Conditions: Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma Recurrent Metastatic Squamous Neck Cancer With Occult Primary Recurrent Salivary Gland Cancer Recurrent Squamous Cell Carcinoma of the Hypopharynx Recurrent Squamous Cell Carcinoma of the Larynx Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity Recurrent Squamous Cell Carcinoma of the Nasopharynx Recurrent Squamous Cell Carcinoma of the Oropharynx Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Recurrent Verrucous Carcinoma of the Larynx Recurrent Verrucous Carcinoma of the Oral Cavity Salivary Gland Squamous Cell Carcinoma Stage IV Squamous Cell Carcinoma of the Hypopharynx Stage IV Squamous Cell Carcinoma of the Nasopharynx Stage IVA Salivary Gland Cancer Stage IVA Squamous Cell Carcinoma of the Larynx Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity Stage IVA Squamous Cell Carcinoma of the Oropharynx Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Stage IVA Verrucous Carcinoma of the Larynx Stage IVA Verrucous Carcinoma of the Oral Cavity Stage IVB Salivary Gland Cancer Stage IVB Squamous Cell Carcinoma of the Larynx Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity Stage IVB Squamous Cell Carcinoma of the Oropharynx Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Stage IVB Verrucous Carcinoma of the Larynx Stage IVB Verrucous Carcinoma of the Oral Cavity Stage IVC Salivary Gland Cancer Stage IVC Squamous Cell Carcinoma of the Larynx Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity Stage IVC Squamous Cell Carcinoma of the Oropharynx Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity Stage IVC Verrucous Carcinoma of the Larynx Stage IVC Verrucous Carcinoma of the Oral Cavity Tongue Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
This pilot randomized phase I/II trial studies the side effects and best dose of PI3K inhibitor BKM120 when given together with cetuximab and to see how well it works in treating patients with recurrent or metastatic head and neck cancer. PI3K inhibitor BKM120 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumors to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving PI3K inhibitor BKM120 together with cetuximab may kill more tumor cells

Detailed description:
PRIMARY OBJECTIVES:

I. Induction of compensatory signaling/feedback loop signaling after one week of BKM120 (PI3K inhibitor BKM120) (run-in) compared to patients not treated with BKM120.

II. Safety and tolerability of combined treatment with BKM120 and cetuximab.

SECONDARY OBJECTIVES:

I. Induction of apoptosis after one week of BKM120 (run-in) compared to patients not treated with BKM.

II. Tumor shrinkage (based Response Evaluation Criteria in Solid Tumors \[RECIST\] version 1.1 \[V1.1\] measurements) in patients treated with combination.

III. Response rate (based RECIST V1.1 measurements) in patients treated with combination.

IV. Overall survival. V. Progression free survival.

OUTLINE: This is a phase I, dose-escalation study of PI3K inhibitor BKM120, followed by a phase II study.

RUN-IN-PERIOD: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive PI3K inhibitor BKM120 orally (PO) once daily (QD) on days -7 to 0. Patients complete 1 week washout before dose escalation.

ARM II: Patients receive no treatment on days -7 to 0.

All patients receive PI3K inhibitor BKM120 PO QD on days 1-28 and cetuximab intravenously (IV) over 60-120 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Arms:
arm 1: Patients receive PI3K inhibitor BKM120 PO QD 100 mg/day on days -7 to 0. Patients complete 1 week washout. 3 patients receive BKM120 PO 80mg / day and cetuximab 500 mg IV /14 days and after dose escalation, 9 patients receive BKM120 PO 100mg / day and cetuximab 500 mg IV /14 days thereafter.

All patients receive PI3K inhibitor BKM120 PO QD day on days 1-28 and cetuximab IV over 60-120 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: PI3K inhibitor BKM120 intervention 2: cetuximab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
  
 
BKM120; Investigator Initiated Protocol 
 
A biomarker driven pilot study of the pan-class I PI3K 
inhibitor NVP-BKM120 in combination with cetuximab 
in patients with recurrent/metastatic Head and Neck 
Cancer 
 
Author(s):  
 
Tanguy Seiwert, MD 
Everett Vokes, MD 
The University of Chicago 
Tel: 773-702-2452 
Fax: 773-702-3002 
Email: tseiwert@medicine.bsd.uchicago.edu 
 
Release date: 
 
2/16/2014 
Version number: 
5.4 
 
 


 
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Table of contents 
 
Table of contents ................................................................................................................. 2
Trial Schema ........................................................................................................................ 4
List of Abbreviations ........................................................................................................... 5
1
Background ........................................................................................................................... 7
1.1
Disease Background ................................................................................................... 7
1.2
BKM120 ..................................................................................................................... 7
1.3
PI3K Pathway and mechanism of action .................................................................... 7
1.3.1
Preclinical studies ........................................................................................ 9
1.3.2
Clinical experience .................................................................................... 13
1.4
Study Rationale ........................................................................................................ 22
2
Study objectives .................................................................................................................. 23
3
Exploratory Investigational plan ........................................................................................ 24
3.1
Overall study design ................................................................................................. 24
3.2
Study population ....................................................................................................... 24
3.2.1
Patient population ...................................................................................... 24
3.2.2
Inclusion and exclusion criteria ................................................................. 24
4
Treatments .......................................................................................................................... 30
4.1
Interruption or discontinuation of treatment / Dose Reductions .............................. 30
4.1.1
Monitoring of BKM120 suspected toxicities ............................................ 43
4.1.2
Known Undesirable Side Effects of BKM120 .......................................... 43
4.2
Treatments ................................................................................................................ 51
4.2.1
BKM120 Administration ........................................................................... 51
4.2.2
Cetuximab Administration ......................................................................... 52
4.2.3
Concomitant therapy .................................................................................. 53
4.3
Visit schedule and assessments ................................................................................ 62
4.3.1
Visit Schedule ............................................................................................ 62
4.3.2
Efficacy assessments (Response) .............................................................. 65
4.3.3
Safety assessments ..................................................................................... 65
4.3.4
Treatment compliance ............................................................................... 65
4.3.5
Serious and Unexpected Suspected Adverse Reaction (SUSAR) ............. 68
4.3.6
Reporting Mechanism / Requirements for the University of 
Chicago Comprehensive Cancer Center ............................................... 69
4.3.7
Reporting Requirements for the Institutional Review Board .................... 70
4.3.8
Reporting Requirements for the FDA ........................................................ 70


 
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4.3.9
Data and Safety Monitoring ....................................................................... 71
4.3.10
Novartis instructions for rapid notification of serious adverse 
events ..................................................................................................... 72
4.4
Correlative Studies and Tissue Collection Tumors .................................................. 76
4.4.1
Assessment of Accessible tumor ............................................................... 76
4.4.2
Archival Tissue and Blood. ....................................................................... 76
4.4.3
Tumor Biopsies .......................................................................................... 77
4.4.4
Correlative Studies ..................................................................................... 78
5
STUDY DESIGN ............................................................................................................... 79
5.1
Design of the 1-week Run-In period ........................................................................ 79
5.2
Design of the Dose Escalation Cohort ...................................................................... 79
5.2.1
Determination of the Maximum Tolerated Dose (MTD) .......................... 80
5.2.2
Dose Escalation Schematic: Dose escalation cohorts and timing 
for enrollment. ....................................................................................... 80
5.2.3
Definition of the Dose-Limiting Toxicity (DLT) for the Dose 
escalation Phase .................................................................................... 80
5.3
Design of the Expansion cohort ............................................................................... 81
6
Registration Procedures and Data Management ................................................................. 81
6.1
Guidelines for Lead Institution ................................................................................. 81
6.2
Guidelines for other participating institutions .......................................................... 81
6.3
Data collection .......................................................................................................... 82
7
Statistical methods .............................................................................................................. 82
7.1
Statistical methods .................................................................................................... 82
7.1.1
Criterion for Success/Primary Objectives ................................................. 82
7.1.2
Evaluation of Primary Objectives .............................................................. 82
7.1.3
Evaluation of Secondary Objectives .......................................................... 84
7.2
Follow-up trial .......................................................................................................... 85
References ................................................................................................................................ 86
8
APPENDICES .................................................................................................................... 92
8.1
Appendix A: Performance Status Criteria ................................................................ 92
8.2
Appendix B: Tissue Sample Collection Form .......................................................... 93
 
 
 




 
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List of Abbreviations 
AE  
 
 
Adverse Event 
AKT   
 
See PKB (protein Kinase B) 
ALT   
 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC   
 
Absolute Neutrophil Count 
AST  
Aspartate aminotransferase/glutamic oxaloacetic 
transaminase/GOT 
BUN   
 
Blood Urea Nitrogen 
CBC   
 
Complete Blood Count 
CK  
 
 
Creatine Kinase 
CK-MB  
 
Creatine Kinase - Muscle and Brain isoenzyme 
CR  
 
 
Complete Response 
CRD   
 
Clinical Research and Development 
CS  
 
 
Cowden Syndrome 
CT  
 
 
Computed Tomography 
CTC   
 
Circulating Tumor Cells 
CTCAE  
 
Common Terminology Criteria for Adverse Events 
DLT   
 
Dose Limiting Toxicity 
DSMB  
 
Drug Safety Monitoring Board 
ECG   
 
Electrocardiogram 
ECHO  
 
Echocardiogram 
EGFR   
 
Epidermal Growth Factor Receptor 
18F-FDG  
 
[18F]-Fluorodeoxyglucose 
FPG   
 
Fasting Plasma Glucose 
GCP   
 
Good Clinical Practice 
GI  
 
 
Gastrointestinal 
HIV   
 
Human Immunodeficiency Virus 
HNC  
 
Head and Neck Cancer 
HNSCC 
 
Head and Neck Squamous Cell Carcinoma 
ICH   
 
International Conference on Harmonization 
IHC 
 
 
Immunohistochemistry 
HDL   
 
High density lipoprotein 


 
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IEC  
 
 
Independent Ethics Committee 
IRB  
 
 
Institutional Review Board 
LDL   
 
Low density lipoprotein 
LVEF   
 
Left Ventricular Ejection fraction 
MRI   
 
Magnetic Resonance Imaging 
MTD   
 
Maximum Tolerated Dose 
MUGA  
 
Multiple Gated Acquisition Scan 
NSCLC 
 
Non-small Cell Lung Cancer 
PD  
 
 
Pharmacodynamic 
PET   
 
Positron Emission Tomography 
PI3K   
 
"#$%&#'()*+,)-$%)($, ./-kinase 
PK  
 
 
Pharmacokinetic 
PKB   
 
Protein Kinase B (or AKT) 
PT  
 
 
Prothrombin Time 
PTEN   
 
Phosphatase and Tensin homolog 
PTT   
 
Partial Thromboplastin Time (also known as APTT) 
QTc   
 
QT interval (corrected) 
RBC  
 
Red Blood Cells 
REB   
 
Research Ethics Board 
RECIST  
 
Response Evaluation In Solid Tumors 
S6K   
 
Protein Kinase S6 
SAE   
 
Serious adverse event 
SCCHN 
 
Squamous Cell Carcinoma of the Head and Neck 
SOP   
 
Standard Operating Procedure 
SUV   
 
Standardized Uptake Value 
TTP   
 
Time to Progression 
ULN   
 
Upper Limit of Normal 
WBC   
 
White Blood Count 
WCBP  
 
Women of Childbearing Potential 
WHO   
 
World Health Organization 
 


 
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1 
Background 
1.1 
Disease Background 
Head and Neck squamous cell carcinoma (HNSCC) is the 6th most common cause of 
cancer death worldwide with more than 600,000 cases annual. In the United States, 
approximately 40,500 new HNSCC cases and 11,000 deaths were expected in 2006. 
HNSCC results in significant morbidity because major vital functions such as 
nutrition, respiration and communication are impaired.  
 
Approximately two thirds of patients with HNSCC will present with locoregional 
disease and despite aggressive local therapy, close to than half will succumb to 
recurrent and/or metastatic disease. If untreated, the median survival of patients with 
metastatic disease is dismal and on the order of 4 months (Bentzen 2005; Ang, 
Berkey et al. 2002).  
 
In patients with recurrent or metastatic HNSCC, the only therapeutic options are 
usually palliative consisting of systemic chemotherapy and the EGFR inhibitor 
cetuximab (Vermorken et al. 2007; Vermorken et al. 2008). Median survival is 
estimated at 10.1 months using a combination of cisplatin/5-FU/cetuximab. Cytotoxic 
chemotherapy can have significant toxicities, consisting of bone marrow suppression, 
nausea/vomiting, rash, hand-foot syndrome, and many others. Better therapeutic 
options are necessary. 
1.2 
BKM120 
NVP-BKM120 (BKM120) is a potent and highly specific oral pan-class I PI3K inhibitor 
that is a 2,6-dimorpholino pyrimidine derivatives. This compound has been studied 
extensively in non-clinical models and is currently being evaluated in clinical trials. 
1.3 
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 (Engelman 2009). 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 


 
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(Engelman 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 (Engelman 2009). 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 (PIK3CA encoding the PI3K catalytic 
%010-)( &22345 67-7% 7-8$*)-6 (#7 &85 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, and others)  
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 options beyond institutional standard of care. Hence, the pan-PI3K 
inhibitor BKM120 treatment potentially addresses an unmet medical need in such 
patients  
A schematic representation of these PI3K components is shown in Figure 1-1. 






 
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(RENCA, 786-0, Caki-1), glioblastoma multiforme (U87MG), prostate cancer (PC3M), 
lung cancer (A549, NCI-H1975), ovarian cancer (A2780), colorectal cancer (HCT116, 
HCT-15) and melanoma (A2058, A375). In vivo PK/PD analyses of tumor tissues shows 
a good correlation between exposure, PI3K pathway blockade (S473P-Akt levels), and 
anti-tumor activity. 
1.3.1.2.1 Nonclinical pharmacokinetics and metabolism 
BKM120 showed favorable pharmacokinetic properties in all animal species tested. The 
absorption of [14C]-BKM120-related radioactivity was >84% in the rat. Oral 
bioavailability was high in rats (73%), was complete in dogs, and was moderate in 
monkeys (42%). The estimated steady state plasma volume of distribution (Vss) was 
high (3.0-3.5 L/kg) in all species tested, suggesting a wide tissue distribution. BKM120 
was found to cross the blood brain barrier in rats with a tissue-to-plasma ratio of 
approximately 2 (Novartis internal data). BKM120 is moderately bound to plasma 
protein in all species examined (about 80%). 
In vitro metabolism studies using human liver microsomes showed that oxidative phase I 
metabolism of BKM120 was predominantly mediated by CYP3A4 (estimated fm > 0.9). 
Formation of a BKM120 N-glucuronide conjugate (Phase II metabolism) via the UDP-
glucuronosyltransferase-1 family, polypeptide A4 (UGT1A4) was also observed in 
human liver microsomes supplemented with uridine 5'-diphospho-glucuronic acid 
(UDPGA). BKM120 and metabolites have a low potential for covalent binding to 
protein. 
BKM120 was determined to be a weak reversible inhibitor of CYP3A4 (IC50 = 8 µM, 
Ki = 13.4 µM unbound) at concentrations reached in the clinic. BKM120 very weakly 
inhibited the CYP2C family (2C8, 2C9 and 2C19) with IC50 values ranging from 35-65 
V; ?.G-WX V; 0-1$0-*DY 9:;2<3 *)* -$( %#$I ()K7-dependent inhibition of CYP450 
enzymes. In GLP toxicology studies, BKM120 exposure in terms of AUC0-24h and 
Cmax increased in a dose proportional manner in rat and dog. Results from the rat 
ADME study showed that radioactivity was mainly excreted into the feces. Renal 
excretion was minor. There was no noticeable drug accumulation in dog or male rats 
after 13 weeks of daily dosing. There was a slight accumulation in female rat (< 2 fold). 
Further information concerning the pharmacokinetic and pharmacodynamics properties 
of BKM120 may be found in the Investigator Brochure. 
1.3.1.2.2 Safety pharmacology and toxicology 
Safety pharmacology studies in rats revealed no effects on neuronal (behavior) or 
respiratory functions. Cardiac safety studies, conducted in vitro and in vivo did not 
indicate a prominent electrophysiological risk. No relevant electrophysiological effect 
was seen in dogs. The only effect considered relevant was a trend towards an increase in 
systolic and diastolic blood pressure, which was observed in two dog telemetry studies. 
In rats and dogs, clinical pathology and histopathology findings showed quantitative 
reductions of lymphoid and erythroid counts and lymphoid tissue hypoplasia. 
The pancreas was seen to be affected by treatment with BKM120, particularly in dogs, 
where acinar cell toxicity was seen in the exocrine part of this organ. At higher doses in 


 
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the 2-week dose-range-finding study in rats, there were histopathological findings in 
both the endocrine as well as the exocrine pancreas. 
Male sexual organs and associated tissues were found to be targets of toxicity in both 
rats and dogs. Changes included minimal to slight germ cell depletion, formation of 
spermatic giant cells and abnormal spermatids, and cellular debris in epididymal tubules. 
Testicular toxicity did not fully reverse after the 4-week treatment-free period in rats 
(highest dose), although a clear trend towards recovery was seen. In individual female 
rats, minimal to slight cyst formation occurred in the Graafian follicles. In dogs, there 
was no effect on female sexual organs.  
Glucose homeostasis was affected in various species (mice, rats, dogs), as expected from 
the mode of action of BKM120. However, these effects were minimal in both rats and 
dogs at the doses used in the 4-week studies. 
Other safety considerations include: 
# After up to 2 weeks of treatment with up to 2.5 mg/kg/day of BKM120, alterations in 
the levels of multiple brain neurotransmitters were seen in rats. 
# No evidence for a direct DNA interaction was found in an Ames test and two 
chromosome aberration tests in vitro with BKM120. However, evidence of a 
genotoxic potential with BKM120 has been seen in vitro and in vivo and is likely 
due to an aneugenic effect.  
# No phototoxic potential or any effect on wound healing has been identified with 
BKM120 in pre-clinical studies. 
In conclusion, the majority of the observed effects were related to the pharmacological 
activity of BKM120 as an inhibitor of PI3K, such as a potential influence on glucose 
homeostasis and the risk of increased blood pressure.   
",7'%7 H7J7H ($ (#7 >-=7%()6'($H/% 9H$8#0H7 J$H '**)()$-', )-J$HK'()$- $- (#7 &H78,)-)8',
testing of BKM120. 
1.3.1.2.3 Pharmacodynamic biomarkers 
The preclinical in vivo studies with xenografted tumors in mice indicate that detectable 
inhibition of AKT phosphorylation, which is an accurate readout of PI3K activity, as 
well as further suppression of downstream signaling (e.g., phosphorylation of S6) was 
obtained soon after BKM120 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 suggesting 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. 
 


 
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1.3.2 
Clinical experience 
1.3.2.1 
Clinical experience with BKM120 
 
As of September 2012, over 600 patients were enrolled into clinical studies with 
BKM120 (as 
single agent or combinations). The Novartis sponsored clinical studies were: 
# Phase I single agent studies [CBKM120X2101], [CBKM120X1101], and 
[CBKM120Z2102] 
# Phase II single agent studies [CBKM120C2201] and [CBKM120D2201] 
# Phase 
I 
combination 
studies 
[CBKM120B2101], 
[CBKM120X2107], 
[BKM120E2101], 
[CBEZ235A2118], [LDE225X2114], [CSTI571X2101], and [CMEK162X2101]. 
# Phase II combination studies [CBKM120F2202] 
# Phase III combination study [CBKM120F2302] 
For the interest of the current protocol, results presented below will focus on phase I 
single agent studies ([CBKM120X2101], [CBKM120X1101]), and phase I combinations 
in breast cancer patients ([CBKM120X2107], [CBEZ235A2118]). Please refer to the 
current version of the IB for more detailed information. 
1.3.2.1.1 Human safety and tolerability data  
Study 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, joint pain. The 
MTD for BKM120 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 4th July 2011 (Graña 2011), patient characteristics of 
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 BKM120 is described in Table 1-2: 


 
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Table 1-1 
Most frequent AEs (> 15%) related to study drug in 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 with dose levels ranging from 25 to 
100mg/day (Doi 2011). Enrolment of 15 patients has been completed, including 9 
patients at 100 mg/day. One DLT (G4 hepatic function abnormal) was observed in the 
100 mg/day group. The most common G3 or G4 adverse events occurring in at least 2 
patients were hepatic function abnormal in 6 patients including transaminase increase in 
2 patients, G3 anemia in 2 patients, hypokalemia in 2 patients. The recommended phase 
2 dose (RP2D) for Japanese has been determined at 100 mg/day, as in the western 
population.  The safety and efficacy of BKM120 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 BKM120 and trastuzumab was shown to be tolerable, and with one dose-limiting 
toxicity (G3 asthenia) the MTD for BKM120 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 II 
portion of the study, as of June 2012, 53 patients have been enrolled and received 
BKM120 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 BKM120. 
 






 
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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 %(H$-6,+ H78$KK7-*7* J$H '-+ &%+8#)'(H)8 '*=7H%7 7=7-( 6H'*7 ` 2Y
Protocol guidelines further disqualify patients with an 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 BKM120 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 4-6 for 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, 
#+&7H6,+87K)' )% 8$-%)*7H7* '% '- [$- ('H67(^ 7JJ78( $J 9:;2<3Y M760,'H K$-)($H)-6 $J
FPG, 
HbA1c, and insulin C-peptide is implemented in BKM120 protocols to evaluate this 
pharmacodynamics effect. Transient increases of plasma glucose levels have been 
reported commonly in patients treated with BKM120. Hyperglycemia observed at 100 
mg/day, regardless of study drug relationship, in ongoing BKM120 studies are 
summarized in Table 1-5. 
 






 
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1.3.2.1.2 Human pharmacokinetic and metabolism data 
Preliminary clinical pharmacokinetic data of BKM120 after single and multiple daily 
dosing is available from the first-in-human trial [CBKM120X2101]. BKM120 was 
administered as a 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.  
BKM120 was rapidly absorbed, with the median time to reach the peak plasma 
concentration (Tmax) ranging from 1.0 to 1.75 hours following 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 BKM120 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 BKM120 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 BKM120 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 BKM120 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 with the Caucasian population 
[CBKM120X2101]. A preliminary population PK analysis, including data from studies 
[CBKM120X2101] and [CBKM120X1101] confirmed those findings (Novartis internal 
data). 
In study [CBKM120B2101], BKM120 was administered with GSK1120212 (a MEK 
inhibitor). Single dose pharmacokinetics of BKM120 appeared to be unaffected by 
concomitant administration of GSK1120212. Concurrent chronic daily administration of 
both drugs, however, consistently resulted in a dose- and time-dependent decrease in 
BKM120 systemic drug exposure. After 28 days of once daily combination treatment of 
BKM120 with GSK1120212 (1.5-2.0 mg), exposure of BKM120 at system steady-state 
was decreased by approximately 45-50%, when compared to the mean value determined 
from [CBKM120X2101]. Decrease in exposure was less pronounced at lower doses of 
GSK1120212 (0.5- 1 mg) (approximately 25%). The overall drug clearance of BKM120 
increased up to 2-fold in the presence GSK1120212. This dose and time dependent 
effect of GSK1120212 on BKM120 oral clearance is most likely explained by induction 
of CYP3A4, a property of GSK1120212, which has been demonstrated in vitro. These 
findings are also consistent with a high dependence of BKM120 clearance on CYP3A4 
activity. Similar changes in the pharmacokinetics of BKM120 could be expected to 
occur when other inducers of CYP3A4 are combined with BKM120 treatment (see 


 
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concomitant medication ). The pharmacokinetics of GSK1120212 was not altered by 
BKM120. 
In study [CBKM120X2107] a daily dosing regimen of BKM120 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 BKM120 in combination with 
trastuzumab was similar to the single agent data. Trastuzumab trough levels were 
consistent with those previously reported to be therapeutic (i.e., generally greater than 20 
V6SK,DY 
1.3.2.1.3 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 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, gemcitabine, docetaxel, paclitaxel, vinorelbine, 
capecitabine, etoposide, anastrazole). As progressive disease developed (bulky lymph 
node involvement and local breast relapse), she was enrolled (April 2009) in the Phase I 
study of BKM120 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 BKM120 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 BKM120 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 BKM120 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 best response, with 20 patients (30%) 
with 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 


 
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metabolic FDG-PET response. However, considering the impact of a PI3K inhibitor on 
glucose metabolism, further data needs to be acquired to understand whether the current 
FDG-PET assessment data can be used as a predictive factor for efficacy. 
With regards 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 and more than 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, one had a tumor with the 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 BKM120 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 4th July 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). 
 
",7'%7 H7J7H ($ (#7 >-=7%()6'($H/% 9H$8#0H7 J$H '**)()$-', )-Jormation on the 
available clinical experience with BKM120. 
 
 
1.4 
Study Rationale 
Head and neck cancer (HNC) is the 6th most common cancer worldwide (~50,000 
cases/year in the US; 60,000 cases/year in Europe). Once recurrent or metastatic head 
and neck cancer carries a poor prognosis with a median survival of only 6-10 months 
(Vermorken et al. 2008; Seiwert et al. 2008).  
 
EGFR is expressed at very high levels in >90% of Head and Neck Cancers (HNC; 
>NSCLC) and treatment with cetuximab (alone or in combination with chemotherapy 
or radiation) is now considered a standard of care. Nevertheless the response rate to 
EGFR inhibitors single agent (cetuximab response rate = 13%, 40-50% stable 
disease) and median progression free survival of 70 days (Vermorken et al. 2007) 
remain disappointing. While treatment benefit is generally considered to be 
comparable to cytotoxic therapies with lower toxicity, the potential of EGFR as a 
therapeutic target in this highly EGFR expressing disease has not been fully 
exploited. Clinically treatment for recurrent/metastatic disease is either given in 
combination with chemotherapy (EXTREME) or after initial cytotoxic chemotherapy. 
 


 
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Cetuximab is the only approved targeted therapy for this disease and the response rate 
is 13% (Vermorken et al. 2007, Seiwert et al 2012). Better treatments are needed. 
Based on the published preclinical literature (Ekshyyan et al. 2010) as well as 
preclinical work done at the Univ. of Chicago we propose to assess the pan-class I 
PI3K inhibitor BKM120 in patients with head and neck cancer with a focus on PI3K 
relevant biomarkers that hold potential to identify patients who will benefit from 
therapy with BKM120 and could be further investigated in an expanded follow-up 
cohort using biomarker prescreening. The PI3K-AKT-mTOR signaling pathway is 
active in more than 80% of head and neck cancers (Ekshyyan et al. 2010). Head and 
Neck cancers have a variety of genetic changes that activate the pathway including 
EGFR amplification (~30%), PI3K mutations (~10%), and PTEN inactivation (5-
10%), as well as other mechanisms which appear to lead to near activation of PI3K 
signaling in HPV(+) head and neck cancers (Shen/Seiwert EORTC-NCI-AACR 
meeting 2010, Berlin). 
Recently HRAS mutations have been described in 3-5% of HNC (Stransky et al. 
2011; Agrawal et al. 2011). Preliminarily such tumors rely heavily on PI3K signaling 
as well (Rampias et al. ASCO 2011), although further evaluation is indicated. 
Preclinical data with PI3K inhibitors (e.g. NVP-BEZ235) suggests strong and 
widespread synergy (in a panel of 40 cell lines) including in tumors with EGFR 
amplification. Interestingly EGFR amplification has been found to be a poor predictor 
of sensitivity to EGFR inhibitor treatment alone and persistent activation of PI3K-
AKT signaling is a potential mechanism of resistance (Cohen et al. 2012 (under 
review)). 
It is well established that mTOR and AKT inhibition in several cancer types up-
regulates compensatory signaling via irs1 and several other upstream receptor 
tyrosine kinases (Chandarlapaty et al. 2011). Work by Rosie Xing (in preparation) 
indicates that the primary mechanism of compensatory RTK up-regulation in head 
and neck cancers is via EGFR and there is prominent synergy between EGFR and 
PI3K with co-targeting approaches. 
 
2 
Study objectives 
Primary 
# One week Run-In (randomized): 
Induction of compensatory signaling/feedback loop signaling after one week of 
BKM120 (run-in) compared to patients not treated with BKM120 (See Section 7 
(Statistical considerations) for details on measurement and power calculation) 
# Combination treatment: 
Safety and tolerability of combined treatment with BKM120 and cetuximab 
 


 
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Secondary 
# Induction of Apoptosis after one week of BKM120 (run-in) compared to patients 
not treated with BKM (See Section 7) 
# Tumor Shrinkage (based RECIST V1.1 measurements) in patients treated with 
combination of  
! Subgroup analysis in patients that are EGFR resistant* 
# Response Rate (based RECIST V1.1 measurements) in patients treated with 
combination of  
! Subgroup analysis in patients that are EGFR resistant* 
# Overall Survival 
# Progression Free survival 
 
* EGFR resistance is defined as progressive disease (RECIST V1.1) on prior systemic 
therapy in the recurrent/metastatic disease setting that at a minimum included an 
EGFR inhibitor and lasted at least 2 weeks. 
 
3 
Exploratory Investigational plan 
3.1 
Overall study design 
Open-label pilot study with serial biopsies in patients with accessible tumor: one pre- 
and one on-treatment biopsies 
! Please see Schema on page 4 
3.2 
Study population 
3.2.1 
Patient population 
Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNC) not 
amenable to curative intent therapy (palliative treatment intent). 
Enrollment target: N=30 patients. We estimate to have at least 5 patients with serial 
tumor biopsies (mandatory for patients with accessible tumor). All patients will have 
to have tumor material available for biomarker evaluation (for accessible tumors that 
are deemed save to biopsy fresh biopsies are mandatory; inaccessible tumor - archival 
tissue is sufficient). 
3.2.2 
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 


 
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Study No.  
 
reviewed by the Principal Investigator or his/her designee prior to enrollment of that 
patient. 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: 
Inclusion criteria  
1. Histologically / cytologically confirmed diagnosis of squamous cell carcinoma of 
Head and Neck origin not amenable to curative intent therapy. Both HPV(+) and 
HPV(-) tumors are eligible. Tumors (squamous histology) of unknown primary 
that are clearly of squamous histology and likely related to the Head and Neck 
area are eligible. 
 
2. Presence of measurable lesions (RECIST V1.1). 
3. Mandatory Tumor biopsy/biopsies in accessible tumors. The determination of 
['887%%)1),)(+^ for biopsy is to be done by the ENT surgeon on examination 
and/or review of trans-sectional imaging (see Section 4.4 and 4.4.3 for details): 
mandatory tumor biopsies (1st and 2nd biopsy are mandatory if accessible, 3rd 
biopsy is optional; see schedule under Section 4.3.1) 
For inaccessible tumors (as defined above and in Sections 4.4 and 4.4.3) 
availability of tissue is required: `10 tumor containing FFPE slides/sections; 12-
18 ideal) 
4. Documented progressive disease/tumor growth, which may include after exposure 
to a platinating agent (e.g. cisplatin or carboplatin) or another cytotoxic 
chemotherapy or radiation in a prior line of therapy, or documented intolerance to 
such an agent. Prior line of therapy may include induction chemotherapy or 
chemoradiotherapy, in addition to treatment for recurrent/metastatic disease. De 
novo metastatic disease is also allowed as long as progressive disease/evidence of 
tumor growth is documented. 
5. b67 ` 2c +7'H% 
6. ECOG performance status $ 2 
7. No more than two lines 
of prior 
cytotoxic 
chemotherapy 
in 
the 
recurrent/metastatic (palliative intent) treatment setting 
8. Prior use of cetuximab or another EGFR inhibitor is allowable and if used as a 
single agent should not be considered as a cytotoxic chemotherapy (nor should 
other targeted therapies be considered as a prior line of cytotoxic chemotherapy). 
9. Patients must have at least one site of measurable disease [if applicable] (per 
RECIST for solid tumors or the appropriate disease classification/criteria for the 
target population) 
10. Adequate 1$-7 K'HH$I J0-8()$- '% %#$I- 1+d b\E ` 2YW e 239SR@ ",'(7,7(% ` 233
x 109/L, Hb >9 g/dL  
11. Total calcium (corrected for serum albumin) within normal limits  


 
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Study No.  
 
12. ;'6-7%)0K ` (#7 ,$I7H ,)K)( $J -$HK', for the institution 
13. Potassium within normal limits for the institution 
14. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 1.5 
x normal range (or a 3.0 x upper limit of normal (ULN) if liver metastases are 
present) 
15. Serum bilirubin within normal range (or a  1.8 x ULN, e.g. if liver metastases are 
present; or total bilirubin a .Y3 e fR\ I)(# *)H78( 1),)H01)- I)(#)- -$HK', H'-67 )-
patients with well documented Gilbert Syndrome) 
16. O7H0K 8H7'()-)-7 a 2YW e fR\ $H <G-#$0H 8,7'H'-87 ` W3 KRSK)- 
17. O7H0K 'K+,'%7 a fR\ 
18. O7H0K ,)&'%7 a fR\ 
19. Fasting plasma glu8$%7 a 120 mg/dL (6.7 mmol/L), if not consider initiation of 
metformin treatment prior to study treatment 
20. Negative serum pregnancy test within 72 hours before starting study treatment in 
women with childbearing potential 
21. Signed informed consent 
22. >\M a <.5 
 
Exclusion criteria 
Patients eligible for enrollment into the treatment phase of this study must not meet 
any of the following criteria: 
 
1. Patients who have received prior treatment with a P13K inhibitor.  
2. No available tumor material for correlative studies (see inclusion criterion 3.) 
3. Patients with a known hypersensitivity to BKM120 or to its excipients, or 
hypersensitivity to cetuximab 
4. Inability to swallow BKM120 capsules. (In the future a different formulation of 
BKM120 may become available and may be approved by Novartis for other 
routes of administration, which would then supersede this exclusion criteria) 
5. More than two prior lines of cytotoxic chemotherapy in the recurrent/metastatic 
disease setting (palliative treatment intent)(excluding single agent use of an EGFR 
inhibitor) 
6. Patients with untreated brain metastases are excluded. However, patients with 
treated brain metastases are eligible if they are > 4 weeks from therapy 
completion (incl. radiation and/or surgery), are clinically stable at the time of 
study entry and are not receiving corticosteroid therapy at the time of study entry. 
7. Patients with acute or chronic liver, renal disease or pancreatitis 


 
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Study No.  
 
8. Patients with the following mood disorders as judged by the Investigator or a 
psychiatrist, or as a re%0,( $J &'()7-(/% K$$* '%%7%%K7-( _07%()$--')H7 (treating 
physician to decide on whether to administer questionnaire): 
# Medically documented history of or active major depressive episode, 
bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a 
history of suicidal attempt or ideation, or homicidal ideation (immediate 
risk of doing harm to others) or patients with active severe personality 
disorders (defined according to DSM- IV) are not eligible.  Note: for 
patients with psychotropic treatments ongoing at baseline, the dose 
and the schedule should not be modified within the previous 6 weeks 
prior to start of study drug. 
#  ` ELEb] v4 grade 3 anxiety  
# Meets the cut-$JJ %8$H7 $J ` 23 )- (#7 "Qg-9 or a cut-$JJ $J ` 2W )- (#7
GAD-h K$$* %8',7@ H7%&78()=7,+@ $H %7,78(% ' &$%)()=7 H7%&$-%7 $J [2@ <@ $H
.^ ($ _07%()$- -0K17H X H76'H*)-6 &$(7-()', J$H %0)8)*', (#$06#(% )- (#7
PHQ-9 (independent of the total score of the PHQ-9)  
 
9. "'()7-(% I)(# *)'HH#7' ` ELEb] v4 grade 2 
10. Patient has active cardiac disease including any of the following:  
# History of clinically significant heart failure (previously assessed) with a 
left ventricular ejection fraction (LVEF) of < 50% as determined by 
Multiple Grated 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 
11. Patient has a history of cardiac dysfunction including any of the following: 
# Myocardial infraction 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 
12. Patient has poorly controlled diabetes mellitus or steroid-induced diabetes 
mellitus (HbA1C>7.5%) 


 
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13. Patients with any history of hyperglycemia (elevated blood glucose level on 
blood chemistries) should be considered for initiation of Metformin treatment 
(500mg, po, twice daily) prior to starting BKM120. Please also see Tables 4-1 and 
4-11. 
14. 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.  
15. Impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients 
with unresolved diarrhea will be excluded as previously indicated 
16. Patients who have been treated with any hematopoietic colony-stimulating growth 
factors (e.g., G-CSF, GM-EOPD a < I77is prior to starting study drug. 
Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to 
enrollment, may be continued 
17. Patients who are 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.   
18. Patients receiving chronic treatment with steroids or another immunosuppressive 
agent other than specified in Exclusion Criterion #4.  
# Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive 
airways diseases), eye drops or local injections (e.g. intr-articular) are 
allowed.  Patients with previously treated brain metastases, who are on 
stable low dose corticosteriods treatment (e,g dexamethasone 2 mg/day, 
predisolone 10 mg/day) for at least 14 days before start of study treatment 
are eligible. 
19. Patients who have taken herbal medications and certain fruits within 7 days prior 
to starting study drug. Herbal medications include, but are not limited to St. 
j$#-/% I$H(@ :'='@ 7&#7*H' ?K' #0'-6D@ 6)-6i$ 1),$1'@ *7#+*H$7&)'-*H$%(7H$-7
(DHEA), yohimbe, saw palmetto, and ginseng.  Fruits include the CYP3A 
inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits.  
20. Patients who are 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 3-5 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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21. "'()7-(% I#$ #'=7 H787)=7* 8#7K$(#7H'&+ $H ('H67(7* '-()8'-87H (#7H'&+ a G
weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study 
drug must recover to a grade 1 before starting the trial  
22. Patients who have received any continuous or intermittent small molecule 
(#7H'&70()8% a < I77i% ?$H a. I77i% J$H ' K$-$8,$-', '-()1$*+D prior to starting 
study drug or who have not recovered from side effects of such therapy.  
23. "'()7-(% I#$ #'=7 H787)=7* I)*7 J)7,* H'*)$(#7H'&+ a 4 weeks or limited field 
radiation for &',,)'()$- a < I77i% &H)$H ($ %('H()-6 %(0*+ *H06 $H I#$ #'=7 -$(
recovered from side effects of such therapy 
24. Patients who hav7 0-*7H6$-7 K'k$H %0H67H+ a < I77i% &H)$H ($ %('H()-6 %(0*+ *H06
or who have not recovered from side effects of such therapy.  
25. Patients who are currently taking therapeutic doses of warfarin sodium or any 
other coumadin-derivative anticoagulant.  
26. Women who are pregnant or breast-feeding or adults of reproductive potential not 
employing an effective method of birth control. 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 
8$-%780()=7 K$-(#%D@ K0%( #'=7 ' -76'()=7 %7H0K &H76-'-8+ (7%( a 72 hours prior 
to initiating treatment. 
# 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. 
# 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 vasectomised 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 
# Oral contraception, injected or implanted hormonal methods are not 
allowed as BKM120 potentially decreases the effectiveness of hormonal 
contraceptives. 
# Fertile males, defined as all males physiologically capable of conceiving 
offspring must use condom during treatment, for 4 weeks (5 T1/2) after 
stopping treatment and for additional 12 weeks (16 weeks in total after 
study drug discontinuation) and should not father a child in this period.  
# Female partner of male study subject should use highly effective 
contraception during dosing of any study agent and for 16 weeks after final 
dose of study therapy. 
 
27. Known diagnosis of human immunodeficiency virus (HIV) infection unless 
patient is fully immunocompetent (CD4>200) and patient is not taking 
antiretroviral therapy. 
28. History of another malignancy within 3 years, except cured basal cell carcinoma 
of the skin or excised carcinoma in situ of the cervix, or any tumor that is after 
clearing with the PI clearly not considered to have impact on prognosis. 
29. Patient is unable or unwilling to abide by the study protocol or cooperate fully 
with the investigator 
4 
Treatments 
4.1 
Interruption or discontinuation of treatment / Dose 
Reductions 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. If administration 
of BKM120 must be interrupted because of unacceptable toxicity, drug dosing will be 
interrupted or modified according to rules described in Table 4-1. Toxicity will be 
assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, 
version 4.0. 
(CTCAEv4.0,http://ctep.cancer.gov/protocolDevelopment/electronic_applications/do
cs/ctcaev4.pdf). 


 
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Table 4-0   BKM120 and Cetuximab dose level modification/dose reduction 
guidelines* 
BKM120 Dose Level 
BKM120 Dose and Schedule 
-1 
60 mg daily 
0* 
80 mg daily* 
1 
100 mg daily  
Cetuximab Dose Level 
Cetuximab Dose and Schedule 
-2 
250 mg/m2 every 2 weeks 
-1 
400 mg/m2 every 2 weeks 
0* 
500 mg/m2 every 2 weeks 
* Starting Dose,  ** No BKM120 doses lower than 60mg will be used  
*Please note that during the run-in period all patients will take single agent BKM120 
100mg po daily. The above dose-escalation table only applies to the cetuximab-
BKM120 combination therapy. 


 
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Clinical study protocol 
 
Study No.  
 
Table 4-1 
 
Criteria for interruption and re-initiation of BKM120 and cetuximab treatment 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
No toxicity 
Maintain dose level 
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 
Maintain dose level 
Grade 3 (ANC < 1.0 
- 
0.5 
x 
109/L) 
Grade 4 (ANC < 0.5 
x 109/L) 
!"#$ %&'( )*$#+ ,('&+-(% $& . /,0%( 12 $3(*4 
# 
56 ,('&+-(% #* . 7 %08'2 $3(* "0#*$0#*
dose level 
# 
If resolved in > 7 days, then " 1 dose 
level 
Maintain dose level 
Febrile neutropenia  
(ANC < 1.0 x 109/L, 
6(-(, 9 :;<=>?@ 
Omit dose until resolved, then " 1 dose level 
Omit 
dose 
until 
resolved, 
reinitiate 
a 
same dose level 
Thrombocytopenia 
Grade 1 (PLT < 
LLN - 75 x 109/L) 
Grade 2 (PLT < 75 
- 50 x 109/L) 
Maintain dose level 
Maintain dose level 
Grade 3 (PLT < 50-
25 x 109/L) 
Omit dose unti+ ,('&+-(% $& . /,0%( 12 $3(*4 
# 
56 ,('&+-(% #* . 7 %08'2 $3(* "0#*$0#*
dose level 
# 
If resolved in > 7 days, then " 1 dose 
level 
Maintain dose level 
Grade 4 (PLT < 25 
x 109/L) 
!"#$ %&'( )*$#+ ,('&+-(% $& . /,0%( 12 $3(* " 
1 dose level 
Omit 
dose 
until 
resolved, 
reinitiate 
a 
same dose level 


 
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Clinical study protocol 
 
Study No.  
 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
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 
Maintain dose level 
Grade 2 (> 1.5 - 3.0 
x ULN) with ALT or 
AST ! 3.0 x ULN 
"#$% &'() *+%$, -)(',.)& %' ! /-0&) 12
then: 
# 
34 -)(',.)& $+ ! 5 &06(2 %7)+ #0$+%0$+
dose level 
# 
If resolved in > 7 days, then " 1 dose 
level 
Maintain dose level 
Grade 3 (> 3.0 - 
10.0 x ULN) with 
ALT or AST ! 3.0 x 
ULN 
Omit dose until resolved t' ! /-0&) 12
then: 
# 
34 -)(',.)& $+ ! 5 &06(2 " 1 dose level 
# 
If resolved in % 7 days discontinue 
patient from study treatment 
Omit 
dose 
until 
-)(',.)& %' ! /-0&) 12
then reinitiate at same 
dose level 
Grade 4 (> 10.0 x 
ULN) 
Omit dose and discontinue patient from 
study treatment 
Omit 
dose 
until 
resolved, 
and 
discontinue 
from 
study treatment 
AST or ALT 
Grade 1 (> ULN - 
3.0 
x 
ULN) 
 
Maintain dose level with LFTs* monitored 
as per protocol 
Maintain dose level 
Grade 2 (> 3.0 - 5.0 
x 
ULN) 
without 
bilirubin elevation 
to > 2.0 x ULN 
"#$% &'() *+%$, -)(',.)& %' ! 8-0&) 12 %7)+ 
# 
34 -)(',.)& $+ ! 5 &06(2 %7)+ #0$+%0$+
dose level 
# 
34 -)(',.)& $+ 9 5 &06(2 %7)+ : 1 &'()
level 
Maintain dose level 
Grade 3 (> 5.0 - 
20.0 
x 
ULN) 
without 
bilirubin 
elevation to > 2.0 x 
ULN 
Omit dose until resolved %' ! /-0&) 1 %7)+; 
# 
34 -)(',.)& $+ ! 5 &06(2 %7)+ #0$+%0$+
dose level 
# 
If resolved in > 7 days, then " 1 dose 
level 
Omit 
dose 
until 
-)(',.)& %' ! /-0&) 12
then reinitiate at same 
dose level 
Grade 4 (> 20.0 x 
ULN) 
without 
bilirubin elevation 
to > 2.0 x ULN 
"#$% &'() *+%$, -)(',.)& %' ! /-0&) 1 2
then " 1 dose level 
Omit 
dose 
until 
-)(',.)& %' ! /-0&) 12
then reinitiate at same 
dose level 
AST or ALT and 
concurrent 
Bilirubin 
 


 
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Clinical study protocol 
 
Study No.  
 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
AST or ALT > 3.0 x 
ULN 
and 
total 
bilirubin > 2.0 x 
ULN 
Discontinue study treatment permanently. 
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. 
 
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. In 
patients not on Metformin, initiate 
Metformin treatment (e.g. 500mg po 
twice daily). Generally management is 
0( <)- $+.)(%$80%'-=( &$(>-)%$'+, with 
Metformin being the first line anti-
diabetic agent. 
# 
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  
# 
check FPG at least weekly for 8 weeks, 
then continue checking at least every 
2 weeks 
Maintain dose level 
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 
! /-0&) 1 
# 
initiate or intensify medication with 
appropriate 
anti-diabetic treatment 
such as metformin; consider adding a 
Maintain dose level 


 
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Clinical study protocol 
 
Study No.  
 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
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 
# 
34 @A/ &')( +'% -)(',.) %' ! /-0&) 1
within 14 days after institution of 
appropriate 
anti-diabetic treatment 
reduce  BKM120/placebo by 1 dose 
level 
 
Continue with anti-diabetic treatment and 
check FPG at least weekly for 8 weeks, then 
continue checking at least every 2 weeks 
 
Grade 3 (> 250 - 
500 mg/dL) [> 13.9 
- 27.8 mmol/L] 
# 
 Omit 
BKM120, 
initiate 
or 
intensify 
medication with appropriate anti-diabetic 
treatment, re-check FPG within 24 hours.  
If grade worsens or improves then follow 
specific grade recommendations.  If FPG 
remains at Grade 3: 
# 
administer intravenous hydration and 
intervention 
for 
electrolyte/ketoacidosis/hyperosmola
r 
disturbances 
as 
clinically 
appropriate 
# 
continue to omit BKM120 
# 
monitor FPG at least twice weekly 
*+%$, @A/ -)(',.)( %' ! Grade 1  
# 
If FPG resolves to ! Grade 1 in 7 days 
or less, then re-start BKM120/placebo 
and " 1 dose level 
# 
If FPG remains greater than Grade 1 
severity for more than 7 days, then 
discontinue patient from BKM120 
# 
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 
Maintain dose level 


 
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Clinical study protocol 
 
Study No.  
 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
(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 BKM120/placebo and 
following guidance for management of 
Grade 3 fasting plasma glucose (FPG) 
Grade 4 (> 500 
#8B&CD
EF
G5HI
mmol/L] 
# 
immediately omit BKM120, 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/hyperos
molar disturbances as clinically 
appropriate 
# 
discontinue patient from 
BKM120/placebo 
# 
instruct patient to follow dietary 
guidelines 
according 
to 
local 
and/or institutional standards for 
management of diabetes mellitus 
(such as those provided by the 
American Diabetes Association) 
during the study 
# 
consider 
use 
of 
oral 
anti-
hyperglycemic therapy such as 
metformin 
# 
check FPG at least weekly for 8 
weeks, then continue checking at 
least every 2 weeks if clinically 
indicated 
For non-fasting plasma glucose >500 
mg/dL (> 27.8 mmol/L) accompanied by 
signs/symptoms of hyperglycemia (for 
example, mental status changes, excessive 
Omit 
dose, 
and 
if 
BKM120 
is 
discontinued 
also 
discontinue 
Cetuximab, otherwise 
reinitiate at the same 
dose 


 
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Page 37 
Clinical study protocol 
 
Study No.  
 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
thirst, polyuria), or presence of blood or 
urine ketones, discontinue BKM120 and 
following guidance for management of 
Grade 4 fasting plasma glucose (FPG). 


 
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Clinical study protocol 
 
Study No.  
 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
CARDIAC 
Cardiac 
A 
Left 
Ventricular systolic 
dysfunction 
 
 
Asymptomatic,  
resting 
ejection 
fraction 50 ? 40%; 
or 
10-20% 
drop 
from baseline 
Maintain dose level 
Maintain dose level 
Symptomatic,  
responsive 
to 
intervention,  
ejection 
fraction 
39 
? 
20% 
or > 20% drop 
from baseline 
"#$% &'() *+%$, -)(',.)& %' ! /-ade 1, then 
" 1 dose level 
LVEF measurement to be repeated, if not 
-)(',.)& %' ! /-0&) 1 J$%7$+ K J))L(2
permanently 
discontinue 
patient 
from 
BKM120 
Maintain dose level 
Refractory 
or 
poorly controlled,  
ejection fraction < 
20% 
Omit dose and discontinue patient from 
BKM120 
Omit 
dose 
and 
discontinue 
patient 
from cetuximab 
Cardiac 
A 
QTc 
prolongation 
 
MN>@ 9 OPP #( QF
Grade 
3)  
or > 60 ms change 
from 
baseline 
on at least two 
separate ECGs 
First Occurrence: 
# 
omit BKM120  
# 
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, 
BKM120 may be restarted at a one 
lower dose level  
Second Occurrence: 
# 
discontinue patient from BKM120 
 
Maintain dose level 
Other 
Cardiac 
Events 
 
 
Grade 1 or 2 
Maintain dose level 
Maintain dose level 
Grade 3 
"#$% &'() *+%$, -)(',.)& %' ! /-0&) 12 %7)+
" 1 dose level 
Maintain dose level 
Grade 4 
Omit dose and discontinue patient from 
BKM120 
Omit 
dose 
and 
discontinue 
patient 
from cetuximab 


 
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Page 39 
Clinical study protocol 
 
Study No.  
 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
OTHER 
Mood alteration 
 
* See Table 4-3  
for 
toxicity 
grading of mood 
questionnaires. 
Questionnaire 
scores should be 
considered when 
assigning the AE 
Grade 
but 
psychiatric 
consult, 
if 
required, 
may 
determine 
the 
grade 
 
 
Grade 
1 
(or 
Grade 
2 
anxiety if present 
at baseline) 
Maintain dose level 
 
Note: If question 9 on the PHQ-9 has a 
positive response, or worsens in severity, 
the 
patient 
should 
be 
referred 
for 
psychiatric consult regardless of the total 
questionnaire score 
Maintain dose level 
Grade 
2 
(for Anxiety only, 
if worsened from 
baseline) 
 
Institute appropriate co-medication under 
the guidance of the psychiatrist. Maintain 
dose level. 
# 
34 %7) >'+&$%$'+ &')( +'% -)(',.) %' !
Grade 1 within 14 days despite medical 
treatment; 
then 
" 
1 
dose 
level 
(continue to co-medicate) 
 
Note: If question 9 on the PHQ-9 has a 
positive response, or worsens in severity, the 
patient should be referred for psychiatric 
consult regardless of the total questionnaire 
score 
 
Maintain dose level 
Grade 3 
Omit dose until resolved to ! /-0&) 12 %7)+
" 1 dose level (co-medicate) 
 
Note: If question 9 on the PHQ-9 has a 
positive response, or worsens in severity, 
the 
patient 
should 
be 
referred 
for 
psychiatric consult regardless of the total 
questionnaire score 
Maintain dose level 
Grade 4 
Omit dose and discontinue patient from 
study 
 
Note: If question 9 on the PHQ-9 has a 
positive response, or worsens in severity, 
the 
patient 
should 
be 
referred 
for 
Omit 
dose 
and 
discontinue 
patient 
from study 
 


 
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Page 40 
Clinical study protocol 
 
Study No.  
 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
psychiatric consult regardless of the total 
questionnaire score 
Rash 
 
Grade 1 
Maintain dose level. Consider to initiate 
appropriate skin toxicity therapy (such as 
antihistamines, 
topical 
corticosteroids, 
minocycline or a macrolide antibiotic)  
See table 4-2 
Grade 2 
Maintain 
dose 
level. 
Initiate/intensify 
appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids) 
See table 4-2 
Grade 3 
"#$% &'() *+%$, -)(',.)& %' RNRST /-0&) !
1, then: 
# 
34 -)(',.)& $+ ! 5 &06(2 " 1 dose level 
# 
If resolved in % 7 days (despite 
appropriate 
skin 
toxicity 
therapy), 
discontinue patient from BKM120 
See table 4-2 
Grade 4 
Omit dose and discontinue patient from 
BKM120 
Omit 
dose 
and 
discontinue 
patient 
from cetuximab 
Fatigue (asthenia) 
 
Grade 1 or 2 
Maintain dose level 
Maintain dose level 
Grade 3 
Omit &'() *+%$, -)(',.)& %' ! /-0&) 12
then: 
# 
34 -)(',.)& $+ ! 5 &06(2 #0$+%0$+ &'()
level 
# 
If resolved in % 7 days, " 1 dose level 
Maintain dose level 
Grade 4 
Omit dose and discontinue patient from 
BKM120 
Omit 
dose 
and 
discontinue 
patient 
from cetuximab 
Other 
non-
hematological 
adverse events 
 
Grade 1 or 2 
Maintain dose level 
Maintain dose level 
Grade 3 
"#$% &'() *+%$, -)(',.)& %' ! /-0&) 12 %7)+
" 1 dose level 
If at least possibly 
related to cetuximab 
and not amenable to 
an established, readily 
effective 
treatment**: 
hold cetuximab until 
-)(',*%$'+ %' !/-0&) GH
See Table 4.2 
Grade 4 
Omit dose and discontinue patient from 
study 
Note; "#$% &'() 4'- F /-0&) K .'#$%$+8 '-
Grade 3 nausea only if the vomiting or 
nausea cannot be controlled with optimal 
antiemetic 
Omit 
dose 
and 
discontinue 
patient 
from study 
 
Pneumonitis 
See Table 4.6 
See Table 4.6 
Cetuximab  
Infusion Reaction 
Maintain 
dose 
level. 
If 
cetuximab 
is 
permanently discontinued, BKM120 may be 
See Table 4-2 


 
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Clinical study protocol 
 
Study No.  
 
Recommended Dose Modifications  
Worst 
toxicity 
(CTCAE Grade)** 
Recommended 
Dose 
Modifications 
for 
BKM120 
Recommended 
Dose 
Modifications 
for 
Cetuximab 
continued as a single agent if deemed 
appropriate 
** Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. 
 
 
Table 4-2 Criteria for Cetuximab dose interruption / re-initiation 
 
Management of Dermatologic Toxicity 
Grade 
3 
Acneform Rash 
Cetuximab 
Outcome 
Cetuximab 
Dose 
Modification 
1st occurrence 
Delay next infusion 1 to 2 
weeks (per treating MD) 
Improvement 
Continue at 500 mg/m2 
No Improvement 
Discontinue cetuximab 
2nd occurrence 
Delay next infusion 1 to 2 
weeks (per treating MD)  
Improvement 
Reduce Dose Level -1 
No Improvement 
Discontinue cetuximab 
3rd occurrence 
Delay next infusion 1 to 2 
weeks (per treating MD) 
Improvement 
Reduce to Dose Level -
2 
No Improvement 
Discontinue cetuximab 
4th occurrence 
Discontinue cetuximab 
 
 
Other Cetuximab related toxicities 
Cetuximab Infusion 
Reaction 
# 
Grade 1 (transient flushing or rash, drug fever <38oC): 
decrease the cetuximab infusion rate by 50% and monitor 
closely for any worsening. 
# 
Grade 2 (rash, flushing, urticaria, dyspnea, drug fever 
9:;&?@4
'$&B
$3(
C($)D#"0E
#*6)'#&*2
0%"#*#'$(,
appropriate therapy, and then restart the cetuximab 
infusion with a decrease in the infusion rate of 50% and 
monitor closely for any worsening. 
# 
Grade 1 or 2 Infusion Reaction manifesting only as a 
delayed drug fever (starting after the cetuximab infusion): 
maintain the cetuximab dose and infusion rate and 
consider 
administering 
acetaminophen 
or 
cyclooxygenase-2 inhibitors (at the dose and schedule of 
$3( #*-('$#F0$&,G' %#'C,($#&*@ B,#&, $& $3( ')E'(H)(*$
cetuximab infusion, if not otherwise contraindicated in the 
patient. 
# 
A 
grade 
3 
reaction 
consists 
of: 
symptomatic 
bronchospasm 
with 
or 
without 
urticaria, 
requiring 
parenteral 
medication(s); 
allergy-related 
edema/angioedema; hypotension. 
# 
A grade 4 reaction (anaphylaxis) is a life-threatening event 
characterized by rapid onset (often within minutes) of 
airway obstruction (bronchospasm, stridor, hoarseness), 
urticaria, and/or hypotension. 
# 
Treatment of a Grade 3 or 4 Infusion Reaction: Stop the 
cetuximab infusion immediately and disconnect infusion 


 
Confidential 
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Clinical study protocol 
 
Study No.  
 
tubing 
from 
the 
patient. 
Administer 
epinephrine, 
bronchodilators, 
antihistamines 
(acceptable 
in 
this 
scenario Aalso see Section 4.2.2), glucocorticoids, 
intravenous fluids, vasopressor agents, oxygen, etc, as 
medically indicated. 
# 
Following a grade 3 or 4 infusion reaction, the patient is to 
receive no further cetuximab treatment. In the event of a 
grade 1 or 2 infusion reaction, the cetuximab infusion rate 
should be permanently reduced by 50%. 
# 
Severe 
infusion 
reactions 
require 
the 
immediate 
interruption 
of 
cetuximab 
therapy 
and 
permanent 
discontinuation from further therapy.  Appropriate medical 
therapies include epinephrine, corticosteroids, intravenous 
antihistamines, bronchodilators, and oxygen .  Patients 
should be carefully observed until the complete resolution 
of all signs and symptoms. 
     Hypomagnesemia 
# 
The incidence of hypomagnesemia (both overall and 
severe [NCI CTC grades 3  & 4])  is increased in patients 
receiving chemotherapy and cetuximab as compared with 
those receiving chemotherapy alone based on controlled 
clinical trials.  Patients receiving cetuximab therapy should be 
monitored for hypomagnesemia. Magnesium repletion may be 
necessary based on clinical judgment. 
# 
 
Drug Fever 
# 
In the event of isolated drug fever, the investigator must 
use clinical judgment to determine if the fever is related to the 
study drug or to an infectious etiology. 
# 
If a patient experiences isolated drug fever, for the next 
dose, pre treat with acetaminophen or non-steroidal anti-
inflammatory agent (investigator discretion), repeat antipyretic 
dose 6 and 12 hours after cetuximab infusion.  The infusion 
rate will remain unchanged for future doses. 
# 
If a patient experiences recurrent isolated drug fever 
following pre-medication and post-dosing with an appropriate 
antipyretic, the infusion rate for subsequent dosing should be 
50% of previous rate.  If fever recurs following infusion rate 
C30*F(2 $3( #*-('$#F0$&, '3&)+% 0''('' $3( B0$#(*$G' +(-(+ &6
discomfort with the event and use clinical judgment to 
determine if the patient should receive further cetuximab. 
Skin toxicities 
# 
Patients developing dermatologic toxicities while receiving 
cetuximab should be monitored for the development of 
inflammatory or infectious sequelae, and appropriate 
treatment of these symptoms initiated.  Dose modifications of 
any future cetuximab infusions should be instituted in case of 
severe (grade 3) acneform rash.  Treatment with topical 
and/or oral antibiotics should be considered; topical 
corticosteroids are not recommended. 
# 
If a patient experiences severe acneform rash, cetuximab 
treatment adjustments should be made according to the 
following table.  In patients with mild and moderate skin 
toxicity, treatment should continue without dose modification. 
# 
Management guidelines for treatment of skin toxicities are 
well established including antibiotics and topical therapies 
following routine clinical practice.  


 
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Clinical study protocol 
 
Study No.  
 
 
4.1.1 Monitoring of BKM120 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 at least 
once a week for 4 weeks, and subsequently at 4-week intervals, until resolution or 
stabilization of the event, whichever comes first. Monitoring should include all 
medically indicated tests appropriate for the respective toxicity and should include the 
tests/items listed in Table 4-11 under EOT (end of therapy) at least once. If a patient 
requires a dose delay of > 28 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 28 days following the last dose of 
BKM120. All SAEs must be reported to Novartis as detailed in Section 3.4.4.2. No 
BKM120 dose level below 60mg daily will be assessed (unless the protocol is 
amended accordingly). 
 
4.1.2 
Known Undesirable Side Effects of BKM120 
4.1.2.1 
Neuropsychiatric events  
 
In an ongoing Phase Ia study of BKM120 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 BKM120. 
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 BKM120 at 
the 100 mg dose level and 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 %+K&($K% ELEb] NH'*7 ` < %#$0,* )KK7*)'(7,+ 17
examined by a psychiatrist and closely followed medically. Medical treatment with 
mood stabilizers (2nd generation antipsychotics) such as olanzapine and quetiapine 
K'+ 17 '&&,)7* '% &7H )-=7%()6'($H/% *)%8H7()$- '-* J$,,$I)-6 consultation of a 
psychiatrist. 
4.1.2.1.1 Management of mood alteration 
 


 
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Clinical study protocol 
 
Study No.  
 
In patients with evidence of mood problems (assessed by the treating 
oncologist/investigator), or a history of mood problems a patient self-rating mood 
questionnaires PHQ-9 (depression) and GAD-7 (anxiety) will be used: 
l ($ %0&&$H( '%%7%%K7-( $J 7,)6)1),)(+ '( O8H77-)-6 
l ($ K$-)($H J$H -7I,+ $880HH)-6 $H I$H%ening mood alterations during the study. 
The following grading system will be used for this study: 
 
 
Table 4-3 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 
9 1= 
Severe 
Grade 3 
 
At Screening, a patient as judged by the investigator or who meets the cut-off score of 
` 22 in the PHQ-9 or a cut-$JJ $J ` 2W )- (#7 Nbm-7 mood scale, respectively, or 
%7,78( ' &$%)()=7 H7%&$-%7 $J n2@ <@ $H ./ ($ _07%()$- -0K17H X Hegarding suicidal 
thoughts or ideation will be excluded from the study. 
 
During the study, patients who meet the cut-$JJ %8$H7 $J ` 23 ?` ELEb] 6H'*7 <
mood alteration) in either questionnaire or indicate a positive response by selecting 
n2@ <@ $H ./ ($ _0estion number 9 on the PHQ-9 must see a psychiatrist for advice on 
the most appropriate medical treatment must see a psychiatrist for diagnosis and 
determination of most appropriate medical treatment. For anxiety, this applies only if 
status has worsened from 1'%7,)-7Y "'()7-(% I#$ 7e&7H)7-87 ` 6H'*7 < K$$* ',(7H'()$-
will be followed twice weekly by patient self-rating mood scale and will be seen 
I77i,+ 1+ (#7 &%+8#)'(H)%( 0-(), H7%$,=7* a grade 1 or baseline (for anxiety). 
Questionnaire responses will be checked by the psychiatrist at the weekly visits (until 
resolution to Grade 1 or baseline (for anxiety).  
 
 






 
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Study No.  
 
 
4.1.2.2 
Hyperglycemia 
 
In preclinical studies, insulin/glucose homeostasis was impacted in various species 
(mice, rats, dogs), as expected from the mode of action of BKM120. 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. Histopathologically, pancreas and liver showed changes, which are in 
concordance with this activity.  
 
Grade 4 Hyperglycemia was also observed in an ongoing Phase Ia study of BKM120 
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 BKM120 treatment 
investigators are advised to adhere to the protocol guidelines outlined in Table 4-1 
and 4-11. Any patients with a history of hyperglycemia should be considered for 
initiation of metformin therapy prior to starting BKM120. 
4.1.2.2.1 Management of severe Hyperglycemia 
 
In addition to the dose modification, metformin treatment, and additional 
hyperglycemia treatment guidelines in Table 4-1 the following steps should be taken 
for persistent hyperglycemia: 
# 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). 
 
l P$H '-+ #+&7H6,+87K)' ` 6H'*7 2@ (#7 &'()7-( %#$0,* 8$-()-07 ($ J$,,$I *)7('H+
guidelines provided by the American Diabetes Association (American Diabetes 
Association 2004). 
 
l P$H 7'8# &'()7-(@ ' K'e)K0K $J < *$%7 H7*08()$-% I),, 17 ',,$I7* 'J(7H I#)8# the 
patient should be discontinued from the study. In addition, a patient must discontinue 
treatment with BKM120, if after treatment is resumed at a lower dose, hyperglycemia 
recurs at a worse severity. 
 
l P$H 7'8# &'()7-(@ $-87 ' *$%7 ,7=7, H7*08()$- #'% occurred, the dose level may not be 
re-escalated in that patient during future treatment cycles with BKM120. 
 
l 9'%7* 0&$- (#7 H7%0,(% $J &H7,)K)-'H+ 8,)-)8', *'(' '-* '8(0', ,'1$H'($H+ =',07%
(e.g., glucose, insulin) generated, the treatment recommendations for study drug 
induced hyperglycemia may be modified as needed.  


 
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Study No.  
 
4.1.2.3 
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 BKM120 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, all patients will be assessed for cardiac diseases before start of 
treatment, while all 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 BKM120 treatment investigators are advised to adhere to the 
protocol guidelines. Vital signs, including pulse rate and blood pressure, will closely 
be followed during the early clinical studies. 
4.1.2.3.1 Management of Cardiac events  
 
At the screening visit a 12-lead electrocardiogram (ECG), and assessment for 
history/symptoms of heart failure will be performed. In patients with a history/clinical 
symptoms of heart failure a MUGA scan (echocardiogram acceptable) will be 
performed to assess clinical status and eligibility. Repeat ECGs will be performed at 
screening and as clinically indicated. A MUGA will be performed/repeated if any 
symptoms consistent with cardiac problems occur.  
In the prior phase I study of BKM120 (Bendell et al. 2012) no evidence of changes in 
ejection fraction/heart failure symptoms were reported. Cetuximab does not affect 
cardiac function and prior reports suggest tolerability of the combination of a PI3K 
inhibitor and cetuximab (Senzer et al 2011 AACR-NCI-EORTC meeting A174).   
 
4.1.2.3.2 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 BKM120 in the single agent setting two cases of 
Pneumonitis occurred. In the study BKM120X2101 one patient experienced 
Pneumonits grade 2 eight weeks after the first dose of BKM120 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 


 
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Study No.  
 
BKM120. 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 IB for more details). 
 
All patients participating in clinical trials administering BKM120 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 dose modifications) in Table 4-6 should be 
followed. Consultation with a pulmonologist is highly recommended for any 
Pneumonitis case identified during the study. 
 
Table 4-6  Management of pneumonitis* 
Worst Grade 
Pneumonitis 
Required 
Investigations 
Management 
of 
Pneumonitis 
BKM120  
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 
BKM120 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 BKM120 dose 
by 1 dose level (see 
Table 
4-0/page 
22) 
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 
Consider 
corticosteroids 
if 
infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Hold treatment with 
BKM120 until recovery 
to < Grade 1. May 
restart study treatment 
within 3 weeks at a 
reduced dose (by one 
level) if evidence of 
clinical benefit. 


 
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Study No.  
 
Worst Grade 
Pneumonitis 
Required 
Investigations 
Management 
of 
Pneumonitis 
BKM120  
Dose Adjustment 
BAL 
is 
recommended. 
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 BKM120. 
*The dose of cetuximab will not be adjusted for pneumonitis. Upon discontinuation 
of BKM120 cetuximab should also be discontinued. 
4.1.2.3.3 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 #$%&' ()*+',)- %+ " grade 1 or 
stabilization (no CTCAE grade change over 4 weeks). 
4.1.2.4 
Study discontinuation  
All interruptions or changes to study drug administration must be recorded. 
It will be documented whether or not each patient completed the clinical study. If for 
any patient either study treatment or observations were discontinued the reason will 


 
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Study No.  
 
be recorded. Reasons that a patient may discontinue participation in a clinical study 
are considered to constitute one of the following: 
1. adverse event(s) 
2. abnormal laboratory value(s) 
3. abnormal test procedure result(s) 
4. disease progression 
5. protocol violation 
6. subject withdrew consent 
7. lost to follow-up 
8. administrative problems 
9. death 
 
4.2 
Treatments 
4.2.1 
BKM120 Administration 
The study drug BKM120 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. BKM120 will be administered on a continuous once daily dosing schedule. 
Patients should be instructed to take the dose of BKM120 daily in the morning, one 
hour after a light breakfast (morning meal) at approximately the same time each day. 
BKM120 should be taken with a glass of water and consumed over as short a time as 
possible. Patients should swallow the capsules as a whole and not chew them.  Do not 
crush capsule. A new formulation may become available in the future and guidelines 
for administration per Novartis should be followed. Patients should continue to fast 
for 2 hours after the administration of each BKM120 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. In addition, on 
the days of full pharmacokinetic sampling, the exact time of any episodes of vomiting 
within the first 4 hours post-dosing on that day and within the first 4 hours following 
(#7 &H7=)$0% *'+/% *$%)-6 K0%( 17 -$(7* whenever possible.   
If the patient forgets to take her/his dose before 6:00 PM, then the dose should be 
withheld that day and BKM120 should be restarted the following day.  
Patients must avoid consumption of St. J$#-/% o$H(@ O7=),,7 $H'-67%@ 6H'&7JH0)( $H
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. 
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 BKM120 dose delay of > 28 days from 


 
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Study No.  
 
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 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. 
 
4.2.2 
Cetuximab Administration 
 
! 
Cetuximab will be given on an outpatient basis every two weeks intravenously 
at a dose of 500mg/m2 (given over 120 minutes the first time, the over 60 
minutes subsequently) (all iv). 
! 
Patients will receive cetuximab intravenous infusions via infusion pump. The 
dose of cetuximab is 500 mg/m2 and is administered over 120 or 60 minutes. 
L#7 *$%7 $J 87(0e)K'1 )% *7&7-*7-( 0&$- (#7 &'()7-(/% 1'%7,)-7 1$*+ I7)6#( )-
kilograms (mg/kg). If there )% ' `<3p 8#'-67 )- 1$*+ I7)6#( JH$K 1'%7,)-7 (#)%
dose should be recalculated. The infusion rate must not exceed 10 mg/minute (5 
mL/minute). Patients should be observed closely during cetuximab infusion and 
for 60 minutes after the infusion. Infusion times may be increased for patients 
who experience mild allergic reactions, but cannot exceed 4 hours. Prior to 
infusion, the appropriate volume of cetuximab will be drawn from the vial with 
a sterile syringe and cetuximab will be transferred from the syringe into a sterile 
evacuated container. Cetuximab will be filtered through a 0.22-VK &H$(7)--
sparing or low- protein binding in-line filter. After infusion, 0.9% normal saline 
will be used to flush the line. 
! 
Premedication with an H1 antagonist (diphenhydramine 25-50 mg I.V. or oral) 
30 minutes prior to infusion should be given for allergic reaction prophylaxis. 
50mg should be administered prior to the first dose of cetuximab in an effort to 
prevent an infusion reaction.  
! 
Four weeks (28 days) constitutes one cycle of treatment.  
! 
If a patient develops a hypersensitivity reaction despite diphenhydramine 
pretreatment, please refer to Table 4-2. Infusion reactions to cetuximab may be 
severe and can occur during or after treatment. Use of H2 blockers is not 
recommended due to interactions with BKM120. b( (#7 &#+%)8)'-/% *)%8H7()$-@
H2 blockers may be used, but should be administered more than 60minutes after 
BKM120 (H2 blockers other than cimetidine should be considered due to 
additional drug interactions of cimetidine). Cetuximab administration may be 
resume* '( (#7 &#+%)8)'-/% *)%8H7()$-. Re-attempting infusion at a slower rate, 
possibly over one hour is appropriate.  Additional treatment of severe allergic 
reactions is at the discretion of the treating physician and may include 
corticosteroids as well as other agents. 
! 
As a routine precaution, patients enrolled in this study will be observed closely 
for any potential adverse events by the medical staff for the duration of the 
cetuximab infusion and until at least 1 hour after the end of the initial infusion, 
in an area with resuscitation equipment and other agents (epinephrine, 
prednisone equivalents, etc.) available. A nurse must be present in the 


 
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Study No.  
 
immediate treatment area throughout the infusion and observation period. A 
physician must be in close proximity to the patient treatment area. Patients 
should be instructed to report any delayed reactions to the investigator 
immediately.  
! 
Details about dose reductions / resumption of therapy on subsequent treatment 
days are provided in Section 4 / Tables 4-1 and 4-2. 
4.2.3 
Concomitant therapy 
All medications (excluding prior chemotherapy and biologic, immunologic or 
radiation therapy) taken within 4 weeks prior to the administration of BKM120 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 BKM120 
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 drug) and significant non-drug therapies (including 
herbal medicines, 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 below 
(Sections 4.2.3.1, and 4.2.3.2).  
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 vitro metabolism studies suggest that oxidative metabolism of BKM120 is 
predominantly mediated by CYP3A4 (fm>0.9), with only minor contributions of 
CYP1A1. As BKM120 is a sensitive CYP3A4 substrate, co-administration of 
BKM120 with strong and moderate CYP3A4 inhibitors and CYP3A4 inducers is 
prohibited.  Refer to Table 4-7 for a list of prohibited drugs.  Please note this list 
may not be comprehensive. 
# Based on in vitro studies, co-administration of BKM120 with CYP3A4 inducers 
is predicted to decrease the systemic exposure to BKM120, thereby increasing the 
risk of exposing the patient to subtherapeutic drug levels.  Refer to Table 4-7 for a 
list of prohibited CYP3A inducers.  Please note that this list may not be 


 
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Study No.  
 
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 4-8 
7-()(,7* [R)%( $J "H$#)1)(7* gL &H$,$-6)-6 *H06%^ ?)Y7Y@ *H06% (#'( 'H7 67-7H',,+
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 no( ,)K)(7* ($ O(Y j$#-/% I$H(@ :'='@ 7&#7*H'
(ma huang), ginko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, ginsing.  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. 
Table 4-7 
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 
I(%#C#*(G' J?+#*#C0++8 K(+(-0*$L M0E+( 0*% 6,&" $3( N*#-(,'#$8 &6 O0'3#*F$&*G' P,)F
Interaction Database based on in vitro studies. Strong inhibitors are predicted to increase 
BKM120 AUC > 5-6&+%2 0*% "&%(,0$( #*3#E#$&,' 0,( B,(%#C$(% $& #*C,(0'( QRI1ST UN? 9 S-
fold but < 5-fold.  
M3#' %0$0E0'( &6 ?VW #*%)C(,' X0' C&"B#+(% 6,&" $3( YPUG' J/)#%0*C( 6&, 5*%)'$,82 P,)F


 
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Study No.  
 
Strong 
CYP3A 
inhibitors 
Moderate CYP3A 
inhibitors 
Strong CYP3A 
inducers 
Moderate 
CYP3A 
inducers 
5*$(,0C$#&* Z$)%#('[L 6,&" $3( 5*%#0*0 N*#-(,'#$8 ZC3&&+ &6 I(%#C#*(G' J?+#*#C0++8 K(+(-0*$L
Table; and from (Pursche et al. 2008). 
All QT-prolonging drugs listed in Table 4-8 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. 
 
Table 4-8 
List of prohibited QT prolonging drugs  
Drug 
QT risk(*) 
Comment 
Amiodarone 
Known 
risk 
for 
TdP 
Females>Males,TdP risk regarded as 
low 
Arsenic trioxide 
Known 
risk 
for 
TdP 
 
Astemizole 
Known 
risk 
for 
TdP 
No Longer available in U.S. 
Bepridil 
Known 
risk 
for 
TdP 
Females>Males 
Chloroquine 
Known 
risk 
for 
TdP 
 
Chlorpromazine 
Known 
risk 
for 
TdP 
 
Cisapride 
Known 
risk 
for 
TdP 
Restricted availability; Females>Males. 
Disopyramide 
Known 
risk 
for 
TdP 
Females>Males 
Dofetilide 
Known 
risk 
for 
TdP 
 
Domperidone 
Known 
risk 
for 
TdP 
Not available in the U.S. 
Droperidol 
Known 
risk 
for 
TdP 
 
Halofantrine 
Known 
risk 
for 
TdP 
Females>Males 
Haloperidol 
Known 
risk 
for 
TdP 
When given intravenously or at higher-
than- recommended doses, risk of 
sudden death, QT prolongation and 


 
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Study No.  
 
Drug 
QT risk(*) 
Comment 
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 
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. 
 


 
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4.2.3.2 
Drugs to be used with caution 
Preliminary in vitro metabolism studies suggest that BKM120 is a weak, reversible 
inhibitor CYP3A4/5 (Ki=13.q V;@ r>sS:)t 3YG I#7H7 r>s )% (#7 '=7H'67 Emax at steady-
state following 100 mg daily dose) and a weak reversible inhibitor of 
CYP2C8/2C9/2C19 (IC50t.G V;@ r>sS>E50=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 4-9 for a list of CYP450 substrates and carefully 
consider their co-administration with BKM120. 
Particularly, caution is advised when BKM120 is co-administered with: 
# Drugs which are substrates for CYP3A4, CYP2C8, CYP2C9 or CYP2C19 and 
which have a narrow therapeutic index. 
# Oral anti-diabetics which are metabolized by CYP2C8 or CYP2C9 can possibly 
result in hypoglycemia. Patients who develop hyperglycemia/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 4-8 for a 
list of QT prolonging medications to be used with caution.  
Note: please refer also to Table 4-8 for a list of prohibited QT prolonging 
medication.  
# Please refer to Table 4-9 for a list of CYP450 substrates and carefully consider 
their co-administration with BKM120.  
# Concomitant treatment with corticosteroids and BKM120 should be avoided, 
whenever possible, during this study. A short duration (< 2 weeks) of systemic 
corticosteriods is allowed (e.g. for chronic obstructive pulmonary disease, or as an 
anti-emetic).  Chronic dosing of corticosteriods is known to induce CYP3A 
enzymes, thereby increasing the risk or reducing BKM120 overall exposure to 
sub-therapeutic levels. 
Table 4-9  
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 


 
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Study No.  
 
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 
 
* M3#' %0$0E0'( &6 ?VW ')E'$,0$(' X0' C&"B#+(% 6,&" $3( 5*%#0*0 N*#-(,'#$8 ZC3&&+ &6 I(%#C#*(G' J?+#*#C0++8
K(+(-0*$L M0E+(2 0*% 6,&" \]3&) ($ 0+< STT^@ 
__ ?VW:U ')E'$,0$(' X(,( C&"B#+(% 6,&" $3( 5*%#0*0 N*#-(,'#$8 ZC3&&+ &6 I(%#C#*(G' J?+#*#C0++8 K(+(-0*$L
M0E+([ 0*% ')BB+("(*$(% E8 $3( YPUG' J/)#%0*C( 6&, 5*%)'$,82 P,)F 5*$(,0C$#&* Z$)%#('L 0*% $he University of 
O0'3#*F$&*G' P,)F 5*$(,0C$#&* P0$0E0'(< 
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). 
 
Table 4-10 
List of QT prolonging drugs to be used with caution 
Drug 
QT risk 
Comment 


 
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Study No.  
 
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 
 


 
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Drug 
QT risk 
Comment 
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 
microspheres 
possible 
risk 
for 
Torsades 
de 
Pointes 
 
Protriptyline 
conditional risk for Torsades de 
Pointes 
 
Ranolazine 
possible 
risk 
for 
Torsades 
de 
Pointes 
 
Risperidone 
possible 
risk 
for 
Torsades 
de 
Pointes 
 


 
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Study No.  
 
Drug 
QT risk 
Comment 
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 
 
4.2.3.3 
QTc Calculation and Formula 
QTc interval is defined as the QT interval corrected for heart rate.  The following 
formula is to be used:  
!"# $ !" % &''()*%+
!"#$%&&'( )*+,-.#/
RR is the interval from the onset of one QRS complex to the onset of next QRS complex 
 
QT is the measure of time between the start of the Q wave and the end of the T wave in 
the heart's electric cycle. 
 


 
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4.3 
Visit schedule and assessments 
4.3.1 
Visit Schedule 


 
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Table 4-11  Evaluation and visit schedule 
 
Examination 
Scree
ning/ 
Baseli
ne 
Only for pts. 
undergoing 
biopsy: 
1 week run-
in (Days -7 
to -1)15 
After optional 
Washout 
period16 
Cycle 1  
(Days 1 to 
28) 
Cycle 2 
 
Cycle 3 and additional cycles 
Day of Cycle 
-28 ! 
-8 
-7 
C1 D1 
C1 
D15 
C2 
D1 
C2 
D15 
C3 
D1 
C3 
D15 
C4 
D1 
C4 
D15 
C5 
D1 
C5 
D15 
U 
EOT 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BKM12011 
 
VUUUUU>'+%$+*'*( daily &'($+8UUUUUUUUUUUUUUUUUUUUUUUUUHHV 
 
Cetuximab12 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
(accessible tumor 
only) 
X 
X14 
 
 
 
 
 
 
 
 
 
 
X
10 
 
Archival tissue QF10 
unstained slides)13 
X 
 
 
Research blood draw 
for normal DNA 
(part of routine draw) 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including skin rash 
assessment) 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Performance Status 
ECOG 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Neuro-psychiatric 
assessment (per the 
treating MD and/or 
self rating mood 
questionnaire)1 
X 
X 
XX17 
X 
X17 
X 
X 
X
  
 
X 
 
X 
 
X 
X 
MUGA 
Optional (only when indicated clinically)2 
12-lead ECG 
X 
 
As clinically indicated.  
Radiological tumor 
assessment/response 
assessment (CT 
Scans)4 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X
4 
X 
Hematology5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
6 
X 
Add-on Chemistry7 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Coagulation Profile8 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Fasting plasma 
glucose9 
X 
X 
X  
X 
X 
X
   
X
  
X 
X 
X 
X
  
X 
X 
X  
Serum Pregnancy 
Test (within 72h of 
starting drug, can be 
done on first day of 
treatment before 
taking BKM120) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Metformin Check3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
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1  If felt to be indicated by the treating physician PHQ-9 and GAD-7 questionnaires will be completed at each 
visit through the end of Cycle 2. Starting with Cycle 3, assessments are to be done on Day 1 of each cycle. 
Symptomatic patien%( QF RNRST 8-0&) 1D #*(% >'+%$+*) J$%7 W*)(%$'++0$-)( '+ 0 J))L,6 X0($( J7$,) 0>%$.)
on the treatment portion of the study. 
2 MUGA indicated ONLY in patients with a history of heart failure/symptoms of heart failure only. 
Reassessment at Cycle 4 and anytime cardiac symptoms occur should be considered. If indicated an 
echocardiogram may also be used, but preferred assessment is by MUGA (See section 4.1.2.3.1). 
3 Any elevated blood sugar level should trigger initiation of Metformin (e.g. 500mg po twice daily) 
or modification of the antidiabetic regimen (as per Table 4-1). Any history of hyperglycemia 
should trigger consideration of Metformin in order to prevent further hyperglycemia. 
4   Screening radiological assessments should be performed within 4-8 weeks of the first dose and at any 
time if respiratory symptoms occur.  Radiological tumor assessment should be performed at baseline within 
28 days before start of treatment and subsequently every 8 weeks, until progression of disease or end of 
treatment. All assessments should be performed within ±7 days of the scheduled day of assessment. The 
assessment at the EOT visit is only to be pe-4'-#)& $4 %7) <-$'- 0(()((#)+% '>>*--)& F 28 days before. 
Comparable alternative imaging modalities may be used (MRI/PET) if indicated. 
5 Hematology - WBC plus differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, 
basophil and other counts, hemoglobin and platelets. Should be performed on D1, and  D15 of cycle 1 and 2 
and day 1 of all subsequent cycles.   
6Serum chemistry: K+, Na+, Ca++, Mg++, bicarbonate, creatinine, BUN, ALT, AST, total bilirubin 
(fractionation only required if total bilirubin is >2, also if bilirubin is >2x NL GGT should be added), alkaline 
phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) 
7Serum chemistry add-on: total cholesterol (if abnormal add HDL, LDL, triclycerides), amylase (add lipase if 
amylase abnormal). All draws should occur within 48 hours of the intended visit. To be drawn at baseline, at 
cycle 2, cycle 3 and then every 4 cycles. 
8 Coagulation - PT or INR, PTT. To be drawn at baseline, at cycle 2, cycle 3 and then every 4 cycles. 
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. 
9 Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as 
clinically indicated. 
10 3rd Tumor biopsy is optional and should be performed at tumor progression in patients, who previously 
responded to treatment. 
11 BKM120 is given daily and self administered by the patient 
12 Cetuximab is given every 14 days starting cycle 1. During cycle 3 and thereafter patients continue to 
receive cetuximab every 2 weeks, but visits with the physician are only every 4 weeks. 
13 Can be substituted with tissue from the fresh biopsy (if sufficient material available) 
14 Tumor on-treatment biopsy (2nd biopsy) should occur after at least 6 days of BKM120 treatment. On the 
day of biopsy the BKM120 dose should be taken 2h before the scheduled biopsy, and the actual biopsy 
should occur 2-4h after the BKM120 dose. 
15 For patients who will undergo biopsy (accessible tumor) a 7-day run-in 
period with either BKM120 (100mg po daily) or no treatment will be done. 
Patients who do not undergo biopsy (archival tissue only) will skip the run-in 
period and start directly with Cycle 1 day 1. 
16 For patients who received BKM120 as part of the 7-day run-in period AND 
are part of the initial dose escalation cohort, there is a 3-8 day washout period 
(minimum 3 days, maximum 8 days) prior to starting combination treatment. 
Patients who do not receive BKM120 during the run-in period AND patients 
that will receive 100mg of BKM120 daily together with cetuximab (after the 
dose-escalation period) may proceed immediately with combination treatment. 
17 Cycle 1 Day 7, and Cycle Day 22 should include an additional neuropsychiatric assessment, which could 
either be done in the office, or if inconvenient for the patients (e.g. travel distance) via phone call. 
Shaded boxes indicate optional/facultative procedure -> see comments under 15/16 or protocol text. 
 
 
 


 
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4.3.2 
Efficacy assessments (Response) 
 
For the purposes of this study, patients should be reevaluated for response every 8 
weeks.  In addition to a baseline scan, confirmatory scans should also be obtained 4-6 
weeks following initial documentation of objective response. In the case of SD, 
follow-up measurements must have met the SD criteria at least once after study entry 
at a minimum interval of 12 weeks. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) (Eisenhauer EA et al, Eur J Ca, 2009).  Changes in 
the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
4.3.3 
Safety assessments  
Safety assessments will consist of monitoring and recording all adverse events and 
serious adverse events, the regular monitoring of hematology, blood chemistry 
values, regular measurement of vital signs and the performance of physical 
examinations. 
These assessments should be performed within ±2 days of the scheduled day of 
assessment except for adverse events that will be evaluated continuously through the 
study. Safety and tolerability will be assessed according to the NIH/NCI CTC 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf. 
Generally cetuximab has been well tolerated in combinations with other targeted and 
chemotherapeutic agents, and combinations of PI3K inhibitors with HER family 
blocking agents are now widely being investigated with not reported evidence of 
severe adverse events to date. Stringent dose reduction measures have been 
implemented (see Section 4.1, page 22). 
Section 5 describes the dose escalation schema and definition of dose limiting 
toxicities. 
Post-Biopsy patients will be followed closely for any evidence of complications. 
Dose delay/reduction rules will be closely followed as outlined (see Section 4.1, page 
22). In addition the PI may elect to further delay treatment if any serious concerns 
about wound healing or unexpected events should occur. 
 
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. 


 
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Study No.  
 
4.3.4.1 
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 the appearance or worsening of any undesirable sign, symptom, 
or medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen after starting 
study drug. Abnormal laboratory values or test results constitute adverse events only 
if they induce clinical signs or symptoms, are considered clinically significant, or 
require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of 
the patient at each visit during the study. Adverse events also may be detected when 
they are volunteered by the patient during or between visits or through physical 
examination, laboratory test, or other assessments. As far as possible, each adverse 
event should be evaluated to determine: 
1. the severity grade (mild, moderate, severe) or (grade 1-4) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication 
taken; 
non-drug 
therapy 
given; 
hospitalization/prolonged 
hospitalization) 
5. whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include 
changes in study drug treatment including possible interruption or discontinuation, 
starting or stopping concomitant treatments, changes in the frequency or nature of 
assessments, hospitalization, or any other medically required intervention. Once an 
adverse event is detected, it should be followed until its resolution, and assessment 
should be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
Information about common side effects already known about the investigational drug 
can be found in the [Investigator%/ Brochure]. This information should be included in 
the patient informed consent and should be discussed with the patient during the 
study as needed. 
4.3.4.2 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  Serious and 
expedited AEs reported as described below must also be reported in routine study 
data submissions. 


 
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4.3.4.3 
Serious adverse events 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
# is fatal or life-threatening 
# results in persistent or significant disability/incapacity 
# constitutes a congenital anomaly/birth defect 
# requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
# routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (specify what this includes) 
# elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since the start of study 
drug 
# treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 
# social reasons and respite care in the absence of any deterioration in the 
&'()7-(/% 67-7H', 8$-*)()$- 
# is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
# after the patient has provided informed consent and until 4 weeks after the patient 
has stopped study treatment/participation 
# after the patient is randomized and until 4 weeks after the patient has stopped 
study treatment 
# after the patient begins taking study drug and until 4 weeks after the patient has 
stopped study treatment 
# after protocol-specified procedures begin (e.g., placebo run-in, washout period, 
double-blind treatment, etc.) and until 4 weeks after the patient has stopped study 
treatment 
# after the start of any 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) 
and until 4 weeks 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 4-week period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. 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 


 
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Study No.  
 
completely unrelated to a previously reported one should be reported separately as a 
new event. 
The investigator must assess and record the relationship of each SAE to each specific 
study drug (if there is more than one study drug), complete the SAE Report in 
English, and send the completed, signed form by fax (877-778-9739) within 24 hours 
to the Novartis Drug Safety and Epidemiology Department. 
The original copy of the SAE Report and the fax confirmation sheet must be kept 
within the Trial Master File at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report 
Form was sent, using a new SAE Report Form stating that this is a follow-up to the 
previously reported SAE and giving the date of the original report. Each re-
occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was 
treated, whether the blind was broken or not (if applicable), and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the r>-=7%()6'($H/% 9H$8#0H7s or Package 
Insert (new occurrence) and is thought to be related to the Novartis study drug, a 
Drug Safety and Epidemiology Department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need 
to issue an Investigator Notification (IN), to inform all investigators involved in any 
study with the same drug that this SAE has been reported. Suspected Unexpected 
Serious Adverse Reactions (SUSARs) will be collected and reported to the competent 
authorities and relevant ethics committees in accordance with Directive 2001/20/EC 
or as per national regulatory requirements in participating countries. 
 
ALL Serious Adverse Events, whether or not they are considered related to the 
study agent MUST be reported to the sponsor-investigator and to the University of 
Chicago Comprehensive Cancer Center (UCCCC).  Refer to Section 4.3.6 for 
reporting guidelines.  
 
 
4.3.5 
Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
A serious adverse event is considered to be a suspected adverse reaction if there 
evidence to suggest a causal relationship to the study agent.  This may include a single 
occurrence of an event strongly associated with drug exposure (e.g. Stevens-Johnson 
Syndrome), one or more occurrence of an event otherwise uncommon is the study 
population, or an aggregate analysis of specific events occurring at greater frequency 
than expected. 
 
Unexpected events are those not listed at the observed specificity or severity in the 
protocol, consent, investigator brochure, FDA-approved package insert, or elsewhere in 


 
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Study No.  
 
the current IND application.  This includes adverse events listed in the protocol, consent 
$H >\m '% $880HH)-6 I)(#)- (#7 8,'%% $J *H06% $H $(#7HI)%7 7e&78(7* JH$K (#7 *H06/%
pharmacological properties but which have not been previously observed with this 
investigational agent.
ALL SUSARS occurring on this clinical trial must be reported to the FDA.  Refer 
to Section 4.3.8 for reporting guidelines. The UChicago CCTO will be responsible 
for all FDA communications on behalf of the IND Holder.  Individual sites should 
not submit any correspondences directly to the FDA.   
4.3.6 
Reporting Mechanism / Requirements for the University of 
Chicago Comprehensive Cancer Center 
 
All serious adverse events (as defined in section 4.3.4.3) and protocol violations/ 
deviations must be reported to the UCCCC Cancer Clinical Trials Office (CCTO) in 
accordance with the UCCCC Data Safety Monitoring Plan.   
 
The responsible party reporting the event (the RN/CRA at the University of Chicago or 
at a participating site) should notify the PI, the Medical Monitor at the University of 
Chicago and the University of Chicago Comprehensive Cancer Center Clinical Trials 
Office (CCTO). The RN/CRA should subsequently report the event to Novartis as 
required by regulation and agreement; this process is described below.   
 
Reporting must be performed within 24 hours of the investigator or staff becoming 
aware of the event by calling and e-mailing the QA Operations Coordinator at (773) 
702!0819 / qaccto@bsd.uchicago.edu as well as e!mailing the details of the event to the 
PI, the Medical Monitor and to the Regulatory Manager identified on the cover page. 
When sending in the 24!hour notification, please provide the following: 
! Your name, site name, and telephone number 
! Subject initials 
! Subject study number 
! U of C IRB protocol number 
! Lead Investigator of study 
! Treating physician 
! Date of event 
! Description of the event (including grade of the event, whether or not the event 
required hospitalization or resulted in the death of the patient).  
 
b,, Ob]/% H7&$H(% H76'H*,7%% $J 6H'*7 $H '((H)10()$- %#$0,* 17 %7-( ($ Novartis 
Pharmaceuticals. See section 4.3.10 below 
 
L#7 Ob] H7&$H( %#$0,* ',%$ 17 %01K)((7* ($ (#7 )-%()(0()$-/% >M9 '88$H*)-6 ($
institutional guidelines (see 4.3.7). 
 


 
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4.3.7 
Reporting Requirements for the Institutional Review Board  
 
At the University of Chicago: Events meeting current IRB reporting criteria must be 
submitted by the principal investigator via (#7 >M9/% 7,78(H$-)8 %01K)%%)$- %+%(7K 
within %.) /012* -)*&3$4%)- ()5+(%&$3 %&6eframesY
m7('),% $J (#7 >M9/% 80HH7-(
reporting 
policy 
and 
timelines 
can 
be 
found 
on 
their 
website 
at: 
http://bsdirb.bsd.uchicago.edu/forms-guidelines/up.html 
 
The responsible research nurse and/or clinical research associate/data manager are 
H7%&$-%)1,7 J$H 7-(7H)-6 (#7 '&&H$&H)'(7 )-J$HK'()$- )-($ (#7 >M9/% 7,78(H$-)8 %01K)%%)$-
system and forwarding the submission to the principal investigator for reporting to the 
IRB.  
 
At other centers: the respective current IRB reporting criteria should be used ! and 
should be comparable to the requirements listed above for the University of Chicago. 
4.3.8 
Reporting Requirements for the FDA 
 
!"#$ $%&'( )#** +, -./'&-%,' &/',0 1/ 234 ",*' +( !1/5&( 6,#),0%7 84 1% %", 9/#:,0$#%( .;
<"#-15.=
 
Per 21 CFR 312.32, the sponsor-investigator is required to notify the FDA and all 
participating investigators of potential serious risks within 15 calendar days of 
determining the information meets FDA reporting requirements.   
 
Unexpected fatal or life-threatening suspected adverse reactions must be reported to the 
FDA by the sponsor-investigator via phone or fax within 7 calendar days.   
 
Current FDA regulations require that all SUSARs (see definition in section 4.3.5) 
occurring on this trial, other findings that suggest a significant risk to humans exposed to 
the investigational drug (e.g. information from pooled analysis of multiple studies), and 
any clinically significant increase in the rate of an expected serious adverse reaction be 
reported as an IND Safety Report.  Refer to Table A below for guidelines for reporting 
these events to the FDA. 
 
In order to meet these requirements, the sponsor-investigator will review all reported 
serious adverse events as they occur and will conduct a literature search to seek new 
safety information and review and analyze all safety information from this clinical trial 
at least annually and more frequently as appropriate. 
 
 
 
 
Table A:  Reporting Requirements 
 


 
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Report Type 
Method of Report 
Responsible 
Party 
Timeline1 
Fatal/Life-Threatening Event 
Yes 
No 
Individual Report 
Form 3500A (MedWatch)7 
RN/CRA 
4 calendar days5 
10 calendar days5 
Other Findings that 
Suggest Significant Risk2 
Narrative3 
PI 
4 calendar day6 
10 calendar days6 
Clinically Significant 
Increased Frequency of 
Suspected Adverse 
Reactions4 
Narrative 
PI 
4 calendar days6 
10 calendar days6 
1: Report Due to CCTO IND Coordinator according to the specified timeline regardless of whether or not all information 
regarding the event is available.  If applicable, a follow-up report should be provided to the IND Coordinator once additional 
information on the event is available.   
2: An IND Protocol Amendment is also required to describe any changes to the protocol, consent, or overall conduct of the study 
made as a result of this information.  All revised documents should be made available to the CCTO IND Coordinator at the time 
of IRB submission. 
3: Copy of relevant publication(s) should be included if applicable.  
4: Details of individual cases should be included as appropriate 
5: From date event was reported to the sponsor-investigator 
6: After information is received by the investigator and determined to meet reporting criteria 
7: Copy should be maintained in the subject research chart and master IND file in the CCTO.  
 
 
All other events (e.g. protocol deviations or other safety concerns) not meeting the 
requirements for IND Safety Reporting (per 21 CFR 312.32) but which require reporting 
to the IRB as an Unanticipated Problem will be reported to the FDA as an informational 
amendment or with the annual report as appropriate. 
 
4.3.9 
Data and Safety Monitoring 
 
Data Safety and Monitoring (DSM) will occur at the weekly University of Chicago Head 
and Neck meetings, which are led by senior level medical oncologists. At each meeting, 
all active studies are reviewed for safety and progress toward completion. Toxicities and 
adverse events will be reviewed at each meeting and a Data Safety and Monitoring form 
documenting the discussion outcome with respect to patient safety, risk level and study 


 
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Study No.  
 
continuation will be filled out for this protocol and signed by either the principal 
investigator, or by his designate if not available.  
 
The study will be audited as per the Audit Program described in the UCCCC Data Safety 
Monitoring Plan.  Patient charts will be audited for protocol compliance items including 
eligibility, completion of procedures, administration of treatment, reporting of toxicities, 
documentation of response, follow-up, data-collection, record keeping, and the 
collection of quality of life and correlative studies.  
 
All participating institutions will receive a trial summary every Monday that will be 
transmitted by e-mail to the principal investigator at the affiliate site. This summary will 
inform the affiliate institutions of the following: 
 
# Number of patients accrued to the protocol, both 
# Number of openings available 
# Any change in the status of the protocol including temporarily on-hold and closed to 
accrual 
# DSM meeting minutes  
 
4.3.10 
Novartis instructions for rapid notification of serious adverse 
events 
The principal investigator has the obligation to report all serious adverse events to 
Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). 
Applicable events will be reported to the IRB and FDA as per their current policies. 
All events reported to the FDA by the investigator are to be filed utilizing the Form 
FDA 3500A (MedWatch Form).  
All 
events 
must 
be 
reported, 
by 
FAX 
(877-778-9739) 
to 
Novartis 
Pharmaceuticals DS&E Department within 24 hours of learning of its 
occurrence. This includes serious, related, labeled (expected) and serious, related, 
unlabeled (unexpected) adverse experiences. All deaths during treatment or within 30 
days following completion of active protocol therapy must be reported within 5 
working days. 
Any serious adverse event occurring after the patient has provided informed consent 
and until 4 weeks after the patient has stopped study participation must be reported. 
This includes the period in which the study protocol interferes with the standard 
medical treatment given to a patient (e.g. treatment withdrawal during washout 
period, change in treatment to a fixed dose of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need 
only be reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious 
adverse experiences will be forwarded to the product manufacturer by the 
investigator. 


 
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4.3.10.1 Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up for 3 months after the termination of the pregnancy 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 (DS&E) 
department. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the Novartis study treatment of 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took 
study treatment in this study. Consent to report information regarding these 
pregnancy outcomes should be obtained from the mother. 
 
The team needs to prepare information for the female partner of the male patient on 
required contraception. This information needs to be given to the male patient at the 
ICF signing for him to share it with his female partner.  
 
Information for female partners of male study participants 
Your male partner is offered to participate in a clinical research study. As a 
prerequisite to participate in this study your partner must agree to use a condom 
during intercourse. This is important because test results of the study treatment in 
pregnant animals indicated that the medicine can harm an unborn baby through the 
sperm. At the same time it is also important that you do not become pregnant while 
your partner is taking the medication. Therefore, you should use a highly effective 
method of birth control (contraception) during the time your male partner receives the 
study treatment and thereafter for another 3 months. Highly effective methods of 
contraception are those methods of birth control that have less than 1% of unwanted 
pregnancy during one year, if used appropriately according to the instructions of the 
manufacturer. 
Those methods are the following: 
 
a)  Placement of an intrauterine device (IUD) or intrauterine system  
(IUS) 


 
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b) Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/vaginal suppository 
 
# Oral contraception, injected or implanted hormonal methods are not 
allowed as BKM120 potentially decreases the effectiveness of hormonal 
contraceptives. 
 
# Fertile males, defined as all males physiologically capable of conceiving 
offspring must use condom during treatment, for 4 weeks (5 T1/2)  after 
stopping treatment and for additional 12 weeks (16 weeks in total after 
study drug discontinuation) and should not father a child in this period.  
 
# Female partner of male study subject should use highly effective contraception 
during dosing of any study agent and for 16 weeks after final dose of study 
therapy. 
 
For details on the most appropriate contraception you may talk to your regular doctor 
or if your male partner agrees with the study doctor. 
 
If you get pregnant despite taking the birth control precautions, please ask your 
partner to inform the study doctor as soon as possible. The study doctor will ask your 
permission to collect information about you, your pregnancy and your child. 
 
4.3.10.2 Laboratory evaluations 
Pregnancy Test 
A serum pregn'-8+ (7%( ?A-HCG) is required for all women of child-bearing potential 
at screening, within 72 hours prior to the first dose of BKM120 (can be done just 
prior to the first administration of BKM120 (Day -7). Note: Postmenopausal women 
must have been amenorr#7)8 J$H ` 2< K$-(#% )- $H*7H ($ 17 8$-%)*7H7* [$J -$--
8#),*17'H)-6 &$(7-()',^Y L#)% %#$0,* 17 *$80K7-(7* '&&H$&H)'(7,+ )- (#7 &'()7-(/%
medical history.  Additional pregnancy tests should be performed if 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. 


 
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Coagulation Profile 
The coagulation profile includes prothrombin time or INR, and activated partial 
thromboplastin time. 
Serum chemistry 
Biochemistry includes the following parameters: K+, Na+, Ca++, Mg++, ALT, AST, 
total bilirubin (if abnormal: direct and indirect), creatinine, GGT (only in case of 
elevated bilirubin), alkaline phosphatase (fractionated if alkaline phosphatase is grade 
2 or higher), bicarbonate, glucose, urea or BUN  
The add-on chemistries will be performed less frequently and include: total 
cholesterol (if abnormal add on: HDL, LDL, triglycerides), amylase (if abnormal add  
lipase), 
All draws should occur within 48 hours of the intended visit.  
Because accurate serum glucose and lipid measurements are required, patients should 
be fasting at the time of the blood sampling. 
 
4.3.10.3 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 in the sitting position as per the visit schedule.  
4.3.10.4 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. 
4.3.10.5 Neuropsychiatric assessments 
Patient self-rating mood questionnaires for anxiety and depression (PHQ-9, GAD-7) 
will be applied if deemed indicated by the treating physician and can be initiated at 
the following time points: 
l O8H77-)-6 and Day -7 
l m'+% 1 and 15 of Cycle 1 
l m'+ 2 and 15 of Cycle 2 
l m'+ 2 $J E+8,7 . and subsequent cycles (only for patients who have not shown 
mood alterations during the first 2 cycles, patients who did should continue to fill out 
the questionnaire on a weekly base). 


 
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Study No.  
 
l ]-* $J O(0*+ (H7'(K7-( 
Additional assessments may be done according to the clinical judgment of the 
Investigator. O+K&($K'()8 &'()7-(% ?` ELEb] 6H'*7 2D K0%( 8$-()-07 I)(#
questionnaires on a weekly basis while active on the treatment portion of the study. 
Instructions on how to instruct the patient to complete the questionnaires as well as 
how to determine the scores will be provided together with each instrument. 
 
4.3.10.6 ECG and MUGA 
A standard 12 lead ECG is to be performed at screening and as clinically indicated.   
MUGA will only be performed to assess eligibility in patients with a history of heart 
failure / hear failure symptoms to determine eligibility. MUGA may be repeated  
anytime clinically indicated e.g. if symptoms of heart failure develop.  An 
echocardiogram (ECHO) may be performed alternatively if a MUGA is 
contraindicated. See section 4.1.2.3.1 for additional details. 
 
4.3.10.7 Performance status 
Performance status will be assessed at screening and per the visit schedule using 
ECOG scale (Appendix A). 
 
4.4 
Correlative Studies and Tissue Collection Tumors  
 
While requirements for tissue and correlational studies are clearly stated and are to be 
implemented stringently, medical necessity, e.g. in the case of potential harm to the 
patient, or other extenuating circumstances may trigger a review and possible waiver per 
the PI on rare occasions. 
4.4.1 
Assessment of Accessible tumor 
Tumors in the upper aerodigestive tract and larger metastatic deposits in other organ 
systems (e.g. a large peripherally located lung metastasis) without undue risk medical 
risk are considered accessible for biopsy. Patients with accessible tumors that are 
deemed safe for biopsy are mandated in order to participate in the protocol to undergo an 
initial (pretreatment) and second on-BKM treatment biopsy (run-in period). A third 
biopsy during the combined treatment is optional. The PI and the treating physician will 
decide whether a tumor lesion is considered accessible prior to initiation of therapy, and 
this assessment is only to updated if the patients disease status or medical status changes 
significantly. 
4.4.2 
Archival Tissue and Blood. 
All patients are required to &H$=)*7 `10 unstained FFPE slides (18-20 slides is 
considered ideal). This requirement can be waived ONLY if a fresh tumor biopsy 
provides adequate tissue.  


 
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Furthermore all patients are required to collect blood for banking of normal DNA  
! See Appendix B for tissue collection form 
4.4.3 
Tumor Biopsies 
Based on clinical examination and/or review of cross-sectional imaging and ENT 
%0H67$- I),, K'i7 (#7 '%%7%%K7-( I#7(#7H ' (0K$H )% n'887%%)1,7/ $H n)--'887%%)1,7/
for biopsy. Tumors that have been deemed to be accessible for biopsy will be 
biopsied by an ENT surgeon (excisional biopsy or core needle biopsy) or via 
interventional radiology (core biopsy). A large (several pass) bronchoscopic biopsy is 
potentially also acceptable, but a discussion about the amount of required tissue 
between the PI and the pulmonary attending performing the procedure is required 
prior to biopsy. Other specialties (e.g. surgeons from other organ areas) may also be 
involved in obtaining tissue/biopsies.  
The first and second biopsy are mandatory in patients with accessible tumor, the third 
biopsy is to be considered in patients who previously responded and subsequently 
progressed. The third biopsy may also be obtained in patients without prior biopsy (in 
setting of prior response and subsequent progression). 
 
4.4.3.1 
Timing of biopsies 
The timing of biopsies can be handled flexibly as long as the following requirements 
are fulfilled. 
Pre-treatment Biopsy: 
# Pretreatment biopsy occurs prior to administration of first dose of BKM120 
On-treatment Biopsy / 2nd Biopsy: 
# On treatment biopsies (2nd biopsy) should occur at least 6 days after initiation 
of treatment with BKM120 
# The PI can extend the run-in period by up to 10 days if required in order to 
allow the mandatory 2nd biopsy 
# On the day of the biopsy the dose of BKM120 should be administered 2 hours 
prior to the planned biopsy, and the actual biopsy should occur 2-4 hours after 
administration of BKM120. 
3rd Biopsy: 
# The third biopsy should be taken at any time point after progression on 
BKM120/cetuximab is demonstrated 
 
4.4.3.2 
Biopsy safety considerations 
Biopsies (Core biopsies and small excisional biopsies) are generally considered safe 
during administration of treatment (based on prior experience with cetuximab). 


 
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Nevertheless in difficult to assess/high risk locations the treatment should be held for 
2-5 days prior to resuming therapy. For larger scale surgeries or should bleeding or 
wound healing complications arise the PI can decide to continue holding therapy and 
will assess how long to hold treatment on a cases by case basis. 
 
4.4.4 
Correlative Studies 
The following correlative studies are planned and are mentioned in the consent form 
for patients. Since correlative studies are not covered under the current clinical trial 
budget additional internal funding will be sought via the University of Chicago 
Cancer Center, CTSA grant, or other funding agencies. Such a follow-up proposal 
will contain the detailed methodology. At a minimum assessment of PIK3CA 
mutation status (Sanger Sequencing), and PTEN expression (IHC) will performed 
even in the absence of additional funding. 
At baseline (archival tissue, or obtained from a new biopsy): 
1. PI3K related mutation testing (PIK3CA, but additional PI3K members/related 
genes may be tested). Anticipated analysis methods: Sanger sequencing of 
PIK3CA (or equivalent method; subject to change) 
2. PI3K related copy number testing (PIK3CA). Anticipated analysis methods: 
qPCR of PIK3CA gene (or equivalent method; subject to change) 
3. HRAS mutation testing; Anticipated analysis methods: Sanger sequencing of 
HRAS (or equivalent method; subject to change) 
4. Evaluation of PTEN/INPP4B evaluation (other tumor suppressors may also be 
evaluated); Anticipated analysis methods: Immunohistochemistry (or 
equivalent method; subject to change) 
5. HPV status; Anticipated analysis methods: p16 immunohistochemistry or 
HPV ISH (or equivalent method; subject to change) 
6. Normal and Tumor RNA and DNA and protein for possible additional studies 
(Patients to specifically consent to banking). Studies could involve more 
advanced genomic analyses including array based approaches or next 
generation sequencing. 
New biopsies in addition will be assessed for the following: 
1. RTK phosphorylation; Anticipated analysis methods: PamGene Kinase Array 
Platform available in the Seiwert/Salgia Laboratories (or equivalent method; 
subject to change). We will specifically look for an increase (from 
baseline/pre-treatment biopsy) in: 
a. pEGFR 
b. pHER3 
c. pIRS1 


 
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2. Apoptosis/Autophagy evaluation; Anticipated analysis methods: TUNEL 
staining (e.g. TUNEL apoptosis detection kit (GenScript), or an equivalent 
method; subject to change) 
3. Differential gene expression; Anticipated analysis methods: gene expression 
arrays (or equivalent method; subject to change) 
4. P-4EBP1 staining; Anticipated analysis methods: Immunohistochemistry (or 
equivalent method; subject to change) 
 
5 
STUDY DESIGN 
The study will consist of two separate phases: a dose-escalating Phase I study followed 
by a fixed dose expansion cohort. 
5.1 
Design of the 1-week Run-In period 
Patients will be randomized between BKM120 given at the recommended Phase II dose 
(Bendell et al 2012) of 100mg daily, or no treatment (non-blinded) and after one week 
will undergo biopsy (both BKM120 and untreated cohort). 
 
Patients treated with BKM120 will have a one week wash-out period (can be prolonged 
if side effects require as per the treating physician). 
Patients not treated with BKM120 may start combination treatment immediately ! either 
as part of the dose escalation cohort (see 5.2) or the Expansion Cohort (see 5.3).  
5.2 
Design of the Dose Escalation Cohort 
The dose escalation phase will assess the safety and tolerability of BKM120 in 
combination with cetuximab in up to 12 patients. 
With the exception of rash there are no significant overlapping toxicities between 
cetuximab and BKM120 (Bendell et al 2012), and prior experience with combination of  
the PI3K inhibitor PX-866 with cetuximab have been well tolerated at full dose of both 
agents (Senzer et al 2011 AACR-NCI-EORTC meeting A174). Combination of BEZ235 
with the HER2 antibody Trastuzumab has also been well tolerated (Krop et al.J Clin 
Oncol 30, 2012 (suppl; abstr 508)) 
Based on experience in other BKM120 combination studies and discussion with 
Novartis we will initiate treatment of BKM120 at 80% of the Phase I defined phase II 
dose (Bendell et al 2012): 80mg; subsequently we will dose escalate to 100mg (= 
recommended Phase 2 dose) at the next dose level (see below). BKM120 dose may be 
reduced down to 60mg as needed, and per the guidance of Novartis no dose level lower 
than 60mg should be used. 
 


 
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5.2.1 
Determination of the Maximum Tolerated Dose (MTD) 
Patients will be carefully assessed with regards to safety and tolerability, using 
NCI Common Terminology Criteria (Cancer Therapy Evaluation Program (CTEP) 
CTCAE, Version 4.0).  
The starting dose of BKM120 will be 80mg daily in combination with full dose 
of cetuximab given biweekly (500mg/m2) 
 
There will be no intra-patient dose escalation. Dose escalation will proceed 
according to a standard "3+3" design.  That is, three patients will be entered at 
each dose level and if 0 out of 3 develop a DLT, three patients will be entered at 
the next higher dose level.  If 1 out of 3 experiences a DLT, three more patients 
will be entered at the same dose level for a total of 6.  Then if none of these three 
has a DLT dose escalation will continue.  If > 2 of the 3-6 patients treated in a 
cohort experience a DLT, dose escalation will stop and three additional patients 
will be entered at the next lowest dose level (see BKM120 dose levels Section 
4.1/Table 4-0) if only three patients were treated previously at that dose.  Dose 
escalation is allowed to proceed if all patients have completed at least 4 weeks of 
active treatment and DLT assessment has been completed.  
 
No BKM120 dose above the recommended single agent dose of 100mg daily will 
be used. 
 
Based on toxicities, feasibility, and clinical impression the dose level for the 
expansion cohort will be determined 
5.2.2 
Dose Escalation Schematic: Dose escalation cohorts and 
timing for enrollment. 
DOSE LEVELS 
BKM120 
dose  
Cetuximab dose 
First Dose Level 
N = 3-6 
80mg daily 
(BKM dose 
level 0) 
500 mg/m2 administered every 2 weeks 
(Cetuximab dose level 0) 
Second Dose Level  
N = 3-6 
100mg daily 
(BKM dose 
level 1) 
500 mg/m2 
administered every 2 weeks 
(Cetuximab dose level 0) 
Expansion cohort 
 
MTD or 
100mg daily 
500 mg/m2 administered every 2 weeks 
(Cetuximab dose level 0) 
Also see Section 4.1, Table 4-0 for dose levels and dose reductions. 
5.2.3 
Definition of the Dose-Limiting Toxicity (DLT) for the Dose 
escalation Phase 
DLT is defined as: 
(1) Any grade 3 or higher non-hematologic toxicity occurring up to 2 weeks after 
the last administration of BKM120 and cetuximab, with the following 
exceptions: 


 
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i. Hyperglycemia ! to be managed as outlined in Table 4-1 
ii. Common cetuximab side effects (rash, hypomagnesemia, infusion 
reactions) that are manageable as outlined in Tables 4-1 and 4-2  
iii. Neuropsychiatric side effects attributed to BKM120 treatment 
amenable to treatment 
iv. Thrombotic events related to indwelling catheters or the underlying 
cancer 
v. Grade 3 diarrhea, nausea, rash, pruritus, and similar events amenable 
to readily available, and effective treatment such as anti-diarrhea, 
anti-nauses, anti-rash, and anti-pruritus medications/treatments. 
(2) Grade 4 thrombocytopenia, neutropenia, anemia  
(3) Intolerable grade 2 and/or intolerable 6H'*7 ` . -70H$%&+8#)'(H)8 %+K&($K% 
 
5.3 
Design of the Expansion cohort 
A total of 18 to 27 patients will be entered into the expansion cohort of the study. 30 
patients in total including both dose escalation and expansion cohorts will be enrolled.   
 
6 
Registration Procedures and Data Management 
6.1 
Guidelines for Lead Institution 
 
All patients should be registered by the responsible Clinical Research Associate and/or 
Research Nurse in the eVelos Database prior the start of protocol treatment.  All 
selection criteria listed in Section 3.2.2 should be confirmed prior to registration.  
 
6.2 
Guidelines for other participating institutions 
 
Eligible participants will be entered on study centrally at the University of Chicago 
by the Lead Clinical Research Associate.  All sites should confirm all selection 
criteria listed in Section 3.2.2 and then complete the subject Registration Form 
and call the Coordinating Center at 773-702-2068 or 773-702-2319 or email 
adekker@medicine.bsd.uchicago.edu or jsteinkamp@medicine.bsd.uchicago.edu 
with the following information prior to start of study.  
 
# 
Provider of information 
# 
Study # and Institution 


 
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Study No.  
 
# 
Treating Physician 
# 
Patient name/initials and hospital ID number 
# 
Patient's zip code of residence 
# 
Date of signed informed consent 
# 
Gender 
# 
Date of birth of patient 
# 
Diagnosis and date of initial diagnosis 
# 
Anticipated start of treatment 
 
A confirmation of registration will be issued by the lead site upon receipt of the 
completed registration form. 
 
Participants MUST be registered with the Lead Institution prior to the start of 
protocol treatment.   
6.3 
Data collection 
Investigators must record the information required by the protocol. Data collection 
will occur at the University of Chicago using the existing clinical trials infrastructure 
and clinical trials data management system (eVelos).  
 
7 
Statistical methods 
7.1 
Statistical methods 
7.1.1 
Criterion for Success/Primary Objectives 
 
# One week Run-In (randomized): 
Induction of compensatory signaling/feedback loop signaling after one week of 
BKM120 (run-in) compared to patients not treated with BKM120 (see below for 
details on measurement and power calculation) 
# Combination treatment: 
Safety and tolerability of combined treatment with BKM120 and cetuximab 
 
 
7.1.2 
Evaluation of Primary Objectives 
 
# One week Run-In (randomized): 
Measurement of pEGFR** will be performed using snap frozen tissue samples using 
the well-established PamGene Kinase array platform available in the Salgia/Seiwert 
laboratories (also see Section 4.4.4). 


 
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The PamGene kinase assay will be performed in triplicates in the initial cases to 
confirm technical reproducibility. Based on prior experience technical reproducibility is 
less than one standard deviation (typically 10-15%)*. 
The difference in phosphorylation baseline to on-treatment will be calculated and 
normalized to achieve a near normal distribution of values. 
Since the effect size is anticipated to be significant we expect an effect size of at 
least two standard deviations (see below table for additional considerations including an 
effect size of 1.5). 
We will enroll patients to achieve a minimum of 12 evaluable biopsies (6 per arm), 
and will aim for 14-18 biopsies as feasible. 
 
Group samples sizes of 6 and 6 achieve 88.9% power to detect a difference of 2 
standard deviations between the null hypothesis that both group means are 0 and the 
alternative hypothesis that the mean of the combination group is 2 with estimated group 
stand deviations of 1 and 1 and with a significance level (alpha) of 0.05 using a two-
sided two-sample t-test. 
Should the number of patient biopsies vary power changes accordingly based on 
a ! two-sided two-sample t-test: 
Power 
N1 
N2 
Alpha 
Beta 
Mean1 
Mean2 
SD1 
SD1 
85% 
9 
9 
0.05 
0.15 
0 
1.5 
a2u 
a2u 
80% 
8 
8 
0.05 
0.20 
0 
1.5 
a2u 
a2u 
89% 
8 
8 
0.10 
0.11 
0 
1.5 
a2u 
a2u 
94% 
7 
7 
0.05 
0.06 
0 
2 
a2u 
a2u 
89% 
6 
6 
0.05 
0.11 
0 
2 
a2u 
a2u 
81% 
5 
5 
0.05 
0.19 
0 
2 
a2u 
a2u 
82% 
4 
4 
0.10 
0.18 
0 
2 
a2u 
a2u 
*Based on prior experience technical reproducibility is less than one standard deviation 
(typically 10-15%)*. 
** While based on preclinical data pEGFR is anticipated to be the most informative 
marker, the PamGene array platform provides information about other pTyr kinases. In 
the case that the related marker pHER3 or another marker e.g. pIRS1 are felt to be a 
more reliable indicators of feedback these markers may be substituted for pEGFR. 
# Combination treatment: 
Safety and tolerability will be assessed using a 3+3 design as outlined in Section 5. 
In addition we will perform a descriptive analysis of safety and tolerability for the 
expansion cohort also. Severe adverse events will be monitored during the entire trial 
period and in addition to the analysis of the dose expansion phase will be analyzed at 
the end of the trial for the entire trial cohort. 
 


 
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7.1.3 
Evaluation of Secondary Objectives 
7.1.3.1 
Apoptosis induction 
Apoptosis will be measured by TUNEL assay on FFPE sections (using a 
commercially available kit (e.g. TUNEL apoptosis detection kit (GenScript), or an 
equivalent method) in a descriptive manner. Since variability is expected to be high, 
and most patients will not show evidence of apoptosis, the description of the an 
increase in the rate of apoptosis will be only descriptive. An absolute increase of 
`23p ?7Y6Y Wp ! 15%) and relative increase of 33%) will be considered meaningful. 
In such cases the underlying genotype (PIK3CA mutations etc.) will be reviewed and 
examined for a possible correlation (descriptive).  
 
7.1.3.2 
Response / Tumor Shrinkage 
 
1) Response `W &'()7-(% H7%pond (RECIST) 
2) Induction of responses in patients with prior EGFR failure/ EGFR stability 
3) Biomarkers 
 
- Generally agents with a response rate below 5-10% are considered of limited benefit 
and further development of a single agent is difficult. Alternative approaches such as 
combination strategies or investigation of subgroups analysis (e.g. gefitinib in HNC) 
are indicated. 
- P$H Q\E ' H7%&$-%7 H'(7 $J `25-20% would be considered clinically meaningful, 
especially if responses can be induced in patients with SD or PD while being treated 
with cetuximab. 
- For comparison:  
! Cetuximab response rate is 7-13% (Vermorken et al. 2007; Seiwert et al 2012) 
! We anticipate that ~50% of patients in this study will have been pretreated 
with cetuximab, or a cetuximab combination. The expected outcome after 
failure of an EGFR inhibitor is very poor; e.g. in a phase II study of 
lapatinib in HNC patients previously treated with an EGFR inhibitor no 
responses were observed and progression free survival was 52 days (de 
Souza et al. 2012).  
 
! 1) Secondary efficacy endpoint: Response rate 
- P0=0.06   (a poorly effective targeted therapies in the 2nd line setting is estimated to 
have a response rate of 6% (assuming 7-13% in cetuximab naïve patients and close to 
0% in cetuximab resistant patients when treated with single agent cetuximab). 
- "2`3Y<3
?8,)-)8',,+ K7'-)-6J0, ',(7H-'()=7 H7%&$-%7 H'(7D 
 
A sample size of 30 achieves 74% power to detect a difference (P1-P0) of 0.1400 
using a one-sided binomial test. The target significant level is 0.0500. The actual 
significance level achieved by this test is 0.0315. These results assume that the 
population proportion under null hypothesis is 0.0600. 
If the number of responders is 5 or more, the null hypothesis is rejected and drug 


 
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called efficacious. 
 
! 2) Secondary efficacy endpoint: Response rate in patients with prior EGFR 
failure 
The prognosis of patients after EGFR failure is very poor (DeSouza et al 2012). Since 
there is no established standard of care after EGFR failure and no targeted therapies 
have proven benefit/activity, response rate in this patient population will be compared 
to a 0% response rate (DeSouza et al, 2012). 
 
Secondary endpoint: Tumor Shrinkage  
Tumor shrinkage will be visualized as a waterfall plot for graphical (qualitative) 
comparison. 
 
! 3) Biomarkers 
We will also fit logistic and Cox (JRSS, 1972) proportional hazards regression 
models to examine the effects of laboratory correlates (Biomarker positive group 
versus biomarker negative group) on response/tumor shrinkage in an exploratory 
fashion. 
 
7.1.3.3 
Overall and Progression free survival 
Kaplan-Meier curves will be generated for overall (OS) and progression free survival 
(PFS) and compared in an exploratory fashion to respective PFS and OS data from a 
prior study of afatinib and cetuximab as single agents in the recurrent metastatic 
disease setting (Seiwert et al, 2012) using a logrank test. We will also fit logistic and 
Cox (JRSS, 1972) proportional hazards regression models to examine the effects of 
laboratory correlates on PFS, and OS in an exploratory fashion. 
 
7.2 
Follow-up trial 
As discussed with the study sponsor and depending on data consistent with significant 
activity the possibility of a follow-up trial or amendment to this trial may be 
considered. 


 
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8 
APPENDICES 
8.1 
Appendix A: 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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8.2 
Appendix B: Tissue Sample Collection Form 
 
BKM120/Cetuximab -- HNC 
Clinician/Research Nurse: Please Fill Out 
Tissue Samples 
Patient Name: ___________________  
 MRN# (if applicable): _______________ 
Patient Protocol ID #: ______________  
Date Tissue Obtained: _________________ 
Institution: ______________________________         Attending Physician: 
__________________ 
Site of Biopsy: ___________________________ Site of Primary Tumor: _______________ 
 
Did Surgical Pathology review tissue for presence of tumor (please circle)?  Yes   No 
Y*#X)- '4 *+(%0$+)& (,$&)( QF10 slides (5 "m thick), 12-18 ideal):___________ 
Frozen Sample from biopsy:  [ ] Pre-treatment;     [ ] Run-in/2nd biopsy; Day:___  
                                                                                        after treatment initiation       
                                       [ ] 3rd Biopsy 
 
Blood collection (please check):  
 
2 EDTA tubes (purple top, serum), 2x10ml: ___        1 SST tube 7.5ml  (gold top):_________  
(e.g. BD#366643 EDTA (K2))                                    (e.g BD#: 367987 SST, 7.5ml)__ 
                                                                                    (If volume <7.5ml provide add. tube/s)__ 
 
Date of blood draw: ________________      Time of blood draw:_____________ 
R'+%0>% A)-('+=( A7'+) Y*#X)-B<08)-B)#0$, 0&&-)((; 
 
Dept. of Pathology (University of Chicago) 
Tissue Bank Intake Coordinator 
5841 S Maryland, MC 3083 
Chicago, IL 60637 
Phone 773-834-8392 or 773-702-0119 
 
Please notify Dr. Seiwert once the sample was submitted: 
Email: tseiwert@medicine.bsd.uchicago.edu; or call tissue bank Tel: 773-599-7501