC ≥ 
2-fold but < 5-fold.  
This database of CYP inducers was compiled from the FDA’s “Guidance for Industry, Drug 
Interaction Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” 
Table; and from (Pursche et al. 2008). 
 
 


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Table 4-9 
List of prohibited QT prolonging drugs  
All QT-prolonging drugs listed in Table 4-9 are prohibited for all patients from screening 
through permanent discontinuation of study treatment.  Table 4-10 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. 
 
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 
sibstrate 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 


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Prohibited QT Prolonging Drugs 
Drug 
QT risk(*) 
Comment 
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. 
 
4.2.3.1 Drugs to be used with caution 
Preliminary in vitro metabolism studies suggest that buparlisib is a weak, reversible inhibitor 
of CYP3A4/5 (Ki=13.6 µM, [I]/Ki= 0.4 where [I] is the average Cmax at steady-state following 
100 mg daily dose) and a weak reversible inhibitor of CYP2C8/2C9/2C19 (IC50=34 µM, 
[I]/IC50=0.15). Note: that with the data available, we are not able 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 carefully monitored for potentiation 
of toxicity due to any individual concomitant medications, and may require dose titration or 
reduction of the drug substrate. Please refer to Table 4-11 for a list of CYP450 substrates and 
carefully consider their co-administration with buparlisib. 
Particular caution is advised when buparlisib is co-administered with: 
 Drugs which are substrates for CYP3A4, CYP2C8, CYP2C9 or CYP2C19 and which 
have a narrow therapeutic index. 
 Oral anti-diabetic drugs which are metabolized by CYP2C8 or CYP2C9 can possibly 
result in hypoglycemia. Patients who develop diabetes mellitus during the study 
should be treated according to the American Diabetes Association guidance. It is 
recommended that treatment start with metformin.  
 If a patient, after study enrollment, requires the concomitant use of any QT prolonging 
medication with a possible or conditional risk for Torsade de Pointes then the 
investigators, at their discretion, may co-administer such medications. Patients 
receiving such medications must be monitored.  Refer to Table 4-10 for a list of QT 
prolonging medications to be used with caution.  
Note: please refer also to Table 4-9 for a list of prohibited QT prolonging 
medications.  
 Please refer to Table 4-11 for a list of CYP450 substrates and carefully consider their 
co-administration with buparlisib.  
 Concomitant treatment with corticosteroids and buparlisib should be avoided, 
whenever possible, during this study. A short duration (< 2 weeks) of systemic 
corticosteroids is allowed (e.g. for chronic obstructive pulmonary disease, or as an 
anti-emetic).  Chronic dosing of corticosteroids is known to induce CYP3A enzymes, 
thereby increasing the risk or reducing buparlisib overall exposure to sub-therapeutic 
levels. Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways 
diseases), eye drops or local injections (e.g. intra-articular) are allowed.   
 
 


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Table 4-10 
List of QT prolonging drugs to be used with caution 
Drug 
QT risk 
Comment 
Alfuzosin 
possible risk for Torsades de Pointes 
 
Amantadine 
possible risk for Torsades de Pointes 
 
Amitriptyline 
conditional risk for Torsades de Pointes 
 
Azithromycin 
possible risk for Torsades de Pointes 
 
Chloral hydrate 
possible risk for Torsades de Pointes 
 
Citalopram 
conditional risk for Torsades de Pointes 
 
Clomipramine 
conditional risk for Torsades de Pointes 
 
Clozapine 
possible risk for Torsades de Pointes 
 
Desipramine 
conditional risk for Torsades de Pointes 
 
Diphenhydramine 
conditional risk for Torsades de Pointes 
 
Dolasetron 
possible risk for Torsades de Pointes 
 
Doxepin 
conditional risk for Torsades de Pointes 
 
Dronedarone 
possible risk for Torsades de Pointes 
 
Felbamate 
possible risk for Torsades de Pointes 
 
Flecainide 
possible risk for Torsades de Pointes 
 
Fluoxetine 
conditional risk for Torsades de Pointes 
 
Foscarnet 
possible risk for Torsades de Pointes 
 
Fosphenytoin 
possible risk for Torsades de Pointes 
 
Galantamine 
conditional risk for Torsades de Pointes 
 
Gatifloxacin 
possible risk for Torsades de Pointes 
 
Gemifloxacin 
possible risk for Torsades de Pointes 
 
Granisetron 
possible risk for Torsades de Pointes 
 
Imipramine 
conditional risk for Torsades de Pointes 
 
Indapamide 
possible risk for Torsades de Pointes 
 
Isradipine 
possible risk for Torsades de Pointes 
 
Levofloxacin 
possible risk for Torsades de Pointes 
 
Lithium 
possible risk for Torsades de Pointes 
 
Mexiletine 
conditional risk for Torsades de Pointes 
 
Moexipril/HCTZ 
possible risk for Torsades de Pointes 
 
Moxifloxacin 
possible risk for Torsades de Pointes 
 
Nicardipine 
possible risk for Torsades de Pointes 
 
Nortriptyline 
conditional risk for Torsades de Pointes 
 
Octreotide 
possible risk for Torsades de Pointes 
 
Ofloxacin 
possible risk for Torsades de Pointes 
 
Ondansetron 
possible risk for Torsades de Pointes 
 
Oxytocin 
possible risk for Torsades de Pointes 
 
Paliperidone 
possible risk for Torsades de Pointes 
 
Paroxetine 
conditional risk for Torsades de Pointes 
 
Perflutren lipid 
possible risk for Torsades de Pointes 
 


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Drug 
QT risk 
Comment 
microspheres 
Protriptyline 
conditional risk for Torsades de Pointes 
 
Ranolazine 
possible risk for Torsades de Pointes 
 
Risperidone 
possible risk for Torsades de Pointes 
 
Roxithromycin* 
possible risk for Torsades de Pointes 
*not available in the 
United States 
Sertindole 
possible risk for Torsades de Pointes 
 
Sertraline 
conditional risk for Torsades de Pointes 
 
Solifenacin 
conditional risk for Torsades de Pointes 
 
Tizanidine 
possible risk for Torsades de Pointes 
 
Trazodone 
conditional risk for Torsades de Pointes 
 
Trimethoprim-Sulfa 
conditional risk for Torsades de Pointes 
 
Trimipramine 
conditional risk for Torsades de Pointes 
 
Venlafaxine 
possible risk for Torsades de Pointes 
 
Ziprasidone 
possible risk for Torsades de Pointes 
 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
 


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Table 4-11 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 et al. 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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4.2.3.2 
Bisphosphonates and denosumab 
The use of bisphosphonates or denosumab is allowed provided patients have been on stable 
doses for at least 4 weeks prior to treatment start. Stable dose and same brand should be 
maintained during the treatment period. Patients requiring initiation of bisphosphonates or 
denosumab treatment during the course of the study should be discontinued due to progressive 
disease unless disease progression can be completely ruled out and is clearly documented in 
the patients’ source documentation. 
4.2.3.3 
Palliative radiotherapy 
Local radiotherapy for analgesic purposes or for lytic lesions at risk of fracture may be carried 
out if required provided no lung tissue will be included in the radiation portal, and no or 
minimal GI tissue will be included in the radiation portal. If palliative radiotherapy is initiated 
after start of study treatment, the reason for its use must be clearly documented and 
progression as per RECIST 1.1 must be ruled out. No dose modification of study treatment is 
needed during palliative radiotherapy. 
4.3 
Visit Schedule and Assessments 
4.3.1 
Visit schedule 
Table 4-12 lists all of the assessments and indicates with an “X” when the visits are to be 
performed. All data obtained from these assessments must be recorded in the patient’s source 
documentation.  
 
Sections 4.3.2 - 4.3.13 lists all of the assessments required for the collection plan for Imaging, 
Clinical Laboratory parameters, and PHQ-9/GAD-7 patient self-reported questionnaires. The 
outlined schedule should be adhered to for all analyses. In general, where possible, every 
effort must be made to follow the schedule outlined in Table 4-12 and in subsequent tables.


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Table 4-12  Schedule of Events 
 
Schedule of Events 
 
Screening 
phase 
Treatment phase 
(cycle is defined as 21 days ± 3 business days) 
Post-treatment 
follow up phase 
(± 7 business days) 
Survival phase 
(± 7 business days) 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Preceding 
cycles  
(Day 1 of 
Each 
Cycle) 
End of 
treatment 
(± 7 
business 
days) 
Endpoint follow up 
(safety and efficacy 
follow up) 
Survival follow up 
(every 2 months 
and more frequent 
if required) 
Days 
-28 
to -1 
1 
1 
1 
1 
 
 
 
Obtain study Informed Consent 
and HIPAA 
X 
 
 
 
 
 
 
 
Collect and send tumor biopsy 
(archival paraffin blocks/slides or 
fresh biopsy)  
X 
(Day -28 to 
-1) 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
ER and PgR status 
X 
 
 
 
 
 
 
 
HER2 status 
X 
 
 
 
 
 
 
 
Relevant medical history/current 
medical conditions (to include 
GPA components) 
X 
 
 
 
 
 
 
 
Diagnosis and extent of cancer 
X 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
(surgery, medication, 
radiotherapy) 
X 
 
 
 
 
 
 
 
Physical examination 
X 
X* 
X 
X 
X 
X 
 
 
Performance status (ECOG) 
X 
X* 
X 
X 
X 
X 
 
 


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Schedule of Events 
 
Screening 
phase 
Treatment phase 
(cycle is defined as 21 days ± 3 business days) 
Post-treatment 
follow up phase 
(± 7 business days) 
Survival phase 
(± 7 business days) 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Preceding 
cycles  
(Day 1 of 
Each 
Cycle) 
End of 
treatment 
(± 7 
business 
days) 
Endpoint follow up 
(safety and efficacy 
follow up) 
Survival follow up 
(every 2 months 
and more frequent 
if required) 
Days 
-28 
to -1 
1 
1 
1 
1 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Weight  
X 
X* 
X 
X 
X 
X 
 
 
Vital signs 
X 
X* 
X 
X 
X 
X 
 
 
Hematology 
X 
X* 
X 
X 
X 
X 
 
 
Biochemistry (CMP) 3 
X 
X* 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
X 
 
 
Amylase and Lipase  
X 
Repeat every 8 weeks 
 
 
Fasting plasma glucose4  
X 
X* 
X 
X 
X 
X 
 
 
Glycosylated Hemoglobin (HbA1c) 
X 
as clinically indicated 
X 
 
 
Coagulation PT or INR,PTT5
X 
Repeat at week 4, then every 8 weeks thereafter 
 
 
Serum/Urine Pregnancy Test
X 
As clinically indicated1 
 
12-lead ECG/EKG 
X 
As clinically indicated 
ECHO/MUGA  
HER2+ patients Only 
X 
Cardiac imaging to repeat every 4 months for 
HER2+ patients on Herceptin Only 
 
 
 
Brain MRI 
X 
8 weeks after initiation of treatment, then every 8 
weeks thereafter 
(Assessments window is ± 7 business days.) 
X 
Per Standard of 
Care for patients 
off all study 
treatment 
 


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Schedule of Events 
 
Screening 
phase 
Treatment phase 
(cycle is defined as 21 days ± 3 business days) 
Post-treatment 
follow up phase 
(± 7 business days) 
Survival phase 
(± 7 business days) 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Preceding 
cycles  
(Day 1 of 
Each 
Cycle) 
End of 
treatment 
(± 7 
business 
days) 
Endpoint follow up 
(safety and efficacy 
follow up) 
Survival follow up 
(every 2 months 
and more frequent 
if required) 
Days 
-28 
to -1 
1 
1 
1 
1 
 
 
 
CT or MRI (Chest, abdomen) 
X 
8 weeks after initiation of treatment, then every 8 
weeks thereafter 
(Assessments window is ± 7 business days.) 
X 
Per Standard of 
Care for patients 
off all study 
treatment 
 
CT or MRI for any site of 
measurable disease (excluding 
bone) 
X6 
If lesion at screening, 8 weeks after initiation of 
treatment, then every 8 weeks thereafter 
(Assessments window is ± 7 business days.) 
X  
(if lesion at 
screening) 
Per Standard of 
Care for patients 
off all study 
treatment 
 
Bone scan 
X 
If bone lesion at screening, 8 weeks after initiation 
of treatment, then every 8 weeks thereafter 
(Assessments window is ± 7 business days.) 
As clinically 
indicated 
As clinically 
indicated 
 
Skin – color photography 
Only if 
skin lesions 
at 
screening 
If skin lesions at screening, 8 weeks after initiation 
of treatment, then every 8 weeks thereafter 
(Assessments window is ± 7 business days.) 
Mandated 
only if skin 
lesions at 
screening 
Per Standard of 
Care for patients 
off all study 
treatment 
 
RECIST version 1.1 
X 
Performed every 8 weeks after initiation of 
treatment, thereafter 
(Assessments window is ± 7 business days.) 
Tumor response will be assessed locally according 
to Response Evaluation Criteria in Solid Tumors 
X 
As clinically 
indicated 
 


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Schedule of Events 
 
Screening 
phase 
Treatment phase 
(cycle is defined as 21 days ± 3 business days) 
Post-treatment 
follow up phase 
(± 7 business days) 
Survival phase 
(± 7 business days) 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Preceding 
cycles  
(Day 1 of 
Each 
Cycle) 
End of 
treatment 
(± 7 
business 
days) 
Endpoint follow up 
(safety and efficacy 
follow up) 
Survival follow up 
(every 2 months 
and more frequent 
if required) 
Days 
-28 
to -1 
1 
1 
1 
1 
 
 
 
MD Anderson Symptom 
Inventory – Brain Tumor 
(MDASI-BT) Assessment 
X 
8 weeks after initiation of treatment, then every 8 
weeks thereafter 
(Window ± 3 business days) 
X 
 
 
Neuro-psychiatric assessment (self 
rating mood questionnaire)2 
X 
X 
X 
X 
X 
X 
 
 
Neurologic assessment 
X 
8 weeks after initiation of treatment, then every 8 
weeks thereafter 
(Assessments window is ± 7 business days.) 
X 
 
 
Prior/concomitant medications 
X 
Continuous 
Up to 30 days after 
last dose of 
treatment 
 
Adverse events 
X 
Continuous 
Up to 30 days after 
last dose of 
treatment 
 
Antineoplastic therapies since 
discontinuation of study treatment 
 
 
 
 
 
 
X 
X 
Buparlisib administration 
 
Daily starting from Cycle 1 Day 1 
 
 
 
Capecitabine administration 
 
Daily 
days 1-14 
Daily 
days 1-14 
Daily days 
1-14 
Daily days 
1-14 
 
 
 
Trastuzumab administration 
(HER2+ MBC 
 
Every 3 weeks 
 
 
 
Patient diary 
 
Continuous 
 
 
 


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Schedule of Events 
 
Screening 
phase 
Treatment phase 
(cycle is defined as 21 days ± 3 business days) 
Post-treatment 
follow up phase 
(± 7 business days) 
Survival phase 
(± 7 business days) 
Cycle 
 
Cycle 1 
Cycle 2 
Cycle 3 
Preceding 
cycles  
(Day 1 of 
Each 
Cycle) 
End of 
treatment 
(± 7 
business 
days) 
Endpoint follow up 
(safety and efficacy 
follow up) 
Survival follow up 
(every 2 months 
and more frequent 
if required) 
Days 
-28 
to -1 
1 
1 
1 
1 
 
 
 
Survival follow up 
 
 
 
 
 
 
 
X 
Note: Cycle 1 only, the baseline values for those assessments (laboratory, physical examination, performance status and vital signs) that are to be done prior to every cycle 
may be used for Cycle 1 assessments as long as they are completed within 2 weeks prior to the patient receiving their first dose of study drug. If more than 2 weeks have 
elapsed since the baseline assessment, the assessment must be repeated.  Assessments need to be put in the order in which they appear in eCRF.  Treatment must begin 
within 5 working days after patient registration to the study, not including weekends or holidays. 
 
1 Serum/urine pregnancy test (β-HCG) is required for all women of child-bearing potential at screening, within 3 business days prior to the first dose of buparlisib. And as 
clinically indicated thereafter. 
2 Questionnaires PHQ-9 and GAD-7 will be completed at each visit. Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis while 
active on the treatment portion of the study. 
3 Biochemistry (CMP) includes K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher), bicarbonate, urea or BUN, albumin, and total protein, to be obtained on the first day of each cycle.  Lab assessments may be performed up 
within 3 business days prior to the scheduled visit, but all other draws should occur within 24 hours of the intended visit.  
4 Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically indicated. 
5 Coagulation – PT, or INR, PTT, and C1D1 assessments may be performed up to 72 hours prior to the scheduled visit. Additional assessments will be performed on Day 1 
of Cycle 2 (within 3 business days prior to dosing) and repeated every other cycle. A repeat coagulation profile panel is required at the time of study treatment 
discontinuation. Patient entering the study while receiving anti-coagulation therapy or those who have the initiation of an anti-coagulation therapy should have their 
coagulation test performed on a weekly basis. 
6 Mandated if suspected lesion at screening. 


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4.3.2 Efficacy assessments 
Tumor response will be assessed locally according to Response Evaluation Criteria in Solid 
Tumors (RECIST), Version 1.1 (Appendix 4). The local investigator’s assessment will be 
used for all endpoint analyses and for treatment decision making with a +/- 7 day window.  
Any delay within this window is not a deviation. 
Table 4-13 Efficacy Assessments 
Procedure 
Screening: 
Day−14 (up 
to -21) to Day 
-1
Treatment phase* 
End of 
treatment* 
Post-treatment follow-
up phase: Efficacy 
follow-up* 
CT or MRI 
(Chest, 
Abdomen) 
Mandated 
8 weeks after initiation of 
treatment and then every 
8 weeks 
(Assessments window is 
± 7 business days.)
Mandated 
Per Standard of Care for 
patients off all study 
treatment 
CT or MRI for 
any site of 
measurable 
disease 
(excluding 
bone) 
Mandated if 
suspected 
lesion at 
screening 
If lesion at screening: 8 
weeks after initiation of 
treatment and then every 
8 weeks 
(Assessments window is 
± 7 business days.)
Mandated if 
lesion at 
screening 
Per Standard of Care for 
patients off all study 
treatment 
Brain MRI 
Mandated 
8 weeks after initiation of 
treatment and then every 
8 weeks 
(Assessments window is 
± 7 business days.) 
Mandated 
Per Standard of Care for 
patients off all study 
treatment 
Bone scan 
Mandated 
If bone lesions at 
screening 
8 weeks after initiation of 
treatment and then every 
8 weeks 
(Assessments window is 
± 7 business days.)
As clinically 
indicated 
As clinically indicated 
Skin -  color 
Photography 
Mandated if 
skin lesions at 
screening 
If skin lesions at 
screening 
8 weeks after initiation of 
treatment and then every 
8 weeks 
(Assessments window is 
± 7 business days.)
Mandated if 
skin lesions 
at screening 
Per Standard of Care 
for patients off all 
study treatment 
*Tumor evaluation at EOT is required for patients who discontinue study treatment before the first 
scheduled post-baseline 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. Tumor assessments 
are to be done every 8 weeks after initiation of treatment. 
 
 


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Neurologic Assessment 
Neurologic assessment should be performed at baseline, every 8 weeks following initiation of 
study treatment, and at the end of treatment visit. Assessment should include cranial nerves 
exam, and motor and sensory exam. In addition, patients should be assessed both for ability 
to walk and for balance using the following criteria: 
 Normal  
 Mildly impaired 
 Moderately impaired 
 Severely impaired (in wheelchair) 
 
Exploratory biomarker analysis – formalin-fixed Paraffin-embedded (FFPE) tumor 
samples 
Tumor tissue (formalin fixed new biopsy or archival) is required, and will be stored for future 
analysis of markers shown to be closely associated with the PI3K pathway, including but not 
limited to PTEN and INPP4B. One tumor block (preferred) or a minimum of 15 paraffin-
dipped unstained slides is required. Fresh biopsy tissue from a resected brain metastasis is 
preferred but an archival sample from the primary breast cancer may be submitted.  
 
Since the archival samples may not be located at the institution where the original diagnosis 
was rendered, the investigational sites will be responsible for locating them and preparing the 
unstained slides (or having them prepared), if necessary. 
 
For all tumor samples, the sample collection information must be captured on the  relevant 
eCRF page(s) and laboratory requisition form(s).  
 
Tumor samples will be sent to designated lab (check CTI) for analysis. See Collection of 
Shipping Information provided by sponsor for more detailed instruction on sample 
preparation and submission information. 
 
4.3.3 Safety assessments 
Safety assessments will consist of the following: monitoring and recording of all adverse 
events and serious adverse events; the regular monitoring of hematology, blood chemistry, 
urinalysis; regular measurement of vital signs, oxygen saturation, physical examination, 
including weight; and performance status. 
 
These assessments should be performed periodically throughout the study, except for adverse 
events that will be evaluated continuously. 
 
All patients who receive at least one dose of study drug will be evaluated for safety. 
Toxicities will be graded and reported according to the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE) Version 4.03 (Appendix 3). Incidence and type of AEs will be 
tabulated and summarized using descriptive statistics. 


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4.3.4 Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to 
return all unused study medication. 
4.3.5 Adverse events  
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. An adverse event is any 
undesirable sign, symptom or medical condition occurring after starting study drug (or 
therapy) even if the event is not considered to be related to study drug (or therapy). Study 
drug (or therapy) includes the drug (or therapy) under evaluation given during any phase of 
the trial. 
 
 If it is unclear what study treatment includes, list all drug(s), other therapies, changes to 
existing therapy, diagnostic procedure, etc. that are specified by the protocol. 
 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment (ie, any procedures specified in 
the protocol). Adverse events occurring before starting study treatment but after signing the 
informed consent form are recorded at baseline. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms or require therapy, 
and are recorded.  
 
4.3.6 Serious adverse events 
 
Information about all serious adverse events will be collected and recorded on the FDA 
MedWatch 3500a form. To ensure patient safety, each serious adverse event must also be 
reported to Delta within 24 hours of learning of its occurrence. A serious adverse event is an 
undesirable sign, symptom, or medical condition which: 
 
1. 
is fatal or life-threatening 
2. 
required or prolonged hospitalization 
3. 
results in persistent or significant disability/incapacity  
4. 
constitutes a congenital anomaly or a birth defect 
5. 
is medically significant, may jeopardize the subject, and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 
Events not considered to be serious adverse events are hospitalizations for the:  
 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 treatment, which was elective or pre-planned, for a pre-existing condition that did not 
worsen 


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 treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission.  
 
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects or congenital abnormalities. 
 
Any serious adverse event occurring after the patient has provided informed consent, has 
started taking the study medication, and until 4 weeks after the patient has stopped study 
participation must be reported. This includes the period in which the study protocol interferes 
with the standard medical treatment given to a patient (e.g., treatment withdrawal during 
washout period, change in treatment to a fixed dose of concomitant medication). The period 
after discontinuing study drug may be extended if there is a strong suspicion that the drug has 
not yet been eliminated. 
 
For instructions about returning Serious Adverse Event Report Forms to Delta refer to the 
protocol section entitled Instructions for Rapid Notification of Serious Adverse Events 
(Section 4.3.7). 
 
4.3.7 Instructions for rapid notification of serious adverse events 
The principal investigator has the obligation to report all serious adverse events to the IRB 
and the sponsor, (Delta Pharmaceuticals Drug Safety and Epidemiology Department 
(DS&E)). Serious adverse events should also be reported to the FDA and IRB in accordance 
with regulations and IRB policy. 
 
The investigator must complete the FDA MedWatch 3500A form and Delta SAE coversheet 
in English, assess the relationship to study treatment and send the initial completed 
MedWatch form and Delta SAE coversheet by Fax to 1.888.299.4565 within 24 hours to the 
local Delta Drug Safety & Epidemiology (DS&E) Department.  The investigator must then 
ensure that the form and coversheet are accurately and fully completed with follow-up 
information and fax those to Delta DS&E Department within 2 to 3 calendar days for deaths 
or life-threatening events and 5 calendar days for other serious adverse events. The original 
and the duplicate copies of the FDA MedWatch form, Delta SAE coversheet, and the fax 
confirmation sheet must be kept with the electronic case report forms (eCRF) at the study 
site.  
  
In addition, all SAEs will be reported by telephone to the Delta Central Safety Department as 
soon as study personnel become aware of the SAE. The SAEs should be reported by 
facsimile within 24 hrs to the Delta Central Safety Department. The site will supply as much 
information as is available at the time of the initial Fax to the Delta Central Safety 
Department (study number, subject initials, subject study number, event), during both 
business and nonbusiness hours, to: 
  
Delta Clinical Research Safety Department 
10101 Woodloch Forest 


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The Woodlands, TX 77380 
SAE Hotline: (281) 863-6503 
Safety Fax: (877) 571-8934 
  
Follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or discontinued study participation. 
The MedWatch form, Delta SAE coversheet, and fax confirmation sheet must be retained.  
  
Pregnancy follow-up should describe the outcome of the pregnancy, including any voluntary 
or spontaneous termination, details of the birth, and the presence or absence of any 
congenital abnormalities or birth defects.  
  
Adverse events will be recorded for the duration of a patient’s study treatment. All AEs, 
regardless of causal relationship, are to be recorded in the source documentation. The 
Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. The diagnosis should be documented as the AE/SAE and 
not the individual signs/symptoms. 
  
All AEs will be graded and reported according to the NCI Common Toxicity Criteria 
(version 4.03). The relationship of each event to the study drug will be assessed by the 
Investigator and recorded on the eCRF. Additional information about each event, such as 
treatment required, whether or not the study drug had to be discontinued, and eventual 
outcome will also be recorded on the eCRF.  
 
Reporting to Novartis  
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 the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department (fax # 877-778-9739).. 
 


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4.3.7.1 
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 Study 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 of buparlisib to any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form. 

4.3.8 Laboratory evaluations 
Pregnancy Test 
A serum pregnancy test (β-HCG) is required for all women of child-bearing potential at 
screening, within 72 hours prior to the first dose of buparlisib. Note: Postmenopausal women 
must have been amenorrheic for ≥ 12 months in order to be considered “of non-childbearing 
potential”. This should be documented appropriately in the patient’s medical history.  
Additional pregnancy tests should be performed as clinically indicated.  
Hematology 
Hematology includes the following parameters: complete blood count (CBC) consisting of 
red blood cell (RBCs), a total white blood cell count (WBC) with differential (total 
neutrophil count including bands, lymphocyte, monocyte, eosinophil, and basophil counts); 
hemoglobin (Hgb); and platelet count to be obtained on the first day of each cycle.  Lab 
assessments may be performed within 3 business days prior to the scheduled visit. 
Coagulation Profile 
The coagulation profile includes prothrombin time or INR, and activated partial 
thromboplastin time to be drawn within 24 hours of the intended visit.  
Serum chemistry  
Biochemistry includes the K+, Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), 
creatinine, GGT, alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or 
higher), bicarbonate, glucose, urea or BUN, albumin, and total protein to be obtained on the 
first day of each cycle.  Lab assessments may be performed within 3 business days prior to 
the scheduled visit. 
Because accurate serum glucose and lipid measurements are required, patients should be 
fasting at the time of the blood sampling. 


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4.3.9 Vital signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. Blood pressure, pulse and respiration rate should be measured on 
patients after at least 3 minutes in the sitting position as per the visit schedule.  
4.3.10 Physical examination 
Physical examination will be performed which must comprise a total body examination 
(general appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities and basic nervous system). 
Significant findings made after the start of study drug which meet the definition of an 
Adverse Event must be recorded. 
4.3.11 Neuropsychiatric assessments 
Patient self-rating mood questionnaires for anxiety and depression (PHQ-9, GAD-7) will be 
applied at: 
 Screening 
 Days 1 of Cycle 1 
 Day 1 of Cycle 2 
 Day 1 of Cycle 3 and subsequent cycles (only for patients who have not shown 
mood alterations during the first 2 cycles, patients who did have mood 
alterations should continue to fill out the questionnaire on a weekly base). 
 End of Study treatment 
Additional assessments may be done according to the clinical judgment of the Investigator. 
Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly 
basis while active on the treatment portion of the study. The nurse or the CRC will provide 
the patient with the instruments and the instructions on how to complete the questionnaires, 
as well as how to determine the scores. See Appendices 5 and 6 for questionnaires. 
4.3.12 ECG/EKG –ECHO/MUGA 
A standard 12 lead ECG is to be performed at screening and as clinically indicated.   
An echocardiogram (ECHO) or MUGA will be performed to assess eligibility for HER2 
positive patients only. ECHO/MUGA will be repeated at 4 month intervals thereafter for 
HER2 positive patients only. There is window of +/- 7 business days for an ECHO/MUGA.  
Any delay within this window is NOT a deviation as per the visit schedule (Table 4-12). 
4.3.13 Performance status 
Performance status will be assessed at screening and per the visit schedule. The ECOG 
Performance Status Scale will be used. (See Appendix 2) 


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4.3.14 Disease-related symptom assessment 
Disease-related symptoms will be assessed at screening, every 8 weeks during treatment, and 
at the end of treatment. The MD Anderson Symptom Inventory – Brain Tumor (MDASI-BT) 
module will be used (see Appendix 6). 
4.3.15 Drug levels and pharmacokinetic assessments 
 
No pharmacokinetic assessments will be performed.  
 
5 
Data management 
5.1 
Data collection 
Investigators must record the information required by the protocol.  
 
6 
Statistical methods 
6.1 
Populations for analysis 
6.1.1 Analysis populations 
 
Intent-To-Treat (ITT) Population: Includes all patients registered on the study (eligible 
and ineligible). This ITT population will be included in overall patient listings, in summary 
tables of patient demographics and baseline disease characteristics, and also in the list of 
treatment discontinuations after enrollment. This population will also be used for analyses of 
overall survival (OS) and time to progression (TTP).  
 
Evaluable Population: Includes all eligible patients who meet the protocol-specified 
efficacy analyses requirements and who have received at least 1 dose of study drug. This 
population will comprise those with a CR, PR, SD, PD, or NE response.  
 
Safety Population: Includes all patients (eligible and ineligible) who receive at least 1 dose 
of study drug. This safety population will also be used for the summaries and analysis of all 
safety parameters (drug exposure, tables of adverse events information, including serious 
adverse events, etc).  
 
6.1.2 Patient characteristics 
All patients entered in the study will be accounted for in the summation. Patient 
demographics and baseline characteristics such as age, race, sex, ECOG PS, and 
ER/PR/HER2 status will be described. Disease stage and histology at baseline, medical 
history, and prior treatment, including WBRT and SRS, will also be summarized. Mean, 
standard deviation, median, minimum and maximum values will be presented for continuous 


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variables, and frequency tables showing numbers and percentages will be presented for 
categorical variables. 
 
6.1.3 Patient disposition 
Patient disposition including the number of patients enrolled, completed, and discontinued 
from the study will be summarized by numbers and percentages. The reasons for 
discontinuation will also be summarized in the same manner. 
 
6.2 
Hypothesis and endpoints 
This is an open-label, one arm, multicenter phase 2 trial of buparlisib plus capecitabine in  
breast cancer patients with brain metastases that have been previously treated with WBRT or 
SRS or both.  
 
CBR will be the primary endpoint for this study and is defined as objective response (CR + 
PR) plus stable disease ≥24 weeks. ORR, OS, TTP, safety, time to deterioration of 
neurologic function, changes in symptom occurrence, and a correlation between PI3K 
pathway-related biomarkers and clinical response are the secondary endpoints and will also 
be followed and described in this study.   
6.3 
Sample size and projected study duration 
14 patients will be entered into each of 3 patient cohorts: ER+/HER2-, HER2+, and triple 
negative disease.    If the true CBR is 30% in any of the 3 cohorts, observing 3 of 10 patients 
achieving clinical benefit will yield a 90% confidence interval for CBR from 6-54%. If the 
true CBR is 15% in any of the 3 cohorts, observing 3 of 10 patients achieving clinical benefit 
will yield a 90% confidence interval for CBR from 1-34%.    If 3 or more of the 14 patients . 
in any cohort has clinical benefit from the combination, we will discuss with Novartis the 
potential of expanding that cohort to enroll addition patients. With an estimated accrual rate 
of 3 patients per month, a follow-up of 12 months, and an additional 6 months for data lock 
and report development, the total time to the initial release of findings would be around 2.5 
years. 
 
6.4 
Statistical methods 
6.4.1 Primary efficacy analysis 
CBR in the patients following WBRT or SRS or both will be the primary endpoint and is 
calculated as the total number of responders (CR or PR) plus stable disease greater than or 
equal to 24 weeks (CR + PR + SD ≥ 24 weeks) divided by the total number of evaluable 
patients.  .   
 


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6.4.2 Secondary efficacy analysis 
The incidence of responses of CR, PR, ORR, SD, PD, and NE (using RECIST 1.1) with 95% 
CI will be tabulated and summarized using descriptive statistics by the exact-binomial 
method in the evaluable population. Time to response and duration of response will be 
calculated.  
 
OS will be measured from the date of registration to the date of death for patients who die. If 
a patient is still alive or is lost to follow up, the patient will be censored at the last contact 
date. OS will be estimated using the Kaplan-Meier method and Breast-GPA-estimated 
method in the ITT population. Number of Patients who died, and causes of death will be 
reported. The Graded Prognostic Assessment (GPA) will be calculated by Karnofsky PS, 
subtype of breast cancer, and age group (Appendix 1).  TTP will be calculated from the date 
of registration to the date of the first documented progression or the date of death due to 
disease progression, whichever comes first. If the patient did not progress or die due to 
disease progression, the patient will be censored at the date of last contact. TTP will be 
summarized using the Kaplan-Meier method in the ITT population.  
 
Toxicity profiles will be tabulated in the safety population. Toxicities will be graded 
according to the NCI Common Terminology Criteria for Adverse Events (version 4.0). 
Subjects enrolled in this study will be carefully monitored during the entire treatment phase 
and will be followed as is appropriate. Incidence and type of adverse events, including 
serious adverse events, will be tabulated. Adverse events that occur >30 days after the 
administration of last treatment will not be reported. Median cycles received, median drug 
delivered per dose and cumulative doses, dose compliances, dose modifications, and reasons 
of the dose modifications will be summarized.  
 
Time to deterioration of neurologic function will be estimated using Kaplan-Meier method in 
safety population. Results of the PHQ-9 Depression Scale will be tabulated, as well as the 
MDASI-BT questionnaire results. 
 
In addition, a correlation between PI3K pathway-related biomarkers and clinical responses 
will also be assessed as a secondary objective in this study.  
 
 
7 
Protocol and Data Development 
7.1 
Ethics 
7.1.1 Institutional review board 
This trial can be undertaken only after review and full approval of the protocol and a Patient 
Informed Consent Form has been obtained from a properly constituted IRB. This written 
approval must be dated and it must clearly identify the protocol, any amendments, the Patient 
Informed Consent Form, Investigator’s Brochure, the name of the Principal Investigator (PI) 
and any applicable recruiting materials and subject compensation programs approved. 
 


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The decision concerning the conduct of the study will be made in writing to the SI.  Copies of 
this decision and of all IRB correspondence will be kept on file at the study site; copies will 
be provided to the sponsor, Delta Clinical Research, LLC. 
 
During the trial, the PI is required to send various documents to the IRB for review for: 
1. 
Changes to the current protocol. 
2. 
Changes to the Investigator’s Brochure. 
3. 
All protocol amendments and Patient Informed Consent Form revisions. 
4. 
Reports of AEs/SAEs that are serious, unexpected, and associated with the 
investigational drug, and any life-threatening problems, or death. 
5. 
Required progress reports. 
 
If local IRB approval is acquired, the Delta Regulatory Affairs Office should be informed via 
research Standard Operation Procedures (SOP). 
 
Particular attention is drawn to the FDA regulations regarding the IRB. The SI provides Delta 
with the necessary assurance that an IRB is responsible for the initial and continuing review 
and approval of the proposed clinical study in accordance with these regulations. At least 
once a year, the IRB will be asked to review and re-approve the clinical trial protocol; the 
request must be documented in writing. At the end of the trial, the SI will notify the IRB that 
the trial has been completed. 
7.1.2 Patient informed consent 
The informed consent should meet the requirements of the latest version of the Declaration of 
Helsinki and any applicable regulations and guidelines. It must be approved by an 
institutional ethics committee/IRB. 
 
Prior to entry into the trial and before any protocol-required procedures are performed, the 
Treating Physician must explain the nature of the trial, its intended purpose, and the 
implications of participation to potential patients or to their legal representatives. They will 
be told about the possible risks and benefits, and the possible adverse experiences. They will 
be informed that patients’ participation is voluntary, and that they may withdraw consent to 
participate at any time. They will also be informed that if patients choose not to participate in 
the trial, alternative treatments are available; such refusal will not prejudice further treatment 
of their disease. Potential patients or their legal representatives must be given the opportunity 
to ask questions about the trial protocol and the procedures involved. 
 
Finally, each patient will be told that his or her records may be accessed by authorized 
personnel of Delta and other authorized individuals without violating the patient’s 
confidentiality, to the extent permitted by the applicable laws and/or regulations. By signing 
the written Patient Informed Consent Form, the patient or his or her legal representative is 
authorizing such access. Following this explanation and prior to entry into the trial, the 
written, dated, and signed Patient Informed Consent Form must be obtained from each 
patient or his or her legal representative; a copy will be given to the person signing the form. 


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7.1.3 Confidentiality of records 
The Treating Physician is required to retain, in a confidential manner, sufficient information 
on each patient (i.e., full name, current address, and social security number) so that the 
patient may be contacted by the FDA or by Delta should the need arise. 
7.2 
Study Records 
7.2.1 Documentation 
For each patient treated with the study drug(s), the Research Coordinator is required to 
prepare and maintain case histories that include all observations and other data pertinent to 
the investigation. This will include all source documents needed to verify the accuracy of all 
observations and other data contained in the eCRFs on each study patient. 
 
The Treating Physician or his/her designee is required to retain the records related to the trial 
for a period of 2 years following the date a marketing application is approved for the 
indication being investigated. If no marketing application is to be filed or if the application is 
not approved for such indication, the records must be retained until 2 years after the 
investigation is discontinued and the regulatory agencies are notified. 
 
The Treating Physician shall retain study drug disposition records, copies of eCRFs (or 
electronic files), and source documents for the maximum period required by the site in which 
the study will be conducted, or for the period specified by Delta, whichever is longer. The 
Investigator must contact Delta prior to destroying any records associated with the study. 
 
If the Investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Prior notice 
of such transfer will be given in writing to Delta. 
 
7.2.2 Electronic case report form procedures 
 
Data will be entered at the site using eCRFs. The Treating Physician or his/her designee is 
responsible for recording all data relating to the trial on the eCRFs. The Treating Physician 
must verify that all data entries on the eCRFs are accurate and correct. eCRFs must be 
completed within 7 calendar days of the end of each cycle and within 7 calendar days 
following completion of study therapy. 
 
If an item is not available or is not applicable, it should be documented as such; no blank 
spaces should be left on any eCRF. 
 
For patients removed from study, their eCRFs must then be completed within 7 calendar 
days of the date of removal from the study. Long-term survival information will be collected. 
 


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7.3 
Monitoring/Site Visits 
Study sites are subject to be monitored by the study sponsor or their designee, and/or by the 
Food and Drug Administration (FDA) or other regulatory agencies. To ensure accuracy, a 
minimal data set from the eCRFs will be compared with a subset of the original patient source 
documents during site visits. The monitor may also review case histories, laboratory 
certifications, IRB records, drug accountability records, and other source documentation. At 
all times, patients’ confidentiality will be maintained. 
Monitoring will take place at different sites. The monitoring plan will be developed by the 
study sponsor or their designee. 
7.4 
Modification of Protocol 
Any changes to this protocol that affect study objectives, study design, study procedures, 
patient population, or significant administrative procedures will require a formal amendment 
to the protocol. Any proposed protocol amendments must be sent in writing to the applicable 
IRB. Prior to implementation, an amendment must be agreed upon by the SI and by Delta 
and approved by the applicable IRB. 
 
General administrative changes to the protocol are minor corrections and/or clarifications that 
do not affect the manner in which the study is to be conducted. Such administrative changes 
will be agreed upon by the SI and will be documented in a memorandum. The applicable IRB 
will be notified of administrative changes according to applicable IRB guidelines. 


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8 
References 
 
Adamo B, Deal AM, Burrows E, et al. Phosphatidylinositol 3-kinase pathway activation in 
breast cancer brain metastases. Breast Cancer Res. 2011; 13(6):R125. 
 
Anders CK, Deal AM, Miller CR, et al. The prognostic contribution of clinical breast cancer 
subtype, age, and race among patients with breast cancer brain metastases. Cancer. 
2011;117(8):1602-11. 
 
Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with 
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APPENDICES 
Appendix 1 – Breast Cancer-Graded Prognostic Assessment (GPA) 
 
Prognostic 
Factor 
GPA Scoring Criteria 
Patient 
Score 
0 
0.5 
1.0 
1.5 
2.0 
Karnofsky 
Performance 
Score 
≤50 
60 
70-80 
90-100 
n/a 
 
Subtype 
Basal 
n/a 
LumA 
HER2 
LumB 
 
Age, years 
≥60 
<60 
n/a 
n/a 
n/a 
 
Sum total 
 
Median survival (months) by GPA: 0-1.0 = 3.4; 1.5-2.0 = 7.7; 2.5-3.0 = 15.1; 3.5-4.0 = 
25.3 
 
 


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Appendix 2 - Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-
care, but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3 – CTCAE Grading 
 
NCI COMMON TERMINOLOGY CRITERIA 
FOR ADVERSE EVENTS (CTCAE) 
Version 4.0 
Published: May 28, 2009 (v4.03: June 14, 2010) 
 
 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf   
 
DO NOT USE CTC VERSION 2.0 OR 3.0 TO GRADE TOXICITIES IN 
THIS STUDY! 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4 – Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
 
 
New response evaluation criteria in solid tumors: Revised RECIST guideline 
(version 1.1) Eisenhauer EA, Therasse P, Bogaerts J, et al. Eur J Cancer. 2009 
Jan;45(2):228-47. 
 
http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf 


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Appendix 5 – Oral Medication Diary 
 
 
 


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Drug Administration Record – to be completed by patient and returned at each visit 
Please begin entries by checking the appropriate box that corresponds to the date treatment 
was started (Calendar Date). For example: If the patient starts treatment on January 24, 2014, 
check the box next to “24” under Calendar Date and continue entries from that date forward. 
 
Patient Initials
 
Arm
 
Patient ID #
 
Month
 
Year
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please return all copies of this  
form to the Clinical Research 
Coordinator at each clinic visit. 
 
 
 
 
 
Calendar
Drug Taken
Date
Yes
No
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
US Oncology, Inc                                                 Study# 11-025 


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Appendix 6 – M.D. Anderson Symptom Inventory-Brain Tumor (MDASI – BT) 
 
(The MD Anderson Symptom Inventory- Brain Tumor Module *Screening, every 8 weeks 
during treatment, End of Treatment (Window ± 3 business days). Any delay within this 
window is not a deviation.) 
 


 
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