Conditions: Thymoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
Thymic tumors are rare tumors, but represent the most common tumors of the anterior mediastinum. Thymoma has an indolent course in advanced disease and has the propensity to spread to the pleura. In first line therapy, combination chemotherapy produces responses in approximately 80% of patients. A number of single agents have activity in recurrent disease, but none are curable. Patients with recurrent thymoma have limited treatment options, and thus novel target modalities are needed.

At the Indiana University Simon Cancer Center (IUSCC), more patients with advance thymoma are seen than any other institution in the country. Our main hypothesis is the PI3K pathway is an important driver for growth and metastasis of thymoma and that inhibition of the PI3K pathway is expected to produce clinically meaningful response in patients with recurrent thymoma.

Detailed description:

Arms:
arm 1: BKM120, 100mg capsule for oral use, taken once daily for two or more months for a maximum of one year. Each cycle is 28 days.

Interventions: intervention 1: BKM120
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
A Phase II Study of BKM120 (Buparlisib) in Relapsed or Refractory 
Thymomas 
 
Study no. IUCRO-0478 
Version no. 4 
Protocol Date: July 13, 2015 
Amendment 1: September 17, 2015 
Amendment 2: 1/24/2017 
Coordinating Center: 
 
Indiana University Simon Cancer Center 
 
 
Principle Investigator: 
Patrick J. Loehrer, Sr., MD 
Director, Indiana University Simon Cancer Center 
535 Barnhill Drive, Room 473 
Indianapolis, IN 46202-5289 
Telephone: 317-274-3539 
Fax: 317-278-4190 
E-mail: ploehrer@iupui.edu 


 
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Table of Contents 
Table of Contents ................................................................................................................ 2 
List of Abbreviations ........................................................................................................... 4 
1 
Background .......................................................................................................................... 7 
1.0 
Disease Background ................................................................................................ 7 
1.1 
BKM120 .................................................................................................................. 7 
1.2 
PI3K Pathway and Mechanism of Action ............................................................... 8 
1.2.1 
Preclinical Studies ................................................................................... 9 
1.2.2 
Clinical Experience ............................................................................... 12 
1.3 
Study Rationale ...................................................................................................... 22 
2 
Study Objectives ................................................................................................................ 26 
3 
Exploratory Investigational plan ....................................................................................... 26 
3.0 
Overall Study Design ............................................................................................. 26 
3.1 
Study Population .................................................................................................... 27 
3.1.1 
Patient Population ................................................................................. 27 
3.1.2 
Inclusion and Exclusion Criteria ........................................................... 27 
4 
Treatments ......................................................................................................................... 32 
4.0 
BKM120 Administration ....................................................................................... 32 
4.1 
Concomitant Therapy ............................................................................................ 33 
4.1.1 
Drugs that are Prohibited ...................................................................... 33 
4.1.2 
Drugs to be Used with Caution ............................................................. 37 
4.2 
Interruption or Discontinuation of Treatment ........................................................ 40 
4.3 
Monitoring of BKM120 Suspected Toxicities ...................................................... 46 
4.4 
Known Undesirable Side Effects of BKM120 ...................................................... 47 
4.4.1 
Neuropsychiatric Events ....................................................................... 47 
4.4.2 
Hyperglycemia ...................................................................................... 50 
4.4.3 
Cardiac Events ...................................................................................... 50 
4.4.4 
Lung Toxicity/Pneumonitis ................................................................... 51 
4.4.5 
Liver Toxicity ........................................................................................ 52 
4.5 
Study Termination ................................................................................................. 54 
4.6 
Visit Schedule and Assessments ............................................................................ 55 
4.6.1 
Visit Schedule ....................................................................................... 55 
4.6.2 
Efficacy Assessments ............................................................................ 56 
4.6.3 
Safety Assessments ............................................................................... 60 
4.6.4 
Treatment Compliance .......................................................................... 60 


 
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4.6.5 
Adverse Events ...................................................................................... 60 
4.6.6 
Laboratory Evaluations ......................................................................... 64 
4.6.7 
Vital Signs ............................................................................................. 67 
4.6.8 
Physical Examination ............................................................................ 67 
4.6.9 
Neuropsychiatric Assessments .............................................................. 67 
4.6.10 
ECG/ECHO ........................................................................................... 68 
4.6.11 
Performance Status ................................................................................ 68 
4.6.12 
Drug Levels and Pharmacokinetic Assessments ................................... 68 
5 
Data Management .............................................................................................................. 68 
5.0 
Data Collection ...................................................................................................... 68 
6 
Patient Consent and Peer Judgment .................................................................................. 69 
7 
Statistical Methods ............................................................................................................ 69 
7.0 
General Considerations .......................................................................................... 69 
7.1 
Study Design .......................................................................................................... 69 
7.2 
Analysis Population ............................................................................................... 69 
7.2.1 
Enrolled Population ............................................................................... 69 
7.2.2 
Safety Population .................................................................................. 69 
7.2.3 
Efficacy Population ............................................................................... 69 
7.3 
Sample Size, Accrual and Study Duration ............................................................ 70 
7.4 
Patient Characteristics ........................................................................................... 70 
7.5 
Significant Protocol Violations.............................................................................. 70 
7.6 
Concomitant Medications ...................................................................................... 70 
7.7 
Exposure and Compliance ..................................................................................... 70 
7.8 
Efficacy Analysis ................................................................................................... 70 
7.9 
Safety Analysis ...................................................................................................... 71 
7.10 
Statistical Analysis of Genetic Data ...................................................................... 71 
7.11 
Interim Analysis ..................................................................................................... 71 
7.12 
Reporting and Exclusions ...................................................................................... 71 
7.12.1 
Evaluation of Toxicity ........................................................................... 71 
7.12.2 
Evaluation of Response ......................................................................... 72 
8 
Data and Safety Monitoring Plan (DSMP) ........................................................................ 72 
9 
References ......................................................................................................................... 73 
APPENDICES .......................................................................................................................... 76 


 
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List of Abbreviations  
AE  
 
 
Adverse Event 
AKT   
 
See PKB (protein Kinase B) 
ALP 
 
 
Alkaline Phosphatase 
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 
CMV  
 
Cytomegalovirus 
CPK  
 
Creatine phosphokinase 
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 
EBV  
 
Epstein-Barr virus 
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 
ICH   
 
International Conference on Harmonization 


 
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IgG 
 
 
Immunoglobulin G 
IgM 
 
 
Immunoglobulin M 
HAV  
 
Hepatitis A 
HBV  
 
Hepatitis B 
HCV  
 
Hepatitis C 
HDL   
 
High density lipoprotein 
HEV  
 
Hepatitis E 
HSV  
 
Herpes Simplex Virus 
IEC  
 
 
Independent Ethics Committee 
IRB  
 
 
Institutional Review Board 
LDH  
 
Lactate dehydrogenase 
LDL   
 
Low density lipoprotein 
LVEF   
 
Left Ventricular Ejection fraction 
MRI   
 
Magnetic Resonance Imaging 
MTD   
 
Maximum Tolerated Dose 
MUGA  
 
Multiple Gated Acquisition Scan 
ORR   
 
Overall Response Rate 
PD  
 
 
Pharmacodynamic 
PET   
 
Positron Emission Tomography 
PI3K   
 
Phosphatidylinositol 3’-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 
SOP   
 
Standard Operating Procedure 


 
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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 
1.0 
Disease Background 
Thymic malignancies are rare, but represent the third most common type of primary mediastinal 
tumor (after lymphoma and germ cell tumors) (Temes, et al 1999) and the most common 
incident tumor type in the anterior mediastinum (Tomaszek 2009). Management is 
multidisciplinary in nature. Surgical resection is favored when disease is localized, and in the 
case of early thymoma, can potentially be curative. 
 
However, in the setting of advanced thymoma or thymic carcinoma, the chance of cure is 
remote, and some combination of chemotherapy and radiation therapy is indicated. Evidence-
based guidelines favor combination chemotherapy regimens in the first line, usually containing 
a platinum agent and some combination of doxorubicin, cyclophosphamide, vincristine and 
etoposide (National Comprehensive Cancer Network Practice Guidelines in Oncology: Thymic 
Malignancies, Version 2.2009). Initial response rates in adjuvant or locally advanced settings 
are good, with response rates over 50% reported in multiple phase II studies such as with PAC 
regimen of cisplatin, doxorubicin and cyclophosphamide plus radiation, with 70% ORR and 93 
months median OS (Loehrer, et al 1997). The ADOC regimen that added vincristine showed an 
ORR of 91% but with a shorter median OS of 15 months raising question about toxicity 
(Fornasiero, et al 1990). Regimens not containing doxorubicin tend to have response rate less 
than 50% in first line therapy (Lemma, et al 2011). 
 
Unfortunately, given the rarity of the disease, there have been few prospective trials of systemic 
therapy in the advanced or metastatic settings, and while these studies have suggested efficacy 
with ORRs ranging from 32 to 56%, there are few comparative data except for historical 
comparisons to consider (Giaccone, et al 1996, Highley, et al 1999, Loehrer, et 2001, Loehrer, 
et al 2004).  
 
Over 50% of patients with locally advanced or metastatic thymic malignancies may fail initial 
therapy and therefore require second-line therapy. Biological agents have been investigated for 
these patients with so far variable rates of response, ranging from 0 to 40%. These included 
octereotide ± prednisone, imatinib, belinostat, gefitinib, and interleukin-2. (Loehrer, et al 2004, 
Palmieri, et al 2002, Giaccone, et al 2009, Giaccone, et al 2011, Kurup, et al 2005, Gordon, et 
al 1995). There is a clear need for better targeted therapies that can target specific mutations 
(Rajan, et al 2010). One of these targets could be PI3K pathway as outlined in the study rationale 
in section 1.3. 
1.1 
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. 


 
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1.2 
PI3K Pathway and Mechanism of Action 
The phosphatidylinositol-3-kinase (PI3K) signaling regulates diverse cellular functions, 
including cell proliferation, survival, translational regulation of protein synthesis, glucose 
metabolism, cell migration, and angiogenesis (Katso, et al 2001). PI3K signaling also serves a 
central role in the pathogenesis of numerous forms of neoplasia. At the structural level, the 
enzyme PI3K is composed of a 110-kDa catalytic subunit and an 85-kDa adaptor subunit. The 
PI3K signaling is modulated by multiple regulators, including growth factors (such as EGF, 
IGF-1, and FGF), hormones (such as estrogen and thyroid hormone), integrins, intracellular 
calcium levels, and RAS signaling. PI3K signaling is negatively regulated at the level of PIP3 
clearance by phospholipid phosphatases, such as the phosphatase and tensin homologue 
(PTEN) protein and the inositol 5-phosphatase-2 (SHIP2) protein.   
Constitutive activation of PI3K signaling is known to be a critical step in mediating the 
transforming potential of oncogenes and tumor suppressors and in many tumor types (Liu 
2009). Resistance to a variety of therapeutic interventions, including chemotherapy, hormonal 
therapy and anti-HER2 therapies, can also be linked to constitutive activation of the PI3K 
pathway (McCubrey 2006). Moreover, preliminary data suggest that activation of the PI3K 
pathway may be a predictor of poor prognostic outcome in many cancers.  
Molecular changes leading to constitutive activation of the PI3K pathway are diverse and 
include, but are not limited to, 
a. Gain-of-function mutations of PI3K subunits (PIK3CA encoding the PI3K catalytic subunit 
p110α; genes encoding the p85 regulatory subunit) or oncogenes encoding positive 
regulators of PI3K (e.g., HER2, EGFR, RAS, Src-family proteins) or  
b. Loss-of-function mutations or epigenetic alterations affecting negative regulators of PI3K 
signaling (e.g., loss of PTEN expression or function) (Chow 2006, Cully 2006). 
Together these observations suggest that PI3K pathway could be a critical therapeutic target for 
the treatment of patients with advanced solid malignancies who often have limited therapeutic 
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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 Figure 1-1 
Schematic representation of the PI3K pathway 
 
1.2.1 
Preclinical Studies 
BKM120 activity against class I PI3K (p110α, -β, -δ and -γ), Class III (Vps34), the class 
IV mTOR related PI3K or PI4Kβ, was assessed using either a luciferase luminescence 
(class I or III PI3Ks and PI4Kβ) or a TR-FRET assay (Class IV mTOR). The IC50 in 
these assays is outlined below in table 1-1: 
Table 1-1 Inhibitory activities (IC50) of BKM120 against other PI3K or related kinases 
 
BKM120 significantly inhibits p110α and the most common p110α mutations (H1047R, 
E454K, E542K), p110β, p110δ and p110γ but not the related proteins Vps34, mTOR or 


 
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PI4Kβ. Hence BKM120 is classified as a pure pan-class I PI3K inhibitor. Enzymatic 
characterization of the inhibitory properties of the compound revealed that BKM120 is a 
mixed inhibitor of PI3Kα with a strong competitive component (largest on Vmax). The 
cocrystal X-ray structure of BKM120 with PI3Kγ confirmed that BKM120 interacts with 
PI3K into the ATP catalytic cleft. 
The PI3K pathway regulates the activity of the mTORC1 complex, when cells are 
challenged through mitogenic stimuli. In order to assess in cells the potential impact of 
the BKM120 on the mTORC1 complex, the compound was tested in TSC1 null cells. 
These cells express a constitutively activated mTORC1 complex that uncouples the 
mTOR pathway from the PI3K upstream input (Kwiatkowski 2003). When exposed to 
TSC1 null MEFS, BKM120 reduced the S235/236P-RPS6 levels with an IC50 of 1785 
nM, in agreement with the data obtained in the mTOR biochemical assay. In contrast, and 
as expected, the allosteric mTORC1 inhibitor RAD001 displayed sub-nanomolar 
inhibitory activity in this assay. 
In contrast to molecules with distinct mechanism of action (BCR-Abl inhibitor STI571, 
mTORC1 allosteric inhibitor RAD001), BKM120 is able to decrease the phosphorylation 
status of various either direct (GSK3β, FKHRL1/FOXO3a) or indirect downstream Akt 
effectors (p70S6K, through mTOR) in the PTEN null U87MG cell line, as efficiently as 
prototypical PI3K inhibitors such as LY294002 and Wortmannin. 
1.2.1.1 
Preclinical Safety 
Please refer to the Investigator’s Brochure for additional information on the preclinical 
testing of BKM120. 
1.2.1.2 
Pharmacodynamics 
BKM120 inhibits wild-type PI3Kα (IC50: 35 nM), with at least 50-fold selectivity towards this 
target compared to other protein kinases as well as against somatic PI3Kα activating mutants 
(H1047R-, E542K-, and E545K-p110α), the other three PI3K paralogs as well as the direct 
downstream effector AKT. BKM120 does not inhibit the related kinases mTOR or Vps34, nor 
does it inhibit other receptors and ion channels profiled (IC50 >10 µM). 
BKM120 reduces the phosphorylation of the direct downstream effector Akt in relevant tumor 
cell lines (e.g., IC50 93 nM for S473P-Akt in Rat1-p110α cells). This biological activity 
correlates with inhibition of various other downstream signaling components and with 
antiproliferative activity in a variety of tumor cell lines. 
BKM120 demonstrates significant tumor growth inhibition in relevant tumor xenografts in mice 
and rats when administered orally, including models of renal cell cancer (RENCA, 786-0, Caki-
1), glioblastoma multiforme (U87MG), prostate cancer (PC3M), lung cancer (A549, NCI-
H1975), ovarian cancer (A2780), colorectal cancer (HCT116, HCT-15) and melanoma (A2058, 
A375). In vivo PK/PD analyses of tumor tissues shows a good correlation between exposure, 
PI3K pathway blockade (S473P-Akt levels), and anti-tumor activity. 
 


 
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1.2.1.2.1 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 μM (34-59 μM 
unbound). BKM120 did not show time-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 rats (< 2 fold). 
Further information concerning the pharmacokinetic and pharmacodynamic properties of 
BKM120 may be found in the Investigator Brochure. 
1.2.1.2.2 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 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 


 
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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. 
Please refer to the Investigator’s Brochure for additional information on the preclinical testing 
of BKM120. 
1.2.1.2.3 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. 
1.2.2 
Clinical Experience 
1.2.2.1 
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]. 


 
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• 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. 
1.2.2.1.1 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 a 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: 
Table 1-2 
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 


 
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patients. The recommended phase 2 dose (RP2D) for Japanese patients 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. 
Details on liver toxicity, mood alterations, pneumonitis, hyperglycemia, skin rash and 
hypersensitivity as side effects of BKM120 are presented below.  
Liver Toxicity 
Liver toxicity has been analyzed based on a search of multiple MedDRA event terms and is 
presented in Table 1-3. Liver function test (LFT) alterations observed during ongoing and 
completed studies have been mostly transaminase enzyme increases (ALT and/or AST). Data 
suggest a higher rate of grade 3/4 liver enzyme elevations in Japanese patients (44.4%) in 
[CBKM120X1101] study, however, the number of patients (9 patients) treated at 100 mg in this 
study was limited. Transaminase elevations typically occur during the first 6 to 8 weeks of 
treatment start. 
 


 
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Table 1-3 Number of patients with liver toxicity 
 
 
Although transaminase increases are relatively common, only a few of the patients with LFT 
alterations had other simultaneous observations related to impaired liver function (e.g. bilirubin 
increase or clinical symptoms). Based on these findings, conservative inclusion criteria and 
guidelines to monitor and to follow patients with LFT alterations (including dose and schedule 
modifications) are currently implemented in study protocols investigating BKM120. Please 
refer to the respective inclusion/exclusion criteria, and Section 4.4.5.2 in this protocol for more 
detailed guidelines. 
 
A recent liver safety review across Novartis-sponsored trials with BKM120 identified several 
potentially drug-induced liver toxicity (DILI) cases (e.g. AST/ALT >3.0 x ULN and TBL >2.0 
x ULN at any time during the treatment, regardless of causality. Upon medical review, most of 
these cases occurred in the context of disease progression in terminally ill, advanced cancer 
patients and/or were confounded by other causes. However, six of these DILI candidates were 
consistent with Hy’s law criteria (e.g. AST/ALT >3.0x ULN and TBL >2.0xULN in the absence 
of cholestasis and other explanatory causes) with probable causal relationship to study 
treatment. Five of these cases were enrolled in study CBKM120F2302 in combination with 
fulvestrant, and one in combination with the investigational drug LDE225 (sonidegib). All 
patients have recovered upon treatment discontinuation except one patient for whom no data is 
available since the patient refused to return for safety follow-up. 
Mood disorders 
Recently, a number of publications demonstrated that the modulation of AKT/GSK3 signaling 
pathway by neurotransmitters is important for the regulation of behavior (Beaulieu 2009). 


 
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Preclinical studies conducted in rats to investigate the effect of BKM120 on different 
neurotransmitters have shown that repeated administration of BKM120 resulted in an enhanced 
decrease in glutamate, dopamine, serotonin and epinephrine as well as in an enhanced increase 
in GABA and HIAA. 
Psychiatric side effects events have been reported in patients treated with BKM120 and are 
currently under investigation. The current data does not allow the identification of any sign or 
symptom which could predict patient susceptibility to BKM120 induced psychiatric disorders. 
A broad range of AEs including (but not limited to) depression, anxiety, mood alteration, 
confusion, affective disorders, insomnia, hallucination, panic disorders, irritability or 
difficulties to concentrate have been reported. 
Considering the initial symptoms reported during the first-in-man [CBKM120X2101] study, 
mood disorders have been analyzed based on HLGT 'Mood disorders and disturbances NEC' or 
HLGT 'Personality disorders disturbances in behavior' or HLGT “Psychiatric and behavioral 
symptoms NEC” or HLGT “suicidal and behaviors NEC”. The frequency of mood disorders 
thus defined, regardless of study drug relationship, ranged from 6.3% in [CBKM120B2101] 
study to 50.0% in dose escalation part of [CBKM120X2107] study, however, the majority of 
events were of grade 1 or 2 severity (Table 1-4). 
Table 1-4 Number of patients with mood disorders 
 
 
Therefore, patients must be regularly and closely monitored for signs and symptoms of 
neuropsychiatric disorders with particular attention to changes in mood and personality. To 
support the identification and the assessment of psychiatric disorders, two self-assessment 
questionnaires, the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-
7 (GAD-7), are part of the protocol. Any AEs (symptom/diagnosis) should be accurately 
reported using CTCAE toxicity/grading. A consultation with a psychiatrist is strongly 


 
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recommended for any psychiatric adverse event grade ≥ 1. 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 jeroveci 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 4-8 for more detailed guidelines on the diagnosis and management of 
Pneumonitis. 
Hyperglycemia events 
The PI3K/AKT pathway plays a significant role in regulating glucose metabolism, particularly 
by regulating glucose transport into adipocytes and muscle tissue. Therefore, hyperglycemia is 
considered as an “on target” effect of BKM120. Regular monitoring of FPG, HbA1c, and 
insulin C-peptide is implemented in BKM120 protocols to evaluate this pharmacodynamic 
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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Table 1-5 Number of patients with hyperglycemia 
 
 
The highest rate of hyperglycemia (57.1%) was reported in [CBKM120C2201], a Phase II study 
conducted in patients with advanced endometrial carcinoma, as this was the only study among 
those listed allowing the enrollment of patients with controlled diabetes mellitus. However, so 
far, there were only two patients that experienced a grade 4 hyperglycemia, and they both were 
treated at the highest dose level (150mg/day) in [CBKM120X2101] study. In order to mitigate 
the potential risk of developing uncontrolled hyperglycemia, only patients with normal 
glycaemia defined as fasting plasma glucose (FPG) ≤ 120 mg/dL are eligible for study entry. 
Patients who have a poorly controlled diabetes mellitus defined as (HbA1c >8%) are excluded. 
In addition, detailed guidelines to monitor patients are recommended including: regular 
monitoring of FPG to early identify hyperglycemia and prevent acute/sub-acute complications, 
caution warranted for patients with history of DM, or taking corticosteroids, or with other severe 
medical conditions (e.g. infections). Hyperglycemia management guidance also includes: 
dietetic measures and appropriate anti-diabetic medications as per investigator’s decision and/or 
local guidelines, consider oral anti-diabetics such as metformin as first-line treatment for 
sustained and more severe hyperglycemia (other drugs as appropriate), if sulfonylurea or insulin 
are initiated, patients should be instructed on how to recognize (and treat) hypoglycemia, for 
patients with history of DM, management should be based on prior anti-DM treatment. 
Detailed guidelines to monitor and manage patients who develop hyperglycemia are provided 
in Table 4-5.  
 
Skin rash and hypersensitivity 
Skin rash is commonly observed in patients treated with BKM120. The rate of skin rash and 
other related event terms ranged from 18.4% to 41.4% in single agent studies with a 


 
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representative number of patients treated with 100mg of BKM120. In one study with nine 
evaluable patients, seven patients (77.8%) reported such events (Table 1-6). Studies of 
BKM120 in combination with other agents tended to report slightly higher frequencies (e.g. 
combination with MEK inhibitor). The skin rashes seen have no typical location or distribution 
pattern, are mainly papulo-macular (only a minority acneiform) and are frequently associated 
with pruritus. Events have been reversible after treatment interruption and/ or dose reduction. 
Effective medications have included antihistamines, topical corticosteroids and/or low-dose 
systemic corticosteroids (the latter should be used with caution due to the increased risk of 
hyperglycemia). There have been few cases reported of allergic reactions and DRESS (drug 
rash with eosinophilia and system symptoms), but these have not been of acute onset or of a 
severe nature. Complementary information collected suggests that sun exposure may exacerbate 
the condition and should be avoided; however, genuine photosensitivity reaction has not been 
confirmed and no phototoxic potential seen pre-clinically. Patients are advised (e.g. in the 
written patient information) to avoid sun exposure, or take measures to protect themselves from 
intense sunlight, during study treatment. 
Table 1-6 Number of patients with hypersensitivity 
 
1.2.2.1.2 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 


 
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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 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 μg/ml). 
1.2.2.1.3 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 


 
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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, July, 4, 2011, 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 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, July, 4, 2011, twenty breast cancer patients were evaluable for 


 
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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). 
 
Please refer to the Investigator’s Brochure for additional information on the available 
clinical experience with BKM120. 
1.3 
Study Rationale 
Thymic tumors are rare tumors, but represent the most common tumors of the anterior 
mediastinum. Thymoma has an indolent course in advanced disease and has the propensity to 
spread to the pleura. In disseminated disease, thymoma has demonstrated sensitivity to a 
broad range of chemotherapeutic agents. In first line therapy, combination chemotherapy 
produces responses in approximately 80% of patients. A number of single agents have activity 
in recurrent disease, but none are curable. Patients with recurrent thymoma have limited 
treatment options, and thus novel target modalities are needed.  
 
At the Indiana University Simon Cancer Center (IUSCC), more patients with advance 
thymoma are seen than any other institution in the country. We have conducted numerous 
trials in advanced disease either at the IUSCC or in collaboration with other institutions or 
national Cooperative Groups. This has permitted us to collect tissue and develop a tumor 
model and the only existing cell line in this disease. Using our collected thymoma tissues, we 
have conducted next generation RNA sequencing of thymomas across various histologic 
types. From this analysis, we identified a unique microRNA cluster on chromosome 19 
(C19MC) that is highly overexpressed in a significant subset of thymomas primarily 
comprised of the A & A/B subtype. 
 
We subsequently validated this observation in additional 35 thymomas by qPCR (Figure 1-2). 
This cluster is normally silent in adult tissues, with normal expression restricted to embryonic 
development. MicroRNAs within the C19MC cluster, miR-517 & miR-519d, have been 
previously demonstrated to inhibit key proteins in the PI3K/AKT pathway. Namely, PTEN, a 
negative regulator of AKT, and p21, a cell cycle arrest protein (Fornari, et al 2012). 
 
 
 
 
 
 


 
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Figure 1-2 
 
 
 
In addition, gene expression analysis reveals over-expression of PIK3CA (aka PI3K p110), 
the canonical activator of AKT (Figure 1-3). To confirm, we performed a quantitative ELISA 
on a validation set of 35 thymomas for phospho-AKT (Ser 473), and demonstrate that C19MC 
positive thymomas have significantly higher levels of phospho-AKT compared to C19MC 
negative thymomas which in-turn has higher levels than adjacent normal tissue (Figure 1-4). 
 
 
 
Figure 1-2 RNA-sequencing identified extensive over-expression of the C19MC cluster in A&A/B 
thymomas in a test set of 13 samples. In this figure we validate the over-expression of the C19MC 
cluster using qPCR in an independent sample set of 35 thymomas. Expression data demonstrates a 
separation of the samples into 2 distinct groups as demonstrated by the upper dendrogram. Red 
represents high-expression, green represents low or no expression. All A & A/B samples were in the 
C19MC positive group (right-fork of the dendrogram), whereas the B1, B2, & B3 samples were in 
the C19MC negative group (left-fork of the dendrogram), except for one discordant B1 sample in the 
C19MC positive group. 


 
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Figure 1-3 
 
Figure 1-3. Network analysis of thymoma RNA-seq data demonstrates over-expressed genes (RED) and 
under-expressed genes (GREEN) in C19MC positive thymomas that would be expected of an over-activated 
PI3K pathway. 
 
 
 


 
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Figure 1-4 
These 
data 
demonstrate 
that 
all 
thymomas have the potential to have 
sensitivity 
to 
PI3K 
inhibition, 
in 
particular those that are positive for 
C19MC. We further tested a variety of 
PI3K, AKT, and mTOR inhibitors in our 
thymoma cell line (IU-TAB-1) and 
found significant activity for several of 
these agents including BEZ235 and 
BKM120 (Figure 1-5). 
 
Our main hypothesis is the PI3K 
pathway is an important driver for 
growth and metastasis of thymoma and 
that inhibition of the PI3K pathway is 
expected to produce clinically meaningful response in 
patients with recurrent thymoma. Our rationale is to use 
BKM120, a pan-PI3K inhibitor, which has shown 
significant cell growth inhibition in thymoma, in a Phase II 
clinical trial to demonstrate clinical efficacy of this agent in 
recurrent disease. 
Figure 1-5. The thymoma cell line, IU-TAB-1, tested with increasing doses of PI3K, AKT, and dual 
PI3K/mTOR inhibitors. Cells were treated for 72 hours and cell viability assessed. The data demonstrates
marked sensitivity of the thymoma cell line to these inhibitors 
Figure 1-4. Protein ELISA for activated phospho-AKT 
(Ser 473) in a validation set of 35 thymomas and 3 normal 
tissues, demonstrating significantly higher phospho-AKT 
in C19MC positive thymomas vs. C19MC negative vs. 
normal tissues. 


 
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2 
Study Objectives 
Primary 
• To evaluate the objective response rate (CR+PR) in patients with thymomas treated with 
BKM120. 
Secondary 
• To evaluate toxicity in patients with thymomas treated with BKM120. 
• To evaluate progression-free survival in patients with thymomas treated with BKM120. 
• To evaluate disease control rate (DCR = CR+PR+SD) in patients with thymomas treated 
with BKM120. 
• To evaluate duration of response of patients with thymomas treated with BKM120. 
• To evaluate overall survival of patients with thymomas treated with BKM120. 
 
Exploratory 
• To determine if there are molecular markers to predict response in patients with thymomas 
treated with BKM120. 
3 
Exploratory Investigational plan 
3.0 
Overall Study Design 
• Purpose: This will be a single arm phase II trial in patients with recurrent thymoma. The 
purpose of the study is to determine the activity of the pan PI3K Inhibitor, BKM120 in 
patients with this disease. 
 
• Planned treatments: BKM120, 100 mg capsule for oral use, taken once daily for two or 
more months for a maximum of one year. Each cycle is 28 days. 
 
• Sequence & duration of study periods: Eligible patients will be treated for two months 
and evaluated. All patients with responding or stable disease will continue on study unless 
there is unacceptable toxicity or progression of disease. Patients will continue on study for 
a maximum of one year or until progression. There will be no dose escalations. 
 
• Blinding: Open Label. 
• Structure: Single Group. 
• Randomization: Non-randomized. 
• Placebo Controlled: No 
• Number of Patients & Centers: 
• 25 thymoma patients (16 in stage 1 + 9 in stage 2) 
• Because some patients may not be evaluable for response, up to 27 patients may be 
accrued to ensure that the number of evaluable patients is 25. 
• Number of Centers: IUSCC, other centers may be added with approval of the sponsor 
(e.g. Georgetown, Stanford, Memorial Sloan-Kettering and MD Anderson). 


 
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3.1 
Study Population 
3.1.1 
Patient Population 
A total of 27 eligible patients with recurrent thymoma who will meet the eligibility criteria will 
be enrolled for this trial. The patients will be enrolled in two stages. 16 eligible patients will be 
enrolled for stage 1 and if at least 2 thymoma patients have response to treatment then the study 
will continue for stage 2 where an additional 9 eligible patients will be enrolled. Because some 
patients may not be evaluable for response, up to 27 patients may be accrued to ensure that the 
number goal of evaluable patients is met. 
3.1.2 
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 
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: 
3.1.2.1 
Inclusion Criteria  
1. Histological confirmation of thymoma. 
2. At least one prior line of platin-based chemotherapy (unless refused or not 
tolerated).  
3. Documented progressive (clinical and/or objective) disease after the most recent 
systemic therapy regimen. 
4. Patients must not have received chemotherapy, radiation therapy, or undergone 
major surgery within 4 weeks prior to enrollment. 
5. Patient must not have other curative treatment options (e.g. surgical resection of 
solitary metastases if feasible, or other proved curative options if they become 
available in the future). 
6. Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 
nonnodal lesions and short axis for nodal lesions) as >20 mm with conventional 
techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam. 
See Section 4 for the evaluation of measurable disease. 
7. Age ≥ 18 years 
8. ECOG performance status ≤ 2 
9. Patient must be able to swallow and retain oral medications 
10. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 
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11. Total calcium (corrected for serum albumin) within normal limits (biphosphonate 
use for malignant hypercalcemia control is not allowed) 
12. Magnesium ≥ the lower limit of normal 
13. Potassium within normal limits for the institution 
14. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 
normal range (or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present) 
15. Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; 
or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients 
with well documented Gilbert Syndrome) 
16. Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min 
17. Serum amylase ≤ ULN 
18. Serum lipase ≤ ULN 
19. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) 
20. HbA1c ≤ 8 % 
21. Negative serum pregnancy test within 72 hours before starting study treatment in 
women with childbearing potential 
22. Signed informed consent 
23. INR ≤ 2 
3.1.2.2 
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. Patients with thymic carcinoma (formerly WHO Type C). 
3. Patients with a known hypersensitivity to BKM120 or to its excipients 
4. Patients with untreated brain metastases are excluded. However, patients with 
metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks from 
therapy completion (incl. radiation and/or surgery), is clinically stable at the time of 
study entry and is receiving low dosage corticosteroid therapy 
5. Patients with acute or chronic liver, renal disease or pancreatitis 
6. Patient has acute viral hepatitis or a history of chronic or active Hepatitis B (HBV) 
or Hepatitis C (HCV) infection, (typically defined by elevated AST/ALT (persistent 
or intermittent), high HBV DNA level, HBsAg positive, or high HCV RNA level 
(testing not mandatory, refer to Section 4.6.6.7 Viral hepatitis serology and other 
tests for hepatotoxicity follow-up).  
7. Patients with the following mood disorders as judged by the Investigator or a 
psychiatrist, or as a result of patient’s mood assessment 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 
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anxiety disorders who are stable at the time of enrollment and on 
antidepressants not listed in Tables 4-0 and 4-1 of the study protocol will be 
permitted to enroll on this study. Note: for patients with psychotropic 
treatments ongoing at baseline, the dose and the schedule should not be 
modified within the previous 6 weeks prior to start of study drug. 
•  ≥ CTCAE grade 3 anxiety  
• Meets the cut-off score of ≥ 12 in the PHQ-9 or a cut-off of ≥ 15 in the 
GAD-7 mood scale, respectively, or selects a positive response of “1, 2, or 
3” to question number 9 regarding potential for suicidal thoughts in the 
PHQ-9 (independent of the total score of the PHQ-9)  
8. Patients with diarrhea ≥ CTCAE grade 2 
9. Patient has known active cardiac disease including any of the following:  
• Left ventricular ejection fraction (LVEF) < 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 
10. 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 
11. Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus 
12. Patients with chronic lung disease, dyspnea at rest, or interstitial lung disease 
13. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., 
active or uncontrolled infection; uncontrolled hypertension, i.e. BP >160/100) 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.  
14. Impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, 


 
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vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients 
with unresolved diarrhea will be excluded as previously indicated 
15. Patients who have been treated with any hematopoietic colony-stimulating growth 
factors (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. 
Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to 
enrollment, may be continued 
16. 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 4-1 or a list of prohibited QT prolonging drugs with risk 
of Torsades de Pointes. 
17. Patients receiving chronic treatment with steroids or another immunosuppressive 
agent.  
• Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive 
airways diseases), eye drops or local injections (e.g. intra-articular) are 
allowed. Patients with previously treated brain metastases, who are on stable 
low dose corticosteriod treatment (e,g dexamethasone 2 mg/day, predisolone 
10 mg/day) for at least 14 days before start of study treatment are eligible. 
18. 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. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. Fruits include the CYP3A inhibitors Seville 
oranges, grapefruit, pummelos, or exotic citrus fruits.  
19. 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 4-0 for a list of prohibited inhibitors and inducers of CYP3A 
(Please note that co-treatment with weak inhibitors of CYP3A is allowed). 
20. Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks 
(6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug 
must recover to a grade 1 before starting the trial  
21. Patients who have received any continuous or intermittent small molecule 
therapeutics (excluding monoclonal antibodies) ≤ 5 effective half-lives prior to 
starting study drug or who have not recovered from side effects of such therapy 
22. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field 
radiation for palliation ≤ 2 weeks prior to starting study drug or who have not 
recovered from side effects of such therapy 
23. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or 
who have not recovered from side effects of such therapy.  
24. Patients who are currently taking therapeutic doses of warfarin sodium or any other 
coumadin-derivative anticoagulant.  
25. 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 


 
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contraceptives may be affected by cytochrome P450 interactions, and are therefore 
not considered effective for this study. Women of child-bearing potential, defined as 
sexually mature women who have not undergone a hysterectomy or who have not 
been naturally postmenopausal for at least 12 consecutive months (i.e., who has had 
menses any time in the preceding 12 consecutive months), must have a negative 
serum pregnancy test ≤ 72 hours prior to initiating treatment. 
• 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 [for US only: 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. 
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 condoms during treatment, for 4 weeks (5 T1/2) after 
stopping treatment and for an additional 12 weeks (16 weeks in total after 
study drug discontinuation) and should not father a child in this period.  


 
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• 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. 
26. Known diagnosis of human immunodeficiency virus (HIV) infection  
27. History of another malignancy within 3 years, except cured basal cell carcinoma of 
the skin or excised carcinoma in situ of the cervix 
28. Patient is unable or unwilling to abide by the study protocol or cooperate fully with 
the investigator 
4 
Treatments 
4.0 
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. 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, , 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 the 
previous day’s dosing must be noted whenever possible. 
If the patient forgets to take her/his dose AFTER 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. John’s Wort, Seville oranges, grapefruit or grapefruit 
juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to the first dose 
of study medication and during the entire study treatment period due to potential CYP3A4 
interaction with the study medication. Patients must avoid concomitant intake of strong and 
moderate CYP3A4/5 inhibitors and inducers. 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 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. 


 
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4.1 
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 in section 4.0.2.1.  
4.1.1 
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 4-0 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 4-0 for a list of prohibited CYP3A 
inducers. Please note that this list may not be comprehensive. Therapeutic doses of warfarin 
sodium (Coumadin®) or any other coumadin-derivative anticoagulants are not permitted. 
• If a patient requires the concomitant use of any medication included in Table 4-1 entitled 
“List of Prohibited QT prolonging drugs” (i.e., drugs that are generally accepted by the 
Qtdrugs.org Advisory Board of the Arizona CERT to have a risk of causing Torsades des 
de Pointes), study treatment administration must be interrupted as long as the patient 
requires therapy with the QT prolonging agent. 
• Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to St. John’s wort, Kava, ephedra (ma huang), ginko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginsing. Patients 
should stop using these herbal medications 7 days prior to first dose of study drug. 


 
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• Hormonal contraceptives may be affected by cytochrome P450 interactions, and are 
therefore not considered effective in this study. 
 
 


 
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Table 4-0 
List of prohibited CYP3A Inhibitors and Inducers  
Strong CYP3A 
inhibitors 
Moderate CYP3A 
inhibitors 
Strong CYP3A 
inducers 
Moderate CYP3A 
inducers 
clarithromycin 
aprepitant 
avasimibe 
bosentan 
conivaptan 
atazanavir 
carbamazepine 
efavirenz 
grapefruit juice 
cimetidine 
Phenobarbital 
(barbiturates) 
etravirine 
indinavir 
ciprofloxacin 
phenytoin 
modafenil 
itraconazole 
darunavir 
rifabutin 
nafcillin 
ketoconazole 
diltiazem 
rifampin  
ritonavir 
lopinavir 
erythromycin 
St. John's Wort  
talviraline 
mibefradil 
fluconazole 
 
tipranavir 
nefazodone 
tofisopam 
 
 
nelfinavir 
verapamil 
 
 
posaconazole 
amprenavir 
 
 
ritonavir 
fosamprenavir 
 
 
saquinavir 
elvitegravir 
 
 
telithromycin 
tipranavir 
 
 
troleandomycin 
 
 
 
voriconazole 
 
 
 
This database of CYP inhibitors was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table and from the University of Washington’s Drug Interaction Database 
based on in vitro studies. Strong inhibitors are predicted to increase BKM120 AUC > 5-fold, and 
moderate inhibitors are predicted to increase BKM120 AUC ≥ 2-fold but < 5-fold.  
This database of CYP inducers was compiled from the FDA’s “Guidance for Industry, Drug 
Interaction Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” Table; 
and from (Pursche et al. 2008). 
 
Table 4-1 
List of prohibited QT prolonging drugs  
All QT-prolonging drugs listed in Table 4-1 are prohibited for all patients from screening 
through permanent discontinuation of study treatment.  Table 4-3 lists drugs with a known risk 
for Torsades de Pointes (TdP) as well as sensitive CYP3A substrates (with narrow TI) with a 
possible or conditional risk for TdP. 
 
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 
 


 
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Drug 
QT risk(*) 
Comment 
Chlorpromazine 
Known risk for TdP 
 
Cisapride 
Known risk for TdP 
Restricted availability; Females>Males. 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
 
Domperidone 
Known risk for TdP 
Not available in the U.S. 
Droperidol 
Known risk for TdP 
 
Halofantrine 
Known risk for TdP 
Females>Males 
Haloperidol 
Known risk for TdP 
When given intravenously or at higher-than- 
recommended doses, risk of sudden death, 
QT prolongation and torsades increases. 
Ibutilide 
Known risk for TdP 
Females>Males 
Levomethadyl 
Known risk for TdP 
 
Mesoridazine 
Known risk for TdP 
 
Methadone 
Known risk for TdP 
Females>Males 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 
Probucol 
Known risk for TdP 
No longer available in U.S. 
Procainamide 
Known risk for TdP 
 
Quetiapine 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 
substrate 
Quinidine 
Known risk for TdP 
Females>Males 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
 
Tacrolimus 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 
sibstrate with narrow TI 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
 
Vardenafil 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 
substrate 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
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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4.1.2 
Drugs to be Used with Caution 
Preliminary in vitro metabolism studies suggest that BKM120 is a weak, reversible inhibitor 
CYP3A4/5 (Ki=13.6 μM, [I]/Ki= 0.4 where [I] is the average Cmax at steady-state following 100 
mg daily dose) and a weak reversible inhibitor of CYP2C8/2C9/2C19 (IC50=34 μM, 
[I]/IC50=0.15). Note: that with the data available, we are not able to confirm whether such 
interactions will occur in patients. Therefore, investigators, at their discretion, may administer 
concomitant medications known to be metabolized by CYP3A4/5, CYP2C8, CYP2C9 and 
CYP2C19. Patients receiving such medications must be carefully monitored for potentiation of 
toxicity due to any individual concomitant medications, and may require dose titration or 
reduction of the drug substrate. Please refer to Table 4-2 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 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 4-3 for a list of QT prolonging medications to be used 
with caution.  
Note: please refer also to Table 4-1 for a list of prohibited QT prolonging medication.  
• Please refer to Table 4-2for 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 corticosteroids is 
allowed (e.g. for chronic obstructive pulmonary disease, or as an anti-emetic). Chronic 
dosing of corticosteroids is known to induce CYP3A enzymes, thereby increasing the risk 
or reducing BKM120 overall exposure to sub-therapeutic levels. 
 
Table 4-2 List of CYP450 substrates to be used with caution 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A** 
amodiaquine 
celecoxib 
amitriptyline 
Adinazolam 
felodipine1 
cerivastatin 
diclofenac 
citalopram 
alfentanil1,2 
fentanyl2 
pioglitazone 
flurbiprofen 
clobazam 
alpha-
dihydroergocryptine1 
flunitrazepam 


 
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repaglinide 
fluvastatin 
clomipramine 
Alprazolam 
fluticasone1 
rosiglitazone 
glibenclamide 
(glyburide) 
clopidogrel  
Amlodipine 
lovastatin1 
torasemide 
gliclazide 
diazepam 
Aripiprazole 
maraviroc1 
troglitazone 
glimepiride 
fluoxetine 
Atorvastatin 
midazolam1 
 
glipizide 
imipramine 
Brecanavir 
nifedipine 
 
indomethacin 
lansoprazole 
brotizolam1 
nisoldipine 
 
irbesartan 
mephobarbital 
budesonide1 
nitrendipine 
 
ketobemidone 
moclobemide 
buspirone1 
perospirone1 
 
lornoxicam 
omeprazole 
Capravirine 
quinine 
 
losartan 
pantoprazole 
Cerivastatin 
sildenafil1 
 
meloxicam 
progesterone 
Chlorpheniramine 
simvastatin1 
 
naproxen 
quazepam 
cyclosporine2 
sirolimus1,2 
 
nateglinide 
rabeprazole 
darifenacin1 
tolvaptan 
 
piroxicam 
sertraline 
Diazepam 
trazodone 
 
rosiglitazone 
S-mephenytoin diergotamine2 
triazolam1 
 
S-ibuprofen 
 
ebastine1 
 
 
sulfamethoxazole  
eletriptan1 
 
 
tenoxicam 
 
eplerenone1 
 
 
tolbutamide 
 
ergotamine2 
 
 
torasemide 
 
Estazolam 
 
 
valdecoxib 
 
everolimus1 
 
* This database of CYP substrates was compiled from the Indiana University School of 
Medicine’s “Clinically Relevant” Table, and from (Zhou et al 2009) 
** CYP3A substrates were compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table; and supplemented by the FDA’s “Guidance for Industry, Drug 
Interaction Studies” and the University of Washington’s Drug Interaction Database. 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-
fold or higher when co-administered with a potent inhibitor of the respective enzyme. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates 
that increases in their exposure levels by the concomitant use of potent inhibitors may lead 
to serious safety concerns (e.g., Torsades de Pointes). 
 


 
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Table 4-3 
List of QT prolonging drugs to be used with caution 
Drug 
QT risk 
Comment 
Alfuzosin 
possible risk for Torsades de Pointes 
 
Amantadine 
possible risk for Torsades de Pointes 
 
Amitriptyline 
conditional risk for Torsades de Pointes 
 
Azithromycin 
possible risk for Torsades de Pointes 
 
Chloral hydrate 
possible risk for Torsades de Pointes 
 
Citalopram 
conditional risk for Torsades de Pointes 
 
Clomipramine 
conditional risk for Torsades de Pointes 
 
Clozapine 
possible risk for Torsades de Pointes 
 
Desipramine 
conditional risk for Torsades de Pointes 
 
Diphenhydramine 
conditional risk for Torsades de Pointes 
 
Dolasetron 
possible risk for Torsades de Pointes 
 
Doxepin 
conditional risk for Torsades de Pointes 
 
Dronedarone 
possible risk for Torsades de Pointes 
 
Felbamate 
possible risk for Torsades de Pointes 
 
Flecainide 
possible risk for Torsades de Pointes 
 
Fluoxetine 
conditional risk for Torsades de Pointes 
 
Foscarnet 
possible risk for Torsades de Pointes 
 
Fosphenytoin 
possible risk for Torsades de Pointes 
 
Galantamine 
conditional risk for Torsades de Pointes 
 
Gatifloxacin 
possible risk for Torsades de Pointes 
 
Gemifloxacin 
possible risk for Torsades de Pointes 
 
Granisetron 
possible risk for Torsades de Pointes 
 
Imipramine 
conditional risk for Torsades de Pointes 
 
Indapamide 
possible risk for Torsades de Pointes 
 
Isradipine 
possible risk for Torsades de Pointes 
 
Levofloxacin 
possible risk for Torsades de Pointes 
 
Lithium 
possible risk for Torsades de Pointes 
 
Mexiletine 
conditional risk for Torsades de Pointes 
 
Moexipril/HCTZ 
possible risk for Torsades de Pointes 
 
Moxifloxacin 
possible risk for Torsades de Pointes 
 
Nicardipine 
possible risk for Torsades de Pointes 
 
Nortriptyline 
conditional risk for Torsades de Pointes 
 
Octreotide 
possible risk for Torsades de Pointes 
 
Ofloxacin 
possible risk for Torsades de Pointes 
 


 
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Drug 
QT risk 
Comment 
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 
 
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 
Interruption or Discontinuation of Treatment 
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 4-4. Toxicity will be 
assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 
4.0. Patients requiring dose reduction due to toxicity will not be dose                         re-
escalated following resolution of the toxicity. 
(CTCAEv4.0, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf). 
All interruptions or changes to study drug administration must be recorded. 


 
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Table 4-4 
BKM120 dose level modification guidelines 
Dose level 
Dose and schedule 
-2 
60 mg daily 
-1 
80 mg daily 
* 0 
100 mg daily 
 
* Starting Dose  
Table 4-5 
Criteria for interruption and re-initiation of BKM120 treatment 
Recommended dose modifications and criteria for treatment interruption and 
re-initiation with treatment-related adverse events  
These changes must be recorded on the Dosage Administration Record CRF 
 
Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
HEMATOLOGICAL 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain  dose level  
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Febrile neutropenia  
(ANC < 1.0 x 109/L, with a single 
temperature of ≥ 38.3 °C or a sustained 
temperature of ≥ 38 °C for more than one 
hour ) 
Omit dose until resolved, then  1 dose level 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50-25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
RENAL 
Serum creatinine  
Grade 1 (< 2 x ULN)  
Maintain dose level  
Grade 2 (2 – 3 x ULN)  
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 – 6.0 x ULN)  
Permanently discontinue patient from BKM120  
Grade 4 (> 6.0 x ULN)  
Permanently discontinue patient from BKM120 
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 


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
Grade 2 (> 1.5 - 3.0 x ULN) with ALT or 
AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) with ALT or 
AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days,  1 dose level 
If resolved in > 7 days discontinue patient from BKM120 
Grade 4 (> 10.0 x ULN) 
Permanently discontinue patient from BKM120 
AST or ALT 
AST or ALT without bilirubin elevation > 2ULN Note: confounding factors and/or alternative causes for increased 
transaminases like concomitant medications, infection, hepato-biliary disorder, obstruction, liver metastasis, etc. 
should be excluded before dose interruption/reduction 
Same grade as baseline (i.e., Grade 0 or 1 
[> ULN – 3.0 x ULN] if presence of liver 
metastasis 
Maintain dose level with LFTs* monitored per protocol 
Increase from baseline Grade 0 to > 1.5 
ULN or from baseline Grade 1 to Grade 2 
Can continue treatment at  1 dose level 
Increase of two grades from baseline 
(from baseline Grade 0 to Grade 2 or from 
baseline Grade 1 to Grade 3) 
Omit dose until resolved to Grade 1 or less, then  1 dose level**  
If no recovery in ≤ 28 days, discontinue permanently BKM120 
Grade 4 (> 20.0 x ULN)  
Discontinue BKM120 permanently 
AST or ALT and concurrent Bilirubin 
AST or ALT > 3.0 x ULN and total 
bilirubin > 2.0 x ULN 
Permanently discontinue BKM120*** 
*(LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline 
phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) and GGT) 
** In case of recurring Grade 3 or higher toxicity after re-challenge, patients should be permanently discontinued 
*** All patients with ALT or AST >3.0x ULN and total bilirubin > 2.0x ULN in the absence of cholestasis ULN 
must immediately be withdrawn from BKM120 and every attempt should be made to carry out the liver event 
follow-up assessments as described below in Section 4.4.5.2 Management of hepatotoxicity (ALT and/or AST >3.0x 
ULN and total bilirubin >2.0x ULN) and Section 4.6.6.7 Viral hepatitis serology and other tests for hepatotoxicity 
follow-up). 
Hepatic toxicity monitoring (*for patients with Gilbert Syndrome: total and direct bilirubin must be monitored, 
intensified monitoring applies to changes in direct bilirubin only; the monitoring includes the following LFTs: 
albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase (fractionated 
if alkaline phosphatase is grade 2 or higher) and GGT): 
Cycle 1 and 2: every other week (if visit schedule allows a more frequent monitoring this should be considered) or 
more frequently if clinically indicated especially for patients with borderline acceptable AST/ ALT or bilirubin* 
values 
Cycle 3 and onward: monthly or more frequently if clinically indicated  
In case of any occurrence of ALT/AST or bilirubin* increase ≥ grade 2 the liver function tests must be monitored 
weekly or more frequently if clinically indicated until resolved to ≤ grade 1 
In case of any occurrence of ALT/ AST or bilirubin* increase ≥ grade 3  the liver function tests must be monitored 
weekly or more frequently if clinically indicated until resolved to ≤ grade 1; hereafter the monitoring should be 
continued every other week or more frequently if clinically indicated until the end of treatment with study medication 
Patients who discontinued study treatment should be monitored weekly, including LFTs* or more frequently if 
clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE grade change over 4 weeks). 
ENDOCRINE/METABOLIC 
Fasting Plasma Glucose (FPG) 


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
Grade 1 (> ULN - 160 mg/dL) (> ULN - 
8.9 mmol/L) 
Maintain dose level, check FPG every week 
● initiate or intensify medication with appropriate anti-diabetic 
treatment as per investigator’s discretion 
● instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes mellitus 
(such as those provided by the American Diabetes Association) 
during the study 
● consider use of oral anti-hyperglycemic therapy such as 
metformin (or intensify existing medications),  
● check FPG at least weekly for 8 weeks, then continue checking at 
least every 2 weeks 
Grade 2 (>160 - 250 mg/dL) (> 8.9 - 13.9 
mmol/L) 
● If signs or symptoms of hyperglycemia (for example, mental 
status changes, excessive thirst, polyuria), manage as for Grade 3 
hyperglycemia (see below) 
● If asymptomatic, maintain dose and re-check FPG within 24 
hours. If grade worsens or improves then follow specific grade 
recommendations. If FPG remains at Grade 2:  
 
○ 
maintain dose level and monitor FPG at least weekly until 
FPG resolves to ≤ Grade 1 
 
○ 
initiate or intensify medication with appropriate anti-
diabetic treatment such as metformin; consider adding a second oral 
agent if not improvement after several days.  
 
○ 
instruct patient to follow dietary guidelines according to 
local and/or institutional standards for management of diabetes 
mellitus (such as those provided by the American Diabetes 
Association) during the study 
 
○ 
if FPG does not resolve to ≤ Grade 1 within 14 days after 
institution of appropriate anti-diabetic treatment reduce BKM120 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/hyperosmolar disturbances as clinically 
appropriate 
● continue to omit BKM120 
● monitor FPG at least twice weekly until FPG resolves to 
≤ Grade 1  
● If FPG resolves to < Grade 1 in 7 days or less, then re-start 
BKM120 and  1 dose level 
● If FPG remains greater than Grade 1 severity for more than 7 
days, then discontinue patient from BKM120  


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for 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 (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 and following 
guidance for management of Grade 3 fasting plasma glucose (FPG) 
Grade 4 (> 500 mg/dL) (≥ 27.8 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/hyperosmolar disturbances as clinically 
appropriate 
● discontinue patient from BKM120 
● instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes mellitus 
(such as those provided by the American Diabetes Association) 
during the study 
● consider use of oral anti-hyperglycemic therapy such as 
metformin 
● check FPG at least weekly for 8 weeks, then continue checking at 
least every 2 weeks if clinically indicated 
For non-fasting plasma glucose >500 mg/dL (> 27.8 mmol/L) 
accompanied by signs/symptoms of hyperglycemia (for example, 
mental status changes, excessive thirst, polyuria), or presence of 
blood or urine ketones, discontinue BKM120 and following guidance 
for management of Grade 4 fasting plasma glucose (FPG). 
CARDIAC 
Cardiac - Left Ventricular systolic dysfunction 
Asymptomatic,  
resting ejection fraction 40-50%; 
or 10-20% drop from baseline 
Maintain dose level, and continue BKM120 with caution 
Repeat LVEF within 4 weeks or as clinically appropriate 
Symptomatic,  
responsive to intervention,  
ejection fraction 20-39% 
or > 20% drop from baseline 
● Omit BKM120 until resolved* (as defined below), then  1 dose 
level 
● LVEF measurement to be repeated, if not resolved* within 21 
days, permanently discontinue patient from BKM120 treatment 
Refractory or poorly controlled,  
ejection fraction < 20% 
● Permanently discontinue patient from BKM120 
*the event is considered resolved when the patient is asymptomatic, has a resting ejection fraction ≥ 40% and 
≤20% decrease from baseline. 
Cardiac – QTc prolongation  


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
QTcF > 500 ms (≥ 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 or >60ms from baseline 
● If QTcF remains > 500 ms or >60ms from baseline, repeat ECG 
as clinically indicated, but at least once a day until the QTcF returns 
to < 480 ms. Seek cardiologist input. 
● Once QTcF prolongation has resolved, BKM120 may be restarted 
at a one lower dose level 
Second Occurrence: 
● Permanently discontinue patient from BKM120 
Other Cardiac Events 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Permanently discontinue patient from BKM120 
OTHER 
Mood alteration/Psychiatric Disorders 
* Note: For all grades, if question 9 on the PHQ-9 has a positive response (as indicated by selecting "1", "2", or 
"3"), omit study drug and refer patient for psychiatric consult regardless of the total questionnaire score or 
CTCAE grading to confirm if study drug should be interrupted or permanently discontinued. 
Grade 1* 
● Maintain dose level 
● Consider psychiatric consultation at the investigator’s discretion 
and introduce optimal management (e.g. as per local guidelines 
and/or psychiatric/expert consultation) 
 
Grade 2* 
● Omit dose until resolved to ≤ Grade 1 or baseline status 
● Consider psychiatric consultation at the investigator’s discretion 
and introduce optimal management (e.g. as per local guidelines 
and/or psychiatric/expert consultation) 
 
● First event:  if the condition resolved to Grade ≤ 1 or to baseline 
status, continue to co-medicate and then maintain the dose level  
● Second and further events:  if the condition resolved to Grade ≤ 1 
or to baseline status, continue to co-medicate and then ↓ 1 dose level 
Grade 3* 
Omit dose until resolved to ≤ Grade 1 or baseline status 
● Psychiatric consultation is required and introduce optimal 
management  
● if the condition resolved to Grade ≤1 or to baseline status, 
continue to co-medicate and then  1 dose level 
Grade 4* 
Permanently discontinue patient from BKM120 
● Psychiatric consultation is required  
● Introduce optimal management (e.g. as per local guidelines) 
Rash 
Grade 1 
Maintain dose level. Consider to initiate appropriate skin toxicity 
therapy (such as antihistamines, topical corticosteroids)  
Grade 2 
First occurrence: Omit dose until resolved to grade ≤ 1 then:  
● If resolved in ≤ 2 weeks, maintain dose level.  
● If resolved in more than 2 weeks,  1 dose level.  
Second occurrence:  1 dose level. 
Initiate/intensify appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids) 


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
Grade 3 
First occurrence: omit dose until resolved to CTCAE Grade ≤ 1; then 
 1 dose level. 
Second occurrence: permanently discontinue patient from BKM120. 
Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation.  
According to the investigators discretion, a paired skin biopsy could 
be obtained (from both an affected and an unaffected skin area for 
local histopathology assessment) if clinical appropriate. 
 
Grade 4 
Permanently discontinue patient from BKM120. 
Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation. 
According to the investigators discretion, a paired skin biopsy could 
be obtained (from both an affected and an unaffected skin area for 
local histopathology assessment) if clinical appropriate. 
 
Fatigue (asthenia) 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then: 
● If resolved in ≤ 7 days, maintain dose level 
● If resolved in > 7 days,  1 dose level 
Pneumonitis  
please see Table 4-8, Section 4.1.2.4.1 for additional follow up for 
selected toxicities 
Other non- hematological adverse events 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Permanently discontinue patient from BKM120 
Note: Omit dose for ≥ Grade 3 vomiting or Grade 3 nausea only if the 
vomiting or nausea cannot be controlled with optimal antiemetic 
 
Mucositis  
Grade 1 / Tolerable Grade 2 
Maintain dose level. 
Non-alcoholic or salt water mouth wash (see also section for 
additional follow up for selected toxicities) 
Intolerable Grade 2 or Grade 3 
First occurrence: hold until resolved to grade ≤ G1 and  1 dose level 
(if stomatitis is readily manageable with optimal management, re-
introduction at the same level might be considered at the discretion of 
the investigator).  
Second occurrence: hold until resolved to grade ≤ G1 and  1 dose 
level. 
Grade 4 
Permanently discontinue patient from BKM120. 
** Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
These changes must be recorded on the Dosage Administration Record eCRF. 
4.3 
Monitoring of BKM120 Suspected Toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event, 
clinically significant laboratory value(s) or abnormal test procedure result(s), must be followed 
as outlined in Table 4-5, at least once a week for 4 weeks, and subsequently at 4-week intervals, 
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delay of > 28 days from the intended day of the next scheduled dose and has had more than two 
dose reductions, 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 4.2.5.1  
4.4 
Known Undesirable Side Effects of BKM120 
4.4.1 
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 symptoms 
CTCAEhy Grade ≥ 2 should immediately be examined by a psychiatrist and closely followed 
medically. Medical treatment with mood stabilizers (2nd generation antipsychotics) such as 
olanzapine and quetiapine may be applied as per investigator’s discretion and following 
consultation of a psychiatrist. 
4.4.1.1 
Management of Mood Alteration 
Guidelines for the treatment of BKM120 induced psychiatric disorders 
Psychiatric adverse events will be closely monitored and evaluated at each planned 
visit until recovery to Grade ≤ 1 or baseline status. The grading of psychiatric adverse 
events/mood alterations must be based on the clinical interpretation of severity 
according to the NCI- CTCAE (v 4.03) guidelines. 
For patients who experience new or worsening of existing psychiatric AEs of Grade 
≥1, psychiatric consultation should be considered as described in Table 4-5. 
Patient self-reported mood questionnaires (GAD-7 and PHQ-9) will be used for 
screening and during the study treatment phase to aid the investigator in identifying 
new or worsening of events. For additional information regarding safety assessments 
based on patient self-reported mood questionnaires, please refer to Section Patient 
self-rating mood questionnaires. 
If question 9 in the PHQ-9 has a positive response (as indicated by selecting "1", "2", 
or "3"), omit treatment with BKM120 and refer the patient to the on-site psychiatrist 


 
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or a local psychiatrist for psychiatric consultation for optimal management regardless 
of the total questionnaire score or CTCAE grading to confirm if study drug should be 
interrupted or permanently discontinued. In this specific case, the psychiatric advice 
can overrule the patient’s PHQ-9 self-assessment. During the study, subjects will be 
monitored at regular scheduled visits (eg, Day 15 of Cycle 1, Day 1 and Day 15 of 
Cycles 2, Day 1 of each subsequent cycle, and at the End of Treatment visit) by the 
investigator/site staff through personal interaction and the two self-reported 
questionnaires. For patients who fax or email their questionnaires; the study nurse 
will promptly review the questionnaires as they become available. Additional 
assessments may be done according to the clinical judgment of the investigator if 
desired. 
 
Table 4-6 GAD-7 anxiety scale 
 


 
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Table 4-7 PHQ-9 depression scale 
 
 
 


 
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4.4.2 
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 4-5. 
4.4.2.1 
Management of Hyperglycemia 
In addition to the dose modification and hyperglycemia treatment guidelines in Table 4-5: 
• Under the supervision of an endocrinologist, an insulin regimen should be initiated 
according to institutional standard of care or the Treat-To-Target Algorithm for Lantus® 
(Riddle, Rosenstock, and Gerich 2003). 
 
• For any hyperglycemia ≥ grade 1, the patient should continue to follow dietary guidelines 
provided by the American Diabetes Association (American Diabetes Association 2004). 
 
• For each patient, a maximum of 2 dose reductions will be allowed after which the patient 
should be discontinued from the study. In addition, a patient must discontinue treatment with 
BKM120, if after treatment is resumed at a lower dose, hyperglycemia recurs at a worse 
severity. 
 
• For each patient, once a dose level reduction has occurred, the dose level may not be re-
escalated in that patient during future treatment cycles with BKM120. 
 
• Based upon the results of preliminary clinical data and actual laboratory values (e.g., glucose, 
insulin) generated, the treatment recommendations for study drug induced hyperglycemia may 
be modified as needed.  
4.4.3 
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 
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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. 
4.4.3.1 
Management of Cardiac Events  
At the screening visit a 12-lead electrocardiogram (ECG), and an echocardiogram or MUGA 
(ECHO/MUGA) will be performed to assess eligibility. Repeat ECGs will be performed at 
screening and as clinically indicated. An ECHO/MUGA will be repeated at Cycle 4 and then 
every 4th cycle thereafter. 
4.4.4 
Lung Toxicity/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 pneumonitis grade 2 eight 
weeks after the first dose of BKM120 at 100 mg 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 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). 
4.4.4.1 
Management of Pneumonitis 
All patients participating in clinical trials with BKM120 will be routinely asked about 
and observed for the occurrence of adverse events which could include new or 
changed pulmonary symptoms (consistent with lung abnormalities). CT scans and 
pulmonary function tests should be done, as clinically indicated, or if there are 
symptoms that indicate that the patient has developed pneumonitis. In case of a 
documented pneumonitis, the guidelines (including dose modifications) in Table 4-8 
should be followed. Consultation with a pulmonologist is highly recommended for 
any pneumonitis case during the study treatment. 


 
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Table 4-8 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, (or as per 
local practice) 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, (or as 
per local practice) 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 3) 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 
28 days. 
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, (or as per local 
practice) until return to within 
normal limits. Bronchoscopy with 
biopsy and / or BAL is 
recommended. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Hold treatment with BKM120 until 
recovery to ≤ Grade 1. May restart 
study treatment within 28 days at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing, if possible, includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat at least 
every 6 weeks, (or as per local 
practice) 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. 
4.4.5 
Liver Toxicity 
4.4.5.1 
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 or bilirubin* values. 
 
Monitoring Cycle 3 and more: monthly or more frequently if clinically indicated. In case of 
any occurrence of ALT/ AST or bilirubin* increase ≥ grade 2 the liver function tests must be 
monitored weekly or more frequently if clinically indicated until resolved to ≤ grade 1. 
 
In case of any occurrence of ALT/ AST or bilirubin* increase ≥ grade 3  the liver function tests 
must be monitored weekly or more frequently if clinically indicated until resolved to ≤ grade 
1; hereafter the monitoring should be continued every other week or more frequently if 
clinically indicated until the end of treatment with study medication. 


 
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Patients who discontinued study treatment should be monitored weekly, including LFTs* or 
more frequently if clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE 
grade change over 4 weeks). 
4.4.5.2 
Management of Hepatotoxicity (ALT and/or AST >3.0x ULN and total 
bilirubin >2.0x ULN)  
Criteria for interruption and re-initiation of BKM120 treatment in case of the occurrence of 
AST, ALT or bilirubin increase are detailed in Section 4.2, Table 4-5. Patients with clinically 
significant liver test abnormalities should perform liver-directed medical history, physical 
examination and other tests as medically indicated to assess potential relationship with study 
treatment and rule out other underlying causes (e.g. disease progression/obstruction, 
infection/hepatitis or other liver diseases, sepsis, metabolic diseases including diabetes, 
concomitant medications including herbals, alcohol, drug-drug interaction, cardiovascular 
disease/ischemia, other organ injuries, etc.). Any pre-existing liver conditions or risk factors 
should be reported in the respective medical history and concomitant medication CRF pages 
(if not done already). All patients with ALT or AST >3.0 x ULN and total bilirubin > 2.0 x 
ULN in the absence of cholestasis (elevation of alkaline phosphatase [ALP] in patients 
without bone metastasis or if bone metastasis are present elevation of 5’-nucleotidase and 
ALP liver fraction) must be immediately withdrawn from BKM120, and every attempt should 
be made to carry out locally the liver event follow-up assessments as described below:  
• Inform the sponsor about the event immediately after its occurrence by reporting the event 
immediately in the clinical database if it meets the criteria for an AE or SAE.  
• Evaluate if associated with the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash or eosinophilia, or other organ involvement.  
• Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), and blood count with differential to assess eosinophilia.  
• Perform liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease including metastasis or new lesions, obstruction/compression, etc.  
• Perform viral hepatitis and other serology tests:  
o Hepatitis C (HCV) serology and viral RNA, Hepatitis B (HBV) serology and viral 
DNA, Hepatitis A (HAV) Immunoglobulin M (IgM) and HAV total  
o Hepatitis E (HEV) serology: IgM and IgG, viral RNA  
o Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Epstein-Barr viral (EBV) 
serology  
• Verify and record the use of concomitant medications, acetaminophen, herbal remedies, and 
other over the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.  
• Consultation with a specialist(s) or a hepatologist(s) is recommended. 


 
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• Liver biopsy as clinically indicated to assess pathological change and degree of potential 
liver injury  
• LFTs should be followed-up weekly until resolve to ≤ grade 1, baseline or stabilization (no 
CTCAE grade change over 4 weeks) and outcome documented on the respective AE and lab 
chemistry pages. 
4.4.6 
Skin Toxicity/Hypersensitivity  
Buparlisib should be discontinued in cases of CTCAE grade 3/4 hypersensitivity reaction and 
medical intervention according to the local standards instituted. 
4.5 
Study Termination 
A patient is considered terminated from the study when the decision to permanently stop the 
study medication and survival follow-up is made. Subjects can terminate their participation in 
this study at any time without penalty or loss of benefits to which the subject is otherwise 
entitled. A subject’s participation may be terminated by the Principal Investigator due to any of 
the following:  
1. adverse event(s) 
2. protocol violation 
3. subject withdrew consent 
4. lost to follow-up 
5. administrative problems 
6. Death 
7. If a patient requires a dose delay of > 28 days from the intended day of the next 
scheduled dose and has had more than two dose reductions, then the patient should be 
discontinued from the study. 
 
The reasons in which a subject is terminated from the study must be documented in the 
patient’s chart or records. 


 
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4.6 
Visit Schedule and Assessments 
4.6.1 
Visit Schedule 
Table 4-9 Evaluation and Visit Schedule 
Examination 
Screeni
ng/ 
Baselin
e 
Cycle 1 
Cycle 2 
 
Cycle 3- Cycle n11  
Follow-
up 
Day of Cycle 
-21 
1 
158 
1 
15
8 
3 
4 
5 
6 
7 
8 
9 
etc 
EOT 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Pathology 
Review9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
Test (within 72 hours 
of first treatment for 
WOCBP) 
X 
As clinically indicated.  
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
X8 
X 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Genomic Analysis 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
(including skin rash 
assessment) 
X 
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 
X 
 
Neuro-psychiatric 
assessment (PH1-9 
& GAD-7)1 
X 
X 
X 
X 
X 
X  X 
X 
X 
X 
X 
X 
X 
X 
 
MUGA/ECHO2 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
12-lead ECG 
X 
 
X 
As clinically indicated 
 
Radiological tumor 
assessment/respons
e assessment (Chest 
CT scan)3 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematology4 
X 
X 
X8 
X 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry5 
X 
X 
X8 
X 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation Profile6 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Fasting plasma 
glucose7 
X 
X  
X8 
X 
X8 
X  X 
 
X 
X 
X  X 
X 
X 
X  
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
Medications 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hepatotoxicity 
follow-up testing 
procedures 
As clinically indicated 
 


 
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1 PHQ-9 and GAD-7 questionnaires will be completed in clinic at each visit through the end of Cycle 2. Symptomatic 
patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis On Day 1 starting at Cycle 3 and for 
all subsequent cycles while active on the treatment portion of the study. Questionnaires on day 15 of cycles 1 and 2, as 
well as any other questionnaires required at times other than the scheduled visits can be completed by the patient at 
home and faxed to the Investigator or the authorized study member for evaluation to fax number (317-274-8007) or sent 
via PDF. 
2 MUGA/ECHO Baseline, Cycle 4 then every 4th cycle.  
3 Radiological tumor assessment should be performed at screening and every 8 weeks from start of treatment until 
progression of disease as per RECIST 1.1, or end of treatment. All assessments should be performed within ±7 days of 
the scheduled day of assessment. Other scans, as appropriate for measurements will be performed at the same time 
interval. 
4 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.   
5Serum chemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, 
lipase, alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric 
acid, total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein are required at 
baseline and at end of treatment. Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin 
(direct and indirect), creatinine, alkaline phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and 
total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained on the first day of odd numbered 
cycles only. C1D1 assessments may be performed up to 72 hours prior to the scheduled visit. All other draws should 
occur within 24 hours of the intended visit. 
6 Coagulation - PT or INR, PTT, and C1D1 assessments may be performed up to 72 hours prior to the scheduled visit. 
Additional assessments will be performed on Day 1 of Cycle 2 (≤ 72 hours prior to dosing) and repeated every other 
cycle. A repeat coagulation profile panel is required at the time of study treatment discontinuation. Patient entering the 
study while receiving anti-coagulation therapy or those who have the initiation of an anti-coagulation therapy should 
have their coagulation test performed on a weekly basis. 
7 Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically 
indicated. 
8 May be performed at outside institution with results transmitted via fax (to fax number 317-274-8007) or via PDF. 
9Pathology will undergo central review by IU Department of Pathology to confirm eligibility which will include obtaining 
blocks or primary or metastatic lesion s which can be obtained prior to the 21-day screening window. 
10Genomic analysis consists of collecting peripheral whole blood prior to the first dose of chemotherapy. DNA and 
RNA will be extracted from a core tumor specimen as part of standard of care prior to enrollment. See Section 4.2.6, 
Collection of Genomics Data. 
11 Assessments for Cycles 3 and beyond will occur on Day 1. 
4.6.2 
Efficacy Assessments 
4.6.2.1 
Anti-Tumor Effect 
Imaging will be obtained at baseline and at the end of every two cycles. Tumor responses will 
be assessed by Response Evaluation Criteria in Solid Tumors Guideline (RECIST v1.1) 
(Eisenhauer, et al 2009). 
4.6.2.2 
Measurement Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1) 
Measurable: 
• 
Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
o 10 mm by CT, MRI or PET scan (slice thickness no greater than 5 mm) 
o 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
o 20 mm by chest X-ray 


 
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• 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT, MRI 
or PET scan (slice thickness recommended to be no greater than 5 mm). At baseline 
and in follow-up, only the short axis will be measured and followed.  
2) 
Non-measurable: 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging. 
4.6.2.3 
Specifications by Methods of Measurements 
1) 
Measurement of Lesions: 
 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the treatment start 
and never more than 4 weeks before the beginning of the treatment. 
 
2) 
Method of Assessment: 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
• 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and ≥10mm diameter as assessed using calipers (e.g. skin nodules). 
For the case of skin lesions, documentation by color photography including a ruler 
to estimate the size of the lesion is suggested. As noted above, when lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the 
study. 
• 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated lung.  
• 
 
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness is 5mm or 
less.  
• 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. 


 
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• 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  
• 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response.  
• 
 
Cytology, histology: These techniques can be used to differentiate between PR 
and CR in rare cases if required by protocol. 
4.6.2.4 
Tumor Response Evaluation 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
• 
When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and will 
be recorded and measured at baseline. 
• 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  
• 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. 
If lymph nodes are to be included in the sum, then as noted above, only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of 
the disease. 
4.6.2.5 
Response Criteria 
For other details and special circumstances of the RECIST 1.1 guidelines, refer directly to 
reference. 
• 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
• 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.  
• 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance 
of one or more new lesions is also considered progression). 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 


 
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Time Point Response of Target Lesions 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not Evaluated 
No 
PR 
PR 
Non-PD 
or Not All Evaluated 
No 
PR 
SD 
Non-PD 
or Not All Evaluated 
No 
SD 
Not All Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
4.6.2.6 
Definitions of Endpoints 
• 
Progression-Free Survival (PFS): Duration of time from start of treatment to time 
of documented progression or death 
• 
Overall Response Rate (ORR): Number of patients who achieve either a partial or 
complete response divided by the number of patients 
• 
Duration of Response (DoR) (Among Responders, PR + CR): A measurement 
from the earliest time when response criteria are met until death or progression.  
Patients still meeting the criteria for response at the end of the study are treated as 
censored. 
• 
Overall Survival (OS): Time from the date of enrollment to the date of death due 
to any cause or the last date the patient was known to be alive (censored observation) 
at the date of data cutoff for the final analysis 
• 
Disease Control Rate (DCR):  Number of patients who achieve either a partial or 
complete response or stable disease for at least 4 months divided by the number of 
patients. 


 
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4.6.3 
Safety Assessments 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine 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. 
4.6.4 
Treatment Compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to return 
all unused study medication. 
4.6.5 
Adverse Events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is 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, 


 
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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 [Investigators’ Brochure]. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
4.6.5.1 
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 patient’s 
general condition 
• 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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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 [Investigator’s Brochure] 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. 
4.6.5.2 
Novartis Instructions for Rapid Notification of Serious Adverse Events 
The principal investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). 
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.  


 
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For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
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+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 


 
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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. 
4.6.6 
Laboratory Evaluations 
4.6.6.1 
Pregnancy Test 
A serum pregnancy test (β-HCG) is required for all women of child-bearing potential at 
screening, within 72 hours prior to the first dose of BKM120. Note: Postmenopausal women 
must have been amenorrheic for ≥ 12 months in order to be considered “of non-childbearing 
potential”. This should be documented appropriately in the patient’s medical history. Additional 
pregnancy tests should be performed as clinically indicated.  
4.6.6.2 
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. 
4.6.6.3 
Coagulation Profile 
The coagulation profile includes prothrombin time or INR, and activated partial thromboplastin 
time. 


 
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4.6.6.4 
Serum Chemistry 
Biochemistry includes the following parameters: K+, Na+, Ca++, Mg++, LDH,ALT, AST, total 
bilirubin (direct and indirect), creatinine, amylase, GGT, lipase, alkaline phosphatase 
(fractionated if alkaline phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, 
total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein 
are required at baseline and at end of treatment.  Subsequent assessments always include K+, 
Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), creatinine, alkaline phosphatase, 
bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total 
cholesterol, HDL, LDL, triglycerides should be obtained on the first day of odd numbered 
cycles only. C1D1 assessments may be performed up to 72 hours prior to the scheduled visit. 
All other draws should occur within 24 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. 
4.6.6.5 
Urinalysis 
Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity) and 
will be performed at screening visit and EOT visit. A microscopic (WBC/HPF, RBC/HPF, and 
any additional findings) exam need only be performed if the urinalysis result is abnormal.  
This must be supplemented with laboratory quantification of any potentially relevant 
abnormalities. 
4.6.6.6 
Hepatotoxicity 
Hepatotoxicity follow-up testing will be performed when needed (refer to Section 4.4.5.2 
Management of hepatotoxicity [ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN]). 
4.6.6.7 
Viral hepatitis serology and other tests for hepatotoxicity follow-up 
Viral hepatitis serologic tests are performed confirm patient’s eligibility when needed per 
clinical judgment and specific patient’s clinical circumstances.  
During study treatment, viral hepatitis serologic and other tests will be performed as per the 
guidelines of management of hepatotoxicity (ALT or AST >3.0x ULN and total bilirubin > 2.0x 
ULN) in patients receiving BKM120. Refer to Section 4.4.5.2 Management of hepatotoxicity 
(ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) for details.  
Viral hepatitis serology includes the following:  
• Hepatitis A IgM antibody and hepatitis A serology total  
• Hepatitis B surface antigen, Hepatitis B Core Antibody (IgM) and viral DNA 
• Hepatitis C serology and viral RNA  
• Hepatitis D RNA (where needed)  
• Hepatitis E IgM and IgG antibody and viral RNA  


 
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Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), and blood count with differential to assess eosinophilia. 
Novartis Confidential Page 18 BKM120 liver toxicity standard language based on protocol 
CBKM120F2303 Amendment 3 Additional viral serology tests may include:  
• Cytomegalovirus IgM antibody  
• Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody 
or monospot testing)  
• Herpes Simplex Virus 
Table 4-10 Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Viral hepatitis serologic tests and other tests 
for hepatotoxicity follow-up * 
HAAb, HBsAg, HBsAb HBcAb, HCV RNA 
or HDV RNA (where needed), HEAb, 
CMVAb, EBcAb, ALP, CPK, LDH, WBC 
(eosinophilia), and others. 
* Hepatotoxicity follow-up testing/procedures will be performed locally (refer to Section 
4.4.5.2 Management of hepatotoxicity [ALT and/or AST >3.0x ULN and total bilirubin >2.0x 
ULN] and Section 4.6.6.7 Viral hepatitis serology and other tests for hepatotoxicity follow-
up). 
4.6.6.8 
Collection of Genomics Data 
A genomic analysis will be performed and analyzed if there are statistically objective responses 
to identify markers for patients who respond and do not respond to therapy. For each patient, 
DNA & RNA will be extracted from a core tumor specimen collected as part of standard of care 
prior to enrollment. Blocks or 5 (10 micron thick) slides should be requested and/or sent to Dr. 
Milan Radovich’s lab for future research studies located at:  
 
Walther Hall, Room R3 C240 
980 W. Walnut Street 
 Indianapolis, IN 46202. 
 
In addition, DNA extracted from 9mL of peripheral whole blood will be collected (in a BD 
Vacutainer EDTA tube) prior to the first dose of therapy for all patients. Extractions will be 
performed in using a Qiagen DNA/RNA All Prep Kit (Qiagen, Valencia CA). For DNA 
sequencing, we will employ high-coverage whole-exome chemistry to ensure capture of both 
structural and nucleotide-level mutations. Briefly, the whole exome sequencing will be 
performed on our group’s own Ion Proton Sequencers. The Ion Proton has been previously 
demonstrated to produce high-quality exomes for germline variation detection. 100ng of 
genomic DNA for both tumor and blood normal will undergo library preparation for the Ion 
Proton Sequencer using the Ion Ampliseq Exome Kit (Life Technologies).  This amplification-
based method of exome enrichment covers 97% of all consensus coding sequence with >90% 
of on-target bases covered and >90% coverage uniformity. Sequencing for this project will 


 
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utilize the Ion Proton PII chip yielding an estimated 400 million high quality 100bp reads per 4 
hour run. In addition, we will also utilize the Ion Hi-Q sequencing chemistry, which uses a new 
polymerase that results in a 90% reduction in the indel error rate for increased accuracy. All 
samples will be sequenced to an average of 100X coverage. Each sequencing run will be 
evaluated for technical quality control metrics including: efficient ion sphere loading, 
percentage of polyclonality, and mean raw accuracy. Following technical quality control, raw 
sequencing reads will be mapped to the human genome (hg19) using the highly efficient TMAP 
algorithm with output in standard BAM format. High confidence SNPs and indel variants will 
be called using the Ampliseq variant caller which incorporates local re-alignment as well as 
filtering for homopolymer induced false-positive indels. A minimum of 10 sequencing reads 
will be needed for a SNP or indel to be called, and only bases with quality values ≥ 20 will be 
considered. Final variant calls will be reported in standard VCF format. For additional quality 
review, we will estimate the average transition/transversion (Ti/Tv) ratio per sample. For RNA-
sequencing of tumor RNA, libraries will be prepared using the Ion Total RNA-Seq Kit v2 (Life 
Technologies), followed by emulsion PCR, templating, and sequencing as described above. 
After quality filtration, we estimate generation of 400 million 100bp fragment sequencing reads 
per sample. For bioinformatics analysis, reads will be mapped to the human genome using the 
STAR algorithm; differential expression using Cufflinks, and visualization using Partek 
Genomics Suite (Partek, Inc). For calling expressed gene fusions, we will use the Tophat-Fusion 
(Broad Institute) and FusionMap (Amgen) algorithms. Of importance, all genomic data will be 
stored on the HIPAA-compliant IU Scholarly Data Archive, and all analyses will be performed 
on secure HIPAA-compliant servers. 
4.6.7 
Vital Signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. Blood pressure, pulse and respiration rate should be measured on 
patients after at least 3 minutes in the sitting position as per the visit schedule.  
4.6.8 
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. 
4.6.9 
Neuropsychiatric Assessments 
Patient self-rating mood questionnaires for anxiety and depression (PHQ-9, GAD-7) will be 
applied at: 
• Screening 
• Days 1 and 15 of Cycle 1 
• Day 1 and 15 of Cycle 2 


 
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• Day 1 of Cycle 3 and subsequent cycles (only for patients who have not shown mood 
alterations during the first 2 cycles, patients who did should continue to fill out the questionnaire 
on a weekly base). 
Questionnaires on day 15 of cycles 1 and 2, as well as any other questionnaires required at times 
other than the scheduled visits can be completed by the patient at home and faxed to the 
Investigator or the authorized study member for evaluation. 
• End of Study treatment 
Additional assessments may be done according to the clinical judgment of the Investigator. 
Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis 
while active on the treatment portion of the study. 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. 
4.6.10 
ECG/ECHO 
A standard 12 lead ECG is to be performed at screening, C1D15 and as clinically indicated. 
An echocardiogram (ECHO) or MUGA will be performed to assess eligibility. ECHO/MUGA 
will be repeated at Cycle 4 and then every 4th cycle thereafter. 
4.6.11 
Performance Status 
Performance status will be assessed at screening and per the visit schedule. The Eastern 
Cooperative Oncology Group (ECOG) Performance Status Scale will be used for this study. 
See Appendix A for details. 
4.6.12 
Drug Levels and Pharmacokinetic Assessments 
• None will be made.  
5 
Data Management 
5.0 
Data Collection 
This study will utilize electronic Case Report Form completion in the OnCore® database. A 
calendar of events and required forms are available in OnCore® at https://cancer.iu.edu/oncore. 
The OnCore® database is a comprehensive database used by the Clinical Trials Research Office 
(CRO) and supported by the Indiana University Cancer Center. OnCore® properly used is 
compliant with Title 21 CFR Part 11. 
Access to data through OnCore® is restricted by user accounts and assigned roles. Once logged 
into the OnCore® system with a user ID and password, OnCore® defines roles for each user 
which limits access to appropriate data. User information and password can be obtained by 
contacting the CRO at 317-274-0930. 
All source documents are to remain in the patient’s clinic file. All documents should be kept 
according to applicable federal guidelines. Clinical trial data in OnCore® are periodically 
monitored by the IU Simon Cancer Center Clinical Trials Monitoring Committee. 


 
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6 
Patient Consent and Peer Judgment 
The protocol and informed consent form for this study must be approved in writing by the 
appropriate Institutional Review Board (IRB) prior to any patient being registered on this study. 
Changes to the protocol, as well as a change of principal investigator, must also be approved by 
the Board. Records of the Institutional Review Board review and approval of all documents 
pertaining to this study must be kept on file by the investigator (housed in the Clinical Research 
Office) and are subject to FDA inspection at any time during the study. Periodic status reports 
must be submitted to the Institutional Review Board at least yearly, as well as notification of 
completion of the study and a final report within 3 months of study completion or termination. 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
7 
Statistical Methods 
7.0 
General Considerations 
Statistical analysis of this study will be the responsibility of the Department of Biostatistics at 
Indiana University School of Medicine. Parameter estimates and relevant summary statistics 
will be reported for both efficacy and safety outcomes. Continuous variables will be 
summarized by means, medians, minima, maxima and standard deviations. Categorical 
variables will be summarized by frequencies and percentages. Missing data will not be imputed. 
Additional exploratory analysis will be conducted when appropriate. Changes from the analysis 
plan will not require an amendment to the protocol unless it changes a significant feature in the 
protocol. The statistical analysis methods are outline below. 
7.1 
Study Design 
This is a single arm, open label, two-stage, phase II clinical trial. No randomization or blinding 
is involved.   
7.2 
Analysis Population 
7.2.1 
Enrolled Population 
The enrolled population comprises all patients who meet the eligibility criteria and are 
registered onto the study. 
7.2.2 
 Safety Population 
The safety population comprises all patients who have received at least one dose of the study 
medication. This set will be used for safety analysis. 
7.2.3 
Efficacy Population 
The efficacy population comprises all patients with disease that is radiographically evaluable at 
initial and at least one follow-up time point. This population will be used for efficacy analysis. 


 
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7.3 
Sample Size, Accrual and Study Duration 
The primary end point of the study is objective response rate (CR+PR) according to RECIST 
1.1 criteria for BKM120 monotherapy in patients with advanced thymomas. All sample size 
estimates are based on the objective response rate. 
 
A two-stage Minimax design will be used with two-sided alpha = .10 and power of 90%.  The 
study will try to rule out a 10% objective response rate (p0= 0.10) and target a modest response 
rate of 30% (p1= 0.30). The study will initially enroll 16 evaluable patients with thymoma; if 0 
to 1 of the 16 patients demonstrate a partial response then no further patients will be accrued. If 
2 or more of the first 16 patients have a response, then accrual would continue until a total of 
25 evaluable patients have been treated. A temporary pause in the accrual to the trial may be 
necessary to ensure that enrollment to the second stage is warranted. If there are 2 to 4 patients 
with a response in the total of 25 evaluable patients, then this would be an uninterestingly low 
rate, while if there were 5 or more patients of the 25 who have a response, this would be 
sufficiently interesting to warrant further study of this agent in later trials. Under the null 
hypothesis (10% response rate), the probability of early termination in this cohort is 52%. 
 
It is anticipated that approximately 2 patients per month overall may enroll on this trial. Thus, 
accrual should be completed in approximately 12-18 months. In order to allow for a small 
number of in-evaluable patients, the accrual ceiling will be set at 27.  
7.4 
Patient Characteristics 
Baseline patient characteristics will be tabulated, such as demographics (age, race, gender), and 
ECOG performance score. 
7.5 
Significant Protocol Violations 
Significant protocol violations such as with respect to eligibility criteria and treatment plan will 
be tabulated. 
7.6 
Concomitant Medications 
Drugs that might affect the study medication, as described in Section 4.0.2, will be tabulated. 
7.7 
Exposure and Compliance 
Exposure to the study medication will be summarized by frequencies and rates of the doses 
given. Reasons of not completing all doses will be tabulated. 
7.8 
Efficacy Analysis 
The main analysis of the primary endpoint, objective response rate (ORR) after two months, 
will be based on the safety population (see section 7.12.2 below). The primary efficacy 
endpoint, ORR (defined as the proportion of patients with the best overall response of PR or 
CR), together with corresponding 95% exact binomial confidence interval, will be calculated.  


 
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A similar analysis will be done for the secondary objective of disease control rate (DCR), 
defined as the proportion of patients with the best overall response of PR or CR or SD of at 
least 4 months). 
Progression free and overall survival will be determined using Kaplan-Meier curves.  Medians 
and other quartiles for each endpoint will be estimated in addition to the corresponding two-
sided 95% confidence intervals.  The results of this analysis may be compared in an informal 
manner to any similarly defined curves available from other published studies in comparable 
patients with the same disease.  We will also repeat all analysis using the efficacy population 
as supportive analyses. 
7.9 
Safety Analysis 
Toxicities according to CTCAE 4.0 will be summarized by frequencies and rates calculated as 
the proportion of patients in the safety population experiencing SAEs, discontinuations due to 
AEs, and AEs.  Two sets of tables will be generated: one for the overall toxicities and one for 
toxicities related to the study medication (possibly related, probably related and definitely 
related). Toxicities will be grouped by system using MedRA preferred terminology. Grade 1 to 
4 will be reported individually and also as grade 3/4.  Deaths will be reported individually.  AE 
related to neuropsychological events (depression and anxiety) will also be tabulated. 
7.10 
Statistical Analysis of Genetic Data 
Statistical analysis will include identification of differentially expressed genes, and pathways 
between tumors than exhibited greater response (CR+PR+SD) compared to those that did not 
(PD) using two-sample t-tests; association of expressed genes and signatures with response 
and survival outcome (multivariable logistic and cox regression, respectively); identification 
of significantly mutated genes associated with response and survival outcome (MutSigCV, 
which determines significance by testing whether the observed mutations in a gene 
significantly exceed the expected counts based on a background model); and association of 
mutational context spectra with response and survival outcomes (Non-Matrix Factorization). 
In addition, data will also be integrated using a variety of tools designed for multi-platform 
approaches. This includes network & pathway analyses (IPA and GeneGo); CNV and 
mutation integrated clusters (IntClust); mutually exclusive modules in cancer (MEMo); drug 
association databases (Metacore, IPA); and multi-platform cluster of clusters (C-of-C). 
7.11 
Interim Analysis 
Efficacy interim analyses will be performed at described above based on the standard two-
stage design. 
7.12 
Reporting and Exclusions 
7.12.1 
Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with BKM120. 


 
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7.12.2 
Evaluation of Response 
All patients included in the study who received any study drug must be assessed for response 
to treatment, even if there are major protocol treatment deviations or if they become ineligible 
after enrollment. Each patient will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database]. 
 
All of the patients who meet the eligibility criteria and are enrolled (with the exception of those 
who received no study medication) should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. Precise definitions for categories 4-9 are 
protocol specific and included in section 4.2.2. 
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. The 95% confidence intervals should also be provided. 
8 
Data and Safety Monitoring Plan (DSMP) 
Investigators will conduct continuous review of data and patient safety. Monthly review 
meetings are required and will include the principle investigator, clinical research specialist 
and/or research nurse (other members per principle investigator’s discretion). Monthly 
meeting summaries should include review of data and patient safety by including for each 
dose level: the number of patients, significant toxicities as described in the protocol, dose 
adjustments and responses observed. Summaries are to be submitted to DSMC@iupui.edu 
weekly and reviewed monthly.  
 
Study Auditing and Monitoring  
All trials conducted at the IUSCC are subject to auditing and/or monitoring. Reports will be 
reviewed by the full DSMC at the time of study review (Reference Risk Table in full DSMC 
Charter).  
 
Early Study Closure  
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks 
(or benefits) to the patient warrant early closure of the study, this recommendation should be 
made in writing to the Data Safety Monitoring Committee. Alternatively, the DSMC may 
initiate suspension or early closure of the study based on its review. 


 
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The DSMC has streamlined the reporting process by utilizing reports from OnCore®. This has 
allowed direct view of reports within the Clinical Trials Management System (CTMS); thus 
discontinuing paper reports. SAE reports are entered into OnCore® monthly and reviewed by 
the DSMC chair and/or coordinator monthly. Findings will be reported to the full DSMC at 
the time of study review.  
 
Reporting Death  
Death will be reported per local IRB reporting guidelines (Section 5.8 of the Unanticipated 
Problems and Noncompliance SOP).  
 
Study Accrual Oversight  
Accrual data will be entered into the IU Simon Cancer Center OnCore® system. The Protocol 
Progress Committee (PPC) reviews study accrual twice per year while the PAC coordinator 
reviews accrual quarterly.  
 
Protocol Deviations  
Protocol deviations are entered into OnCore® and reviewed by the DSMC chair and/or 
coordinator monthly. Findings will be reported to the full DSMC at the time of study review.  
9 
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APPENDICES 
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. 
 
 

SAP_001.pdf: 
 
 
 
 
 
A Phase II Study of BKM120 (Buparlisib) in Relapsed or Refractory 
Thymomas 
 
Study no. IUCRO-0478 
Version no. 4 
Protocol Date: July 13, 2015 
Amendment 1: September 17, 2015 
Amendment 2: 1/24/2017 
Coordinating Center: 
 
Indiana University Simon Cancer Center 
 
 
Principle Investigator: 
Patrick J. Loehrer, Sr., MD 
Director, Indiana University Simon Cancer Center 
535 Barnhill Drive, Room 473 
Indianapolis, IN 46202-5289 
Telephone: 317-274-3539 
Fax: 317-278-4190 
E-mail: ploehrer@iupui.edu 


 
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Table of Contents 
Table of Contents ................................................................................................................ 2 
List of Abbreviations ........................................................................................................... 4 
1 
Background .......................................................................................................................... 7 
1.0 
Disease Background ................................................................................................ 7 
1.1 
BKM120 .................................................................................................................. 7 
1.2 
PI3K Pathway and Mechanism of Action ............................................................... 8 
1.2.1 
Preclinical Studies ................................................................................... 9 
1.2.2 
Clinical Experience ............................................................................... 12 
1.3 
Study Rationale ...................................................................................................... 22 
2 
Study Objectives ................................................................................................................ 26 
3 
Exploratory Investigational plan ....................................................................................... 26 
3.0 
Overall Study Design ............................................................................................. 26 
3.1 
Study Population .................................................................................................... 27 
3.1.1 
Patient Population ................................................................................. 27 
3.1.2 
Inclusion and Exclusion Criteria ........................................................... 27 
4 
Treatments ......................................................................................................................... 32 
4.0 
BKM120 Administration ....................................................................................... 32 
4.1 
Concomitant Therapy ............................................................................................ 33 
4.1.1 
Drugs that are Prohibited ...................................................................... 33 
4.1.2 
Drugs to be Used with Caution ............................................................. 37 
4.2 
Interruption or Discontinuation of Treatment ........................................................ 40 
4.3 
Monitoring of BKM120 Suspected Toxicities ...................................................... 46 
4.4 
Known Undesirable Side Effects of BKM120 ...................................................... 47 
4.4.1 
Neuropsychiatric Events ....................................................................... 47 
4.4.2 
Hyperglycemia ...................................................................................... 50 
4.4.3 
Cardiac Events ...................................................................................... 50 
4.4.4 
Lung Toxicity/Pneumonitis ................................................................... 51 
4.4.5 
Liver Toxicity ........................................................................................ 52 
4.5 
Study Termination ................................................................................................. 54 
4.6 
Visit Schedule and Assessments ............................................................................ 55 
4.6.1 
Visit Schedule ....................................................................................... 55 
4.6.2 
Efficacy Assessments ............................................................................ 56 
4.6.3 
Safety Assessments ............................................................................... 60 
4.6.4 
Treatment Compliance .......................................................................... 60 


 
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4.6.5 
Adverse Events ...................................................................................... 60 
4.6.6 
Laboratory Evaluations ......................................................................... 64 
4.6.7 
Vital Signs ............................................................................................. 67 
4.6.8 
Physical Examination ............................................................................ 67 
4.6.9 
Neuropsychiatric Assessments .............................................................. 67 
4.6.10 
ECG/ECHO ........................................................................................... 68 
4.6.11 
Performance Status ................................................................................ 68 
4.6.12 
Drug Levels and Pharmacokinetic Assessments ................................... 68 
5 
Data Management .............................................................................................................. 68 
5.0 
Data Collection ...................................................................................................... 68 
6 
Patient Consent and Peer Judgment .................................................................................. 69 
7 
Statistical Methods ............................................................................................................ 69 
7.0 
General Considerations .......................................................................................... 69 
7.1 
Study Design .......................................................................................................... 69 
7.2 
Analysis Population ............................................................................................... 69 
7.2.1 
Enrolled Population ............................................................................... 69 
7.2.2 
Safety Population .................................................................................. 69 
7.2.3 
Efficacy Population ............................................................................... 69 
7.3 
Sample Size, Accrual and Study Duration ............................................................ 70 
7.4 
Patient Characteristics ........................................................................................... 70 
7.5 
Significant Protocol Violations.............................................................................. 70 
7.6 
Concomitant Medications ...................................................................................... 70 
7.7 
Exposure and Compliance ..................................................................................... 70 
7.8 
Efficacy Analysis ................................................................................................... 70 
7.9 
Safety Analysis ...................................................................................................... 71 
7.10 
Statistical Analysis of Genetic Data ...................................................................... 71 
7.11 
Interim Analysis ..................................................................................................... 71 
7.12 
Reporting and Exclusions ...................................................................................... 71 
7.12.1 
Evaluation of Toxicity ........................................................................... 71 
7.12.2 
Evaluation of Response ......................................................................... 72 
8 
Data and Safety Monitoring Plan (DSMP) ........................................................................ 72 
9 
References ......................................................................................................................... 73 
APPENDICES .......................................................................................................................... 76 


 
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List of Abbreviations  
AE  
 
 
Adverse Event 
AKT   
 
See PKB (protein Kinase B) 
ALP 
 
 
Alkaline Phosphatase 
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 
CMV  
 
Cytomegalovirus 
CPK  
 
Creatine phosphokinase 
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 
EBV  
 
Epstein-Barr virus 
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 
ICH   
 
International Conference on Harmonization 


 
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IgG 
 
 
Immunoglobulin G 
IgM 
 
 
Immunoglobulin M 
HAV  
 
Hepatitis A 
HBV  
 
Hepatitis B 
HCV  
 
Hepatitis C 
HDL   
 
High density lipoprotein 
HEV  
 
Hepatitis E 
HSV  
 
Herpes Simplex Virus 
IEC  
 
 
Independent Ethics Committee 
IRB  
 
 
Institutional Review Board 
LDH  
 
Lactate dehydrogenase 
LDL   
 
Low density lipoprotein 
LVEF   
 
Left Ventricular Ejection fraction 
MRI   
 
Magnetic Resonance Imaging 
MTD   
 
Maximum Tolerated Dose 
MUGA  
 
Multiple Gated Acquisition Scan 
ORR   
 
Overall Response Rate 
PD  
 
 
Pharmacodynamic 
PET   
 
Positron Emission Tomography 
PI3K   
 
Phosphatidylinositol 3’-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 
SOP   
 
Standard Operating Procedure 


 
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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 
1.0 
Disease Background 
Thymic malignancies are rare, but represent the third most common type of primary mediastinal 
tumor (after lymphoma and germ cell tumors) (Temes, et al 1999) and the most common 
incident tumor type in the anterior mediastinum (Tomaszek 2009). Management is 
multidisciplinary in nature. Surgical resection is favored when disease is localized, and in the 
case of early thymoma, can potentially be curative. 
 
However, in the setting of advanced thymoma or thymic carcinoma, the chance of cure is 
remote, and some combination of chemotherapy and radiation therapy is indicated. Evidence-
based guidelines favor combination chemotherapy regimens in the first line, usually containing 
a platinum agent and some combination of doxorubicin, cyclophosphamide, vincristine and 
etoposide (National Comprehensive Cancer Network Practice Guidelines in Oncology: Thymic 
Malignancies, Version 2.2009). Initial response rates in adjuvant or locally advanced settings 
are good, with response rates over 50% reported in multiple phase II studies such as with PAC 
regimen of cisplatin, doxorubicin and cyclophosphamide plus radiation, with 70% ORR and 93 
months median OS (Loehrer, et al 1997). The ADOC regimen that added vincristine showed an 
ORR of 91% but with a shorter median OS of 15 months raising question about toxicity 
(Fornasiero, et al 1990). Regimens not containing doxorubicin tend to have response rate less 
than 50% in first line therapy (Lemma, et al 2011). 
 
Unfortunately, given the rarity of the disease, there have been few prospective trials of systemic 
therapy in the advanced or metastatic settings, and while these studies have suggested efficacy 
with ORRs ranging from 32 to 56%, there are few comparative data except for historical 
comparisons to consider (Giaccone, et al 1996, Highley, et al 1999, Loehrer, et 2001, Loehrer, 
et al 2004).  
 
Over 50% of patients with locally advanced or metastatic thymic malignancies may fail initial 
therapy and therefore require second-line therapy. Biological agents have been investigated for 
these patients with so far variable rates of response, ranging from 0 to 40%. These included 
octereotide ± prednisone, imatinib, belinostat, gefitinib, and interleukin-2. (Loehrer, et al 2004, 
Palmieri, et al 2002, Giaccone, et al 2009, Giaccone, et al 2011, Kurup, et al 2005, Gordon, et 
al 1995). There is a clear need for better targeted therapies that can target specific mutations 
(Rajan, et al 2010). One of these targets could be PI3K pathway as outlined in the study rationale 
in section 1.3. 
1.1 
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. 


 
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1.2 
PI3K Pathway and Mechanism of Action 
The phosphatidylinositol-3-kinase (PI3K) signaling regulates diverse cellular functions, 
including cell proliferation, survival, translational regulation of protein synthesis, glucose 
metabolism, cell migration, and angiogenesis (Katso, et al 2001). PI3K signaling also serves a 
central role in the pathogenesis of numerous forms of neoplasia. At the structural level, the 
enzyme PI3K is composed of a 110-kDa catalytic subunit and an 85-kDa adaptor subunit. The 
PI3K signaling is modulated by multiple regulators, including growth factors (such as EGF, 
IGF-1, and FGF), hormones (such as estrogen and thyroid hormone), integrins, intracellular 
calcium levels, and RAS signaling. PI3K signaling is negatively regulated at the level of PIP3 
clearance by phospholipid phosphatases, such as the phosphatase and tensin homologue 
(PTEN) protein and the inositol 5-phosphatase-2 (SHIP2) protein.   
Constitutive activation of PI3K signaling is known to be a critical step in mediating the 
transforming potential of oncogenes and tumor suppressors and in many tumor types (Liu 
2009). Resistance to a variety of therapeutic interventions, including chemotherapy, hormonal 
therapy and anti-HER2 therapies, can also be linked to constitutive activation of the PI3K 
pathway (McCubrey 2006). Moreover, preliminary data suggest that activation of the PI3K 
pathway may be a predictor of poor prognostic outcome in many cancers.  
Molecular changes leading to constitutive activation of the PI3K pathway are diverse and 
include, but are not limited to, 
a. Gain-of-function mutations of PI3K subunits (PIK3CA encoding the PI3K catalytic subunit 
p110α; genes encoding the p85 regulatory subunit) or oncogenes encoding positive 
regulators of PI3K (e.g., HER2, EGFR, RAS, Src-family proteins) or  
b. Loss-of-function mutations or epigenetic alterations affecting negative regulators of PI3K 
signaling (e.g., loss of PTEN expression or function) (Chow 2006, Cully 2006). 
Together these observations suggest that PI3K pathway could be a critical therapeutic target for 
the treatment of patients with advanced solid malignancies who often have limited therapeutic 
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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 Figure 1-1 
Schematic representation of the PI3K pathway 
 
1.2.1 
Preclinical Studies 
BKM120 activity against class I PI3K (p110α, -β, -δ and -γ), Class III (Vps34), the class 
IV mTOR related PI3K or PI4Kβ, was assessed using either a luciferase luminescence 
(class I or III PI3Ks and PI4Kβ) or a TR-FRET assay (Class IV mTOR). The IC50 in 
these assays is outlined below in table 1-1: 
Table 1-1 Inhibitory activities (IC50) of BKM120 against other PI3K or related kinases 
 
BKM120 significantly inhibits p110α and the most common p110α mutations (H1047R, 
E454K, E542K), p110β, p110δ and p110γ but not the related proteins Vps34, mTOR or 


 
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PI4Kβ. Hence BKM120 is classified as a pure pan-class I PI3K inhibitor. Enzymatic 
characterization of the inhibitory properties of the compound revealed that BKM120 is a 
mixed inhibitor of PI3Kα with a strong competitive component (largest on Vmax). The 
cocrystal X-ray structure of BKM120 with PI3Kγ confirmed that BKM120 interacts with 
PI3K into the ATP catalytic cleft. 
The PI3K pathway regulates the activity of the mTORC1 complex, when cells are 
challenged through mitogenic stimuli. In order to assess in cells the potential impact of 
the BKM120 on the mTORC1 complex, the compound was tested in TSC1 null cells. 
These cells express a constitutively activated mTORC1 complex that uncouples the 
mTOR pathway from the PI3K upstream input (Kwiatkowski 2003). When exposed to 
TSC1 null MEFS, BKM120 reduced the S235/236P-RPS6 levels with an IC50 of 1785 
nM, in agreement with the data obtained in the mTOR biochemical assay. In contrast, and 
as expected, the allosteric mTORC1 inhibitor RAD001 displayed sub-nanomolar 
inhibitory activity in this assay. 
In contrast to molecules with distinct mechanism of action (BCR-Abl inhibitor STI571, 
mTORC1 allosteric inhibitor RAD001), BKM120 is able to decrease the phosphorylation 
status of various either direct (GSK3β, FKHRL1/FOXO3a) or indirect downstream Akt 
effectors (p70S6K, through mTOR) in the PTEN null U87MG cell line, as efficiently as 
prototypical PI3K inhibitors such as LY294002 and Wortmannin. 
1.2.1.1 
Preclinical Safety 
Please refer to the Investigator’s Brochure for additional information on the preclinical 
testing of BKM120. 
1.2.1.2 
Pharmacodynamics 
BKM120 inhibits wild-type PI3Kα (IC50: 35 nM), with at least 50-fold selectivity towards this 
target compared to other protein kinases as well as against somatic PI3Kα activating mutants 
(H1047R-, E542K-, and E545K-p110α), the other three PI3K paralogs as well as the direct 
downstream effector AKT. BKM120 does not inhibit the related kinases mTOR or Vps34, nor 
does it inhibit other receptors and ion channels profiled (IC50 >10 µM). 
BKM120 reduces the phosphorylation of the direct downstream effector Akt in relevant tumor 
cell lines (e.g., IC50 93 nM for S473P-Akt in Rat1-p110α cells). This biological activity 
correlates with inhibition of various other downstream signaling components and with 
antiproliferative activity in a variety of tumor cell lines. 
BKM120 demonstrates significant tumor growth inhibition in relevant tumor xenografts in mice 
and rats when administered orally, including models of renal cell cancer (RENCA, 786-0, Caki-
1), glioblastoma multiforme (U87MG), prostate cancer (PC3M), lung cancer (A549, NCI-
H1975), ovarian cancer (A2780), colorectal cancer (HCT116, HCT-15) and melanoma (A2058, 
A375). In vivo PK/PD analyses of tumor tissues shows a good correlation between exposure, 
PI3K pathway blockade (S473P-Akt levels), and anti-tumor activity. 
 


 
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1.2.1.2.1 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 μM (34-59 μM 
unbound). BKM120 did not show time-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 rats (< 2 fold). 
Further information concerning the pharmacokinetic and pharmacodynamic properties of 
BKM120 may be found in the Investigator Brochure. 
1.2.1.2.2 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 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 


 
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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. 
Please refer to the Investigator’s Brochure for additional information on the preclinical testing 
of BKM120. 
1.2.1.2.3 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. 
1.2.2 
Clinical Experience 
1.2.2.1 
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]. 


 
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• 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. 
1.2.2.1.1 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 a 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: 
Table 1-2 
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 


 
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patients. The recommended phase 2 dose (RP2D) for Japanese patients 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. 
Details on liver toxicity, mood alterations, pneumonitis, hyperglycemia, skin rash and 
hypersensitivity as side effects of BKM120 are presented below.  
Liver Toxicity 
Liver toxicity has been analyzed based on a search of multiple MedDRA event terms and is 
presented in Table 1-3. Liver function test (LFT) alterations observed during ongoing and 
completed studies have been mostly transaminase enzyme increases (ALT and/or AST). Data 
suggest a higher rate of grade 3/4 liver enzyme elevations in Japanese patients (44.4%) in 
[CBKM120X1101] study, however, the number of patients (9 patients) treated at 100 mg in this 
study was limited. Transaminase elevations typically occur during the first 6 to 8 weeks of 
treatment start. 
 


 
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Table 1-3 Number of patients with liver toxicity 
 
 
Although transaminase increases are relatively common, only a few of the patients with LFT 
alterations had other simultaneous observations related to impaired liver function (e.g. bilirubin 
increase or clinical symptoms). Based on these findings, conservative inclusion criteria and 
guidelines to monitor and to follow patients with LFT alterations (including dose and schedule 
modifications) are currently implemented in study protocols investigating BKM120. Please 
refer to the respective inclusion/exclusion criteria, and Section 4.4.5.2 in this protocol for more 
detailed guidelines. 
 
A recent liver safety review across Novartis-sponsored trials with BKM120 identified several 
potentially drug-induced liver toxicity (DILI) cases (e.g. AST/ALT >3.0 x ULN and TBL >2.0 
x ULN at any time during the treatment, regardless of causality. Upon medical review, most of 
these cases occurred in the context of disease progression in terminally ill, advanced cancer 
patients and/or were confounded by other causes. However, six of these DILI candidates were 
consistent with Hy’s law criteria (e.g. AST/ALT >3.0x ULN and TBL >2.0xULN in the absence 
of cholestasis and other explanatory causes) with probable causal relationship to study 
treatment. Five of these cases were enrolled in study CBKM120F2302 in combination with 
fulvestrant, and one in combination with the investigational drug LDE225 (sonidegib). All 
patients have recovered upon treatment discontinuation except one patient for whom no data is 
available since the patient refused to return for safety follow-up. 
Mood disorders 
Recently, a number of publications demonstrated that the modulation of AKT/GSK3 signaling 
pathway by neurotransmitters is important for the regulation of behavior (Beaulieu 2009). 


 
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Preclinical studies conducted in rats to investigate the effect of BKM120 on different 
neurotransmitters have shown that repeated administration of BKM120 resulted in an enhanced 
decrease in glutamate, dopamine, serotonin and epinephrine as well as in an enhanced increase 
in GABA and HIAA. 
Psychiatric side effects events have been reported in patients treated with BKM120 and are 
currently under investigation. The current data does not allow the identification of any sign or 
symptom which could predict patient susceptibility to BKM120 induced psychiatric disorders. 
A broad range of AEs including (but not limited to) depression, anxiety, mood alteration, 
confusion, affective disorders, insomnia, hallucination, panic disorders, irritability or 
difficulties to concentrate have been reported. 
Considering the initial symptoms reported during the first-in-man [CBKM120X2101] study, 
mood disorders have been analyzed based on HLGT 'Mood disorders and disturbances NEC' or 
HLGT 'Personality disorders disturbances in behavior' or HLGT “Psychiatric and behavioral 
symptoms NEC” or HLGT “suicidal and behaviors NEC”. The frequency of mood disorders 
thus defined, regardless of study drug relationship, ranged from 6.3% in [CBKM120B2101] 
study to 50.0% in dose escalation part of [CBKM120X2107] study, however, the majority of 
events were of grade 1 or 2 severity (Table 1-4). 
Table 1-4 Number of patients with mood disorders 
 
 
Therefore, patients must be regularly and closely monitored for signs and symptoms of 
neuropsychiatric disorders with particular attention to changes in mood and personality. To 
support the identification and the assessment of psychiatric disorders, two self-assessment 
questionnaires, the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-
7 (GAD-7), are part of the protocol. Any AEs (symptom/diagnosis) should be accurately 
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recommended for any psychiatric adverse event grade ≥ 1. 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 jeroveci 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 4-8 for more detailed guidelines on the diagnosis and management of 
Pneumonitis. 
Hyperglycemia events 
The PI3K/AKT pathway plays a significant role in regulating glucose metabolism, particularly 
by regulating glucose transport into adipocytes and muscle tissue. Therefore, hyperglycemia is 
considered as an “on target” effect of BKM120. Regular monitoring of FPG, HbA1c, and 
insulin C-peptide is implemented in BKM120 protocols to evaluate this pharmacodynamic 
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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Table 1-5 Number of patients with hyperglycemia 
 
 
The highest rate of hyperglycemia (57.1%) was reported in [CBKM120C2201], a Phase II study 
conducted in patients with advanced endometrial carcinoma, as this was the only study among 
those listed allowing the enrollment of patients with controlled diabetes mellitus. However, so 
far, there were only two patients that experienced a grade 4 hyperglycemia, and they both were 
treated at the highest dose level (150mg/day) in [CBKM120X2101] study. In order to mitigate 
the potential risk of developing uncontrolled hyperglycemia, only patients with normal 
glycaemia defined as fasting plasma glucose (FPG) ≤ 120 mg/dL are eligible for study entry. 
Patients who have a poorly controlled diabetes mellitus defined as (HbA1c >8%) are excluded. 
In addition, detailed guidelines to monitor patients are recommended including: regular 
monitoring of FPG to early identify hyperglycemia and prevent acute/sub-acute complications, 
caution warranted for patients with history of DM, or taking corticosteroids, or with other severe 
medical conditions (e.g. infections). Hyperglycemia management guidance also includes: 
dietetic measures and appropriate anti-diabetic medications as per investigator’s decision and/or 
local guidelines, consider oral anti-diabetics such as metformin as first-line treatment for 
sustained and more severe hyperglycemia (other drugs as appropriate), if sulfonylurea or insulin 
are initiated, patients should be instructed on how to recognize (and treat) hypoglycemia, for 
patients with history of DM, management should be based on prior anti-DM treatment. 
Detailed guidelines to monitor and manage patients who develop hyperglycemia are provided 
in Table 4-5.  
 
Skin rash and hypersensitivity 
Skin rash is commonly observed in patients treated with BKM120. The rate of skin rash and 
other related event terms ranged from 18.4% to 41.4% in single agent studies with a 


 
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representative number of patients treated with 100mg of BKM120. In one study with nine 
evaluable patients, seven patients (77.8%) reported such events (Table 1-6). Studies of 
BKM120 in combination with other agents tended to report slightly higher frequencies (e.g. 
combination with MEK inhibitor). The skin rashes seen have no typical location or distribution 
pattern, are mainly papulo-macular (only a minority acneiform) and are frequently associated 
with pruritus. Events have been reversible after treatment interruption and/ or dose reduction. 
Effective medications have included antihistamines, topical corticosteroids and/or low-dose 
systemic corticosteroids (the latter should be used with caution due to the increased risk of 
hyperglycemia). There have been few cases reported of allergic reactions and DRESS (drug 
rash with eosinophilia and system symptoms), but these have not been of acute onset or of a 
severe nature. Complementary information collected suggests that sun exposure may exacerbate 
the condition and should be avoided; however, genuine photosensitivity reaction has not been 
confirmed and no phototoxic potential seen pre-clinically. Patients are advised (e.g. in the 
written patient information) to avoid sun exposure, or take measures to protect themselves from 
intense sunlight, during study treatment. 
Table 1-6 Number of patients with hypersensitivity 
 
1.2.2.1.2 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 


 
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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 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 μg/ml). 
1.2.2.1.3 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 


 
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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, July, 4, 2011, 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 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, July, 4, 2011, twenty breast cancer patients were evaluable for 


 
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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). 
 
Please refer to the Investigator’s Brochure for additional information on the available 
clinical experience with BKM120. 
1.3 
Study Rationale 
Thymic tumors are rare tumors, but represent the most common tumors of the anterior 
mediastinum. Thymoma has an indolent course in advanced disease and has the propensity to 
spread to the pleura. In disseminated disease, thymoma has demonstrated sensitivity to a 
broad range of chemotherapeutic agents. In first line therapy, combination chemotherapy 
produces responses in approximately 80% of patients. A number of single agents have activity 
in recurrent disease, but none are curable. Patients with recurrent thymoma have limited 
treatment options, and thus novel target modalities are needed.  
 
At the Indiana University Simon Cancer Center (IUSCC), more patients with advance 
thymoma are seen than any other institution in the country. We have conducted numerous 
trials in advanced disease either at the IUSCC or in collaboration with other institutions or 
national Cooperative Groups. This has permitted us to collect tissue and develop a tumor 
model and the only existing cell line in this disease. Using our collected thymoma tissues, we 
have conducted next generation RNA sequencing of thymomas across various histologic 
types. From this analysis, we identified a unique microRNA cluster on chromosome 19 
(C19MC) that is highly overexpressed in a significant subset of thymomas primarily 
comprised of the A & A/B subtype. 
 
We subsequently validated this observation in additional 35 thymomas by qPCR (Figure 1-2). 
This cluster is normally silent in adult tissues, with normal expression restricted to embryonic 
development. MicroRNAs within the C19MC cluster, miR-517 & miR-519d, have been 
previously demonstrated to inhibit key proteins in the PI3K/AKT pathway. Namely, PTEN, a 
negative regulator of AKT, and p21, a cell cycle arrest protein (Fornari, et al 2012). 
 
 
 
 
 
 


 
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Figure 1-2 
 
 
 
In addition, gene expression analysis reveals over-expression of PIK3CA (aka PI3K p110), 
the canonical activator of AKT (Figure 1-3). To confirm, we performed a quantitative ELISA 
on a validation set of 35 thymomas for phospho-AKT (Ser 473), and demonstrate that C19MC 
positive thymomas have significantly higher levels of phospho-AKT compared to C19MC 
negative thymomas which in-turn has higher levels than adjacent normal tissue (Figure 1-4). 
 
 
 
Figure 1-2 RNA-sequencing identified extensive over-expression of the C19MC cluster in A&A/B 
thymomas in a test set of 13 samples. In this figure we validate the over-expression of the C19MC 
cluster using qPCR in an independent sample set of 35 thymomas. Expression data demonstrates a 
separation of the samples into 2 distinct groups as demonstrated by the upper dendrogram. Red 
represents high-expression, green represents low or no expression. All A & A/B samples were in the 
C19MC positive group (right-fork of the dendrogram), whereas the B1, B2, & B3 samples were in 
the C19MC negative group (left-fork of the dendrogram), except for one discordant B1 sample in the 
C19MC positive group. 


 
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Figure 1-3 
 
Figure 1-3. Network analysis of thymoma RNA-seq data demonstrates over-expressed genes (RED) and 
under-expressed genes (GREEN) in C19MC positive thymomas that would be expected of an over-activated 
PI3K pathway. 
 
 
 


 
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Figure 1-4 
These 
data 
demonstrate 
that 
all 
thymomas have the potential to have 
sensitivity 
to 
PI3K 
inhibition, 
in 
particular those that are positive for 
C19MC. We further tested a variety of 
PI3K, AKT, and mTOR inhibitors in our 
thymoma cell line (IU-TAB-1) and 
found significant activity for several of 
these agents including BEZ235 and 
BKM120 (Figure 1-5). 
 
Our main hypothesis is the PI3K 
pathway is an important driver for 
growth and metastasis of thymoma and 
that inhibition of the PI3K pathway is 
expected to produce clinically meaningful response in 
patients with recurrent thymoma. Our rationale is to use 
BKM120, a pan-PI3K inhibitor, which has shown 
significant cell growth inhibition in thymoma, in a Phase II 
clinical trial to demonstrate clinical efficacy of this agent in 
recurrent disease. 
Figure 1-5. The thymoma cell line, IU-TAB-1, tested with increasing doses of PI3K, AKT, and dual 
PI3K/mTOR inhibitors. Cells were treated for 72 hours and cell viability assessed. The data demonstrates
marked sensitivity of the thymoma cell line to these inhibitors 
Figure 1-4. Protein ELISA for activated phospho-AKT 
(Ser 473) in a validation set of 35 thymomas and 3 normal 
tissues, demonstrating significantly higher phospho-AKT 
in C19MC positive thymomas vs. C19MC negative vs. 
normal tissues. 


 
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2 
Study Objectives 
Primary 
• To evaluate the objective response rate (CR+PR) in patients with thymomas treated with 
BKM120. 
Secondary 
• To evaluate toxicity in patients with thymomas treated with BKM120. 
• To evaluate progression-free survival in patients with thymomas treated with BKM120. 
• To evaluate disease control rate (DCR = CR+PR+SD) in patients with thymomas treated 
with BKM120. 
• To evaluate duration of response of patients with thymomas treated with BKM120. 
• To evaluate overall survival of patients with thymomas treated with BKM120. 
 
Exploratory 
• To determine if there are molecular markers to predict response in patients with thymomas 
treated with BKM120. 
3 
Exploratory Investigational plan 
3.0 
Overall Study Design 
• Purpose: This will be a single arm phase II trial in patients with recurrent thymoma. The 
purpose of the study is to determine the activity of the pan PI3K Inhibitor, BKM120 in 
patients with this disease. 
 
• Planned treatments: BKM120, 100 mg capsule for oral use, taken once daily for two or 
more months for a maximum of one year. Each cycle is 28 days. 
 
• Sequence & duration of study periods: Eligible patients will be treated for two months 
and evaluated. All patients with responding or stable disease will continue on study unless 
there is unacceptable toxicity or progression of disease. Patients will continue on study for 
a maximum of one year or until progression. There will be no dose escalations. 
 
• Blinding: Open Label. 
• Structure: Single Group. 
• Randomization: Non-randomized. 
• Placebo Controlled: No 
• Number of Patients & Centers: 
• 25 thymoma patients (16 in stage 1 + 9 in stage 2) 
• Because some patients may not be evaluable for response, up to 27 patients may be 
accrued to ensure that the number of evaluable patients is 25. 
• Number of Centers: IUSCC, other centers may be added with approval of the sponsor 
(e.g. Georgetown, Stanford, Memorial Sloan-Kettering and MD Anderson). 


 
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3.1 
Study Population 
3.1.1 
Patient Population 
A total of 27 eligible patients with recurrent thymoma who will meet the eligibility criteria will 
be enrolled for this trial. The patients will be enrolled in two stages. 16 eligible patients will be 
enrolled for stage 1 and if at least 2 thymoma patients have response to treatment then the study 
will continue for stage 2 where an additional 9 eligible patients will be enrolled. Because some 
patients may not be evaluable for response, up to 27 patients may be accrued to ensure that the 
number goal of evaluable patients is met. 
3.1.2 
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 
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: 
3.1.2.1 
Inclusion Criteria  
1. Histological confirmation of thymoma. 
2. At least one prior line of platin-based chemotherapy (unless refused or not 
tolerated).  
3. Documented progressive (clinical and/or objective) disease after the most recent 
systemic therapy regimen. 
4. Patients must not have received chemotherapy, radiation therapy, or undergone 
major surgery within 4 weeks prior to enrollment. 
5. Patient must not have other curative treatment options (e.g. surgical resection of 
solitary metastases if feasible, or other proved curative options if they become 
available in the future). 
6. Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 
nonnodal lesions and short axis for nodal lesions) as >20 mm with conventional 
techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam. 
See Section 4 for the evaluation of measurable disease. 
7. Age ≥ 18 years 
8. ECOG performance status ≤ 2 
9. Patient must be able to swallow and retain oral medications 
10. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 
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11. Total calcium (corrected for serum albumin) within normal limits (biphosphonate 
use for malignant hypercalcemia control is not allowed) 
12. Magnesium ≥ the lower limit of normal 
13. Potassium within normal limits for the institution 
14. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 
normal range (or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are present) 
15. Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; 
or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients 
with well documented Gilbert Syndrome) 
16. Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min 
17. Serum amylase ≤ ULN 
18. Serum lipase ≤ ULN 
19. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) 
20. HbA1c ≤ 8 % 
21. Negative serum pregnancy test within 72 hours before starting study treatment in 
women with childbearing potential 
22. Signed informed consent 
23. INR ≤ 2 
3.1.2.2 
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. Patients with thymic carcinoma (formerly WHO Type C). 
3. Patients with a known hypersensitivity to BKM120 or to its excipients 
4. Patients with untreated brain metastases are excluded. However, patients with 
metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks from 
therapy completion (incl. radiation and/or surgery), is clinically stable at the time of 
study entry and is receiving low dosage corticosteroid therapy 
5. Patients with acute or chronic liver, renal disease or pancreatitis 
6. Patient has acute viral hepatitis or a history of chronic or active Hepatitis B (HBV) 
or Hepatitis C (HCV) infection, (typically defined by elevated AST/ALT (persistent 
or intermittent), high HBV DNA level, HBsAg positive, or high HCV RNA level 
(testing not mandatory, refer to Section 4.6.6.7 Viral hepatitis serology and other 
tests for hepatotoxicity follow-up).  
7. Patients with the following mood disorders as judged by the Investigator or a 
psychiatrist, or as a result of patient’s mood assessment 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 
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anxiety disorders who are stable at the time of enrollment and on 
antidepressants not listed in Tables 4-0 and 4-1 of the study protocol will be 
permitted to enroll on this study. Note: for patients with psychotropic 
treatments ongoing at baseline, the dose and the schedule should not be 
modified within the previous 6 weeks prior to start of study drug. 
•  ≥ CTCAE grade 3 anxiety  
• Meets the cut-off score of ≥ 12 in the PHQ-9 or a cut-off of ≥ 15 in the 
GAD-7 mood scale, respectively, or selects a positive response of “1, 2, or 
3” to question number 9 regarding potential for suicidal thoughts in the 
PHQ-9 (independent of the total score of the PHQ-9)  
8. Patients with diarrhea ≥ CTCAE grade 2 
9. Patient has known active cardiac disease including any of the following:  
• Left ventricular ejection fraction (LVEF) < 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 
10. 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 
11. Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus 
12. Patients with chronic lung disease, dyspnea at rest, or interstitial lung disease 
13. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., 
active or uncontrolled infection; uncontrolled hypertension, i.e. BP >160/100) 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.  
14. Impairment of gastrointestinal (GI) function or GI disease that may significantly 
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vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients 
with unresolved diarrhea will be excluded as previously indicated 
15. Patients who have been treated with any hematopoietic colony-stimulating growth 
factors (e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. 
Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to 
enrollment, may be continued 
16. 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 4-1 or a list of prohibited QT prolonging drugs with risk 
of Torsades de Pointes. 
17. Patients receiving chronic treatment with steroids or another immunosuppressive 
agent.  
• Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive 
airways diseases), eye drops or local injections (e.g. intra-articular) are 
allowed. Patients with previously treated brain metastases, who are on stable 
low dose corticosteriod treatment (e,g dexamethasone 2 mg/day, predisolone 
10 mg/day) for at least 14 days before start of study treatment are eligible. 
18. 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. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng. Fruits include the CYP3A inhibitors Seville 
oranges, grapefruit, pummelos, or exotic citrus fruits.  
19. 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 4-0 for a list of prohibited inhibitors and inducers of CYP3A 
(Please note that co-treatment with weak inhibitors of CYP3A is allowed). 
20. Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks 
(6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug 
must recover to a grade 1 before starting the trial  
21. Patients who have received any continuous or intermittent small molecule 
therapeutics (excluding monoclonal antibodies) ≤ 5 effective half-lives prior to 
starting study drug or who have not recovered from side effects of such therapy 
22. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field 
radiation for palliation ≤ 2 weeks prior to starting study drug or who have not 
recovered from side effects of such therapy 
23. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or 
who have not recovered from side effects of such therapy.  
24. Patients who are currently taking therapeutic doses of warfarin sodium or any other 
coumadin-derivative anticoagulant.  
25. 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 


 
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contraceptives may be affected by cytochrome P450 interactions, and are therefore 
not considered effective for this study. Women of child-bearing potential, defined as 
sexually mature women who have not undergone a hysterectomy or who have not 
been naturally postmenopausal for at least 12 consecutive months (i.e., who has had 
menses any time in the preceding 12 consecutive months), must have a negative 
serum pregnancy test ≤ 72 hours prior to initiating treatment. 
• 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 [for US only: 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. 
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 condoms during treatment, for 4 weeks (5 T1/2) after 
stopping treatment and for an additional 12 weeks (16 weeks in total after 
study drug discontinuation) and should not father a child in this period.  


 
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• 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. 
26. Known diagnosis of human immunodeficiency virus (HIV) infection  
27. History of another malignancy within 3 years, except cured basal cell carcinoma of 
the skin or excised carcinoma in situ of the cervix 
28. Patient is unable or unwilling to abide by the study protocol or cooperate fully with 
the investigator 
4 
Treatments 
4.0 
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. 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, , 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 the 
previous day’s dosing must be noted whenever possible. 
If the patient forgets to take her/his dose AFTER 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. John’s Wort, Seville oranges, grapefruit or grapefruit 
juice, grapefruit hybrids, pummelos and exotic citrus fruits from 7 days prior to the first dose 
of study medication and during the entire study treatment period due to potential CYP3A4 
interaction with the study medication. Patients must avoid concomitant intake of strong and 
moderate CYP3A4/5 inhibitors and inducers. 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 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. 


 
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4.1 
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 in section 4.0.2.1.  
4.1.1 
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 4-0 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 4-0 for a list of prohibited CYP3A 
inducers. Please note that this list may not be comprehensive. Therapeutic doses of warfarin 
sodium (Coumadin®) or any other coumadin-derivative anticoagulants are not permitted. 
• If a patient requires the concomitant use of any medication included in Table 4-1 entitled 
“List of Prohibited QT prolonging drugs” (i.e., drugs that are generally accepted by the 
Qtdrugs.org Advisory Board of the Arizona CERT to have a risk of causing Torsades des 
de Pointes), study treatment administration must be interrupted as long as the patient 
requires therapy with the QT prolonging agent. 
• Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to St. John’s wort, Kava, ephedra (ma huang), ginko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginsing. Patients 
should stop using these herbal medications 7 days prior to first dose of study drug. 


 
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• Hormonal contraceptives may be affected by cytochrome P450 interactions, and are 
therefore not considered effective in this study. 
 
 


 
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Table 4-0 
List of prohibited CYP3A Inhibitors and Inducers  
Strong CYP3A 
inhibitors 
Moderate CYP3A 
inhibitors 
Strong CYP3A 
inducers 
Moderate CYP3A 
inducers 
clarithromycin 
aprepitant 
avasimibe 
bosentan 
conivaptan 
atazanavir 
carbamazepine 
efavirenz 
grapefruit juice 
cimetidine 
Phenobarbital 
(barbiturates) 
etravirine 
indinavir 
ciprofloxacin 
phenytoin 
modafenil 
itraconazole 
darunavir 
rifabutin 
nafcillin 
ketoconazole 
diltiazem 
rifampin  
ritonavir 
lopinavir 
erythromycin 
St. John's Wort  
talviraline 
mibefradil 
fluconazole 
 
tipranavir 
nefazodone 
tofisopam 
 
 
nelfinavir 
verapamil 
 
 
posaconazole 
amprenavir 
 
 
ritonavir 
fosamprenavir 
 
 
saquinavir 
elvitegravir 
 
 
telithromycin 
tipranavir 
 
 
troleandomycin 
 
 
 
voriconazole 
 
 
 
This database of CYP inhibitors was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table and from the University of Washington’s Drug Interaction Database 
based on in vitro studies. Strong inhibitors are predicted to increase BKM120 AUC > 5-fold, and 
moderate inhibitors are predicted to increase BKM120 AUC ≥ 2-fold but < 5-fold.  
This database of CYP inducers was compiled from the FDA’s “Guidance for Industry, Drug 
Interaction Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” Table; 
and from (Pursche et al. 2008). 
 
Table 4-1 
List of prohibited QT prolonging drugs  
All QT-prolonging drugs listed in Table 4-1 are prohibited for all patients from screening 
through permanent discontinuation of study treatment.  Table 4-3 lists drugs with a known risk 
for Torsades de Pointes (TdP) as well as sensitive CYP3A substrates (with narrow TI) with a 
possible or conditional risk for TdP. 
 
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 
 


 
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Drug 
QT risk(*) 
Comment 
Chlorpromazine 
Known risk for TdP 
 
Cisapride 
Known risk for TdP 
Restricted availability; Females>Males. 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
 
Domperidone 
Known risk for TdP 
Not available in the U.S. 
Droperidol 
Known risk for TdP 
 
Halofantrine 
Known risk for TdP 
Females>Males 
Haloperidol 
Known risk for TdP 
When given intravenously or at higher-than- 
recommended doses, risk of sudden death, 
QT prolongation and torsades increases. 
Ibutilide 
Known risk for TdP 
Females>Males 
Levomethadyl 
Known risk for TdP 
 
Mesoridazine 
Known risk for TdP 
 
Methadone 
Known risk for TdP 
Females>Males 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 
Probucol 
Known risk for TdP 
No longer available in U.S. 
Procainamide 
Known risk for TdP 
 
Quetiapine 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 
substrate 
Quinidine 
Known risk for TdP 
Females>Males 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
 
Tacrolimus 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 
sibstrate with narrow TI 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
 
Vardenafil 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 
substrate 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
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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4.1.2 
Drugs to be Used with Caution 
Preliminary in vitro metabolism studies suggest that BKM120 is a weak, reversible inhibitor 
CYP3A4/5 (Ki=13.6 μM, [I]/Ki= 0.4 where [I] is the average Cmax at steady-state following 100 
mg daily dose) and a weak reversible inhibitor of CYP2C8/2C9/2C19 (IC50=34 μM, 
[I]/IC50=0.15). Note: that with the data available, we are not able to confirm whether such 
interactions will occur in patients. Therefore, investigators, at their discretion, may administer 
concomitant medications known to be metabolized by CYP3A4/5, CYP2C8, CYP2C9 and 
CYP2C19. Patients receiving such medications must be carefully monitored for potentiation of 
toxicity due to any individual concomitant medications, and may require dose titration or 
reduction of the drug substrate. Please refer to Table 4-2 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 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 4-3 for a list of QT prolonging medications to be used 
with caution.  
Note: please refer also to Table 4-1 for a list of prohibited QT prolonging medication.  
• Please refer to Table 4-2for 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 corticosteroids is 
allowed (e.g. for chronic obstructive pulmonary disease, or as an anti-emetic). Chronic 
dosing of corticosteroids is known to induce CYP3A enzymes, thereby increasing the risk 
or reducing BKM120 overall exposure to sub-therapeutic levels. 
 
Table 4-2 List of CYP450 substrates to be used with caution 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A** 
amodiaquine 
celecoxib 
amitriptyline 
Adinazolam 
felodipine1 
cerivastatin 
diclofenac 
citalopram 
alfentanil1,2 
fentanyl2 
pioglitazone 
flurbiprofen 
clobazam 
alpha-
dihydroergocryptine1 
flunitrazepam 


 
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repaglinide 
fluvastatin 
clomipramine 
Alprazolam 
fluticasone1 
rosiglitazone 
glibenclamide 
(glyburide) 
clopidogrel  
Amlodipine 
lovastatin1 
torasemide 
gliclazide 
diazepam 
Aripiprazole 
maraviroc1 
troglitazone 
glimepiride 
fluoxetine 
Atorvastatin 
midazolam1 
 
glipizide 
imipramine 
Brecanavir 
nifedipine 
 
indomethacin 
lansoprazole 
brotizolam1 
nisoldipine 
 
irbesartan 
mephobarbital 
budesonide1 
nitrendipine 
 
ketobemidone 
moclobemide 
buspirone1 
perospirone1 
 
lornoxicam 
omeprazole 
Capravirine 
quinine 
 
losartan 
pantoprazole 
Cerivastatin 
sildenafil1 
 
meloxicam 
progesterone 
Chlorpheniramine 
simvastatin1 
 
naproxen 
quazepam 
cyclosporine2 
sirolimus1,2 
 
nateglinide 
rabeprazole 
darifenacin1 
tolvaptan 
 
piroxicam 
sertraline 
Diazepam 
trazodone 
 
rosiglitazone 
S-mephenytoin diergotamine2 
triazolam1 
 
S-ibuprofen 
 
ebastine1 
 
 
sulfamethoxazole  
eletriptan1 
 
 
tenoxicam 
 
eplerenone1 
 
 
tolbutamide 
 
ergotamine2 
 
 
torasemide 
 
Estazolam 
 
 
valdecoxib 
 
everolimus1 
 
* This database of CYP substrates was compiled from the Indiana University School of 
Medicine’s “Clinically Relevant” Table, and from (Zhou et al 2009) 
** CYP3A substrates were compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table; and supplemented by the FDA’s “Guidance for Industry, Drug 
Interaction Studies” and the University of Washington’s Drug Interaction Database. 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-
fold or higher when co-administered with a potent inhibitor of the respective enzyme. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates 
that increases in their exposure levels by the concomitant use of potent inhibitors may lead 
to serious safety concerns (e.g., Torsades de Pointes). 
 


 
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Table 4-3 
List of QT prolonging drugs to be used with caution 
Drug 
QT risk 
Comment 
Alfuzosin 
possible risk for Torsades de Pointes 
 
Amantadine 
possible risk for Torsades de Pointes 
 
Amitriptyline 
conditional risk for Torsades de Pointes 
 
Azithromycin 
possible risk for Torsades de Pointes 
 
Chloral hydrate 
possible risk for Torsades de Pointes 
 
Citalopram 
conditional risk for Torsades de Pointes 
 
Clomipramine 
conditional risk for Torsades de Pointes 
 
Clozapine 
possible risk for Torsades de Pointes 
 
Desipramine 
conditional risk for Torsades de Pointes 
 
Diphenhydramine 
conditional risk for Torsades de Pointes 
 
Dolasetron 
possible risk for Torsades de Pointes 
 
Doxepin 
conditional risk for Torsades de Pointes 
 
Dronedarone 
possible risk for Torsades de Pointes 
 
Felbamate 
possible risk for Torsades de Pointes 
 
Flecainide 
possible risk for Torsades de Pointes 
 
Fluoxetine 
conditional risk for Torsades de Pointes 
 
Foscarnet 
possible risk for Torsades de Pointes 
 
Fosphenytoin 
possible risk for Torsades de Pointes 
 
Galantamine 
conditional risk for Torsades de Pointes 
 
Gatifloxacin 
possible risk for Torsades de Pointes 
 
Gemifloxacin 
possible risk for Torsades de Pointes 
 
Granisetron 
possible risk for Torsades de Pointes 
 
Imipramine 
conditional risk for Torsades de Pointes 
 
Indapamide 
possible risk for Torsades de Pointes 
 
Isradipine 
possible risk for Torsades de Pointes 
 
Levofloxacin 
possible risk for Torsades de Pointes 
 
Lithium 
possible risk for Torsades de Pointes 
 
Mexiletine 
conditional risk for Torsades de Pointes 
 
Moexipril/HCTZ 
possible risk for Torsades de Pointes 
 
Moxifloxacin 
possible risk for Torsades de Pointes 
 
Nicardipine 
possible risk for Torsades de Pointes 
 
Nortriptyline 
conditional risk for Torsades de Pointes 
 
Octreotide 
possible risk for Torsades de Pointes 
 
Ofloxacin 
possible risk for Torsades de Pointes 
 


 
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Drug 
QT risk 
Comment 
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 
 
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 
Interruption or Discontinuation of Treatment 
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 4-4. Toxicity will be 
assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 
4.0. Patients requiring dose reduction due to toxicity will not be dose                         re-
escalated following resolution of the toxicity. 
(CTCAEv4.0, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf). 
All interruptions or changes to study drug administration must be recorded. 


 
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Table 4-4 
BKM120 dose level modification guidelines 
Dose level 
Dose and schedule 
-2 
60 mg daily 
-1 
80 mg daily 
* 0 
100 mg daily 
 
* Starting Dose  
Table 4-5 
Criteria for interruption and re-initiation of BKM120 treatment 
Recommended dose modifications and criteria for treatment interruption and 
re-initiation with treatment-related adverse events  
These changes must be recorded on the Dosage Administration Record CRF 
 
Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
HEMATOLOGICAL 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain  dose level  
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Febrile neutropenia  
(ANC < 1.0 x 109/L, with a single 
temperature of ≥ 38.3 °C or a sustained 
temperature of ≥ 38 °C for more than one 
hour ) 
Omit dose until resolved, then  1 dose level 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50-25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
RENAL 
Serum creatinine  
Grade 1 (< 2 x ULN)  
Maintain dose level  
Grade 2 (2 – 3 x ULN)  
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 – 6.0 x ULN)  
Permanently discontinue patient from BKM120  
Grade 4 (> 6.0 x ULN)  
Permanently discontinue patient from BKM120 
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 


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
Grade 2 (> 1.5 - 3.0 x ULN) with ALT or 
AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) with ALT or 
AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days,  1 dose level 
If resolved in > 7 days discontinue patient from BKM120 
Grade 4 (> 10.0 x ULN) 
Permanently discontinue patient from BKM120 
AST or ALT 
AST or ALT without bilirubin elevation > 2ULN Note: confounding factors and/or alternative causes for increased 
transaminases like concomitant medications, infection, hepato-biliary disorder, obstruction, liver metastasis, etc. 
should be excluded before dose interruption/reduction 
Same grade as baseline (i.e., Grade 0 or 1 
[> ULN – 3.0 x ULN] if presence of liver 
metastasis 
Maintain dose level with LFTs* monitored per protocol 
Increase from baseline Grade 0 to > 1.5 
ULN or from baseline Grade 1 to Grade 2 
Can continue treatment at  1 dose level 
Increase of two grades from baseline 
(from baseline Grade 0 to Grade 2 or from 
baseline Grade 1 to Grade 3) 
Omit dose until resolved to Grade 1 or less, then  1 dose level**  
If no recovery in ≤ 28 days, discontinue permanently BKM120 
Grade 4 (> 20.0 x ULN)  
Discontinue BKM120 permanently 
AST or ALT and concurrent Bilirubin 
AST or ALT > 3.0 x ULN and total 
bilirubin > 2.0 x ULN 
Permanently discontinue BKM120*** 
*(LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline 
phosphatase (fractionated if alkaline phosphatase is grade 2 or higher) and GGT) 
** In case of recurring Grade 3 or higher toxicity after re-challenge, patients should be permanently discontinued 
*** All patients with ALT or AST >3.0x ULN and total bilirubin > 2.0x ULN in the absence of cholestasis ULN 
must immediately be withdrawn from BKM120 and every attempt should be made to carry out the liver event 
follow-up assessments as described below in Section 4.4.5.2 Management of hepatotoxicity (ALT and/or AST >3.0x 
ULN and total bilirubin >2.0x ULN) and Section 4.6.6.7 Viral hepatitis serology and other tests for hepatotoxicity 
follow-up). 
Hepatic toxicity monitoring (*for patients with Gilbert Syndrome: total and direct bilirubin must be monitored, 
intensified monitoring applies to changes in direct bilirubin only; the monitoring includes the following LFTs: 
albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase (fractionated 
if alkaline phosphatase is grade 2 or higher) and GGT): 
Cycle 1 and 2: every other week (if visit schedule allows a more frequent monitoring this should be considered) or 
more frequently if clinically indicated especially for patients with borderline acceptable AST/ ALT or bilirubin* 
values 
Cycle 3 and onward: monthly or more frequently if clinically indicated  
In case of any occurrence of ALT/AST or bilirubin* increase ≥ grade 2 the liver function tests must be monitored 
weekly or more frequently if clinically indicated until resolved to ≤ grade 1 
In case of any occurrence of ALT/ AST or bilirubin* increase ≥ grade 3  the liver function tests must be monitored 
weekly or more frequently if clinically indicated until resolved to ≤ grade 1; hereafter the monitoring should be 
continued every other week or more frequently if clinically indicated until the end of treatment with study medication 
Patients who discontinued study treatment should be monitored weekly, including LFTs* or more frequently if 
clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE grade change over 4 weeks). 
ENDOCRINE/METABOLIC 
Fasting Plasma Glucose (FPG) 


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
Grade 1 (> ULN - 160 mg/dL) (> ULN - 
8.9 mmol/L) 
Maintain dose level, check FPG every week 
● initiate or intensify medication with appropriate anti-diabetic 
treatment as per investigator’s discretion 
● instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes mellitus 
(such as those provided by the American Diabetes Association) 
during the study 
● consider use of oral anti-hyperglycemic therapy such as 
metformin (or intensify existing medications),  
● check FPG at least weekly for 8 weeks, then continue checking at 
least every 2 weeks 
Grade 2 (>160 - 250 mg/dL) (> 8.9 - 13.9 
mmol/L) 
● If signs or symptoms of hyperglycemia (for example, mental 
status changes, excessive thirst, polyuria), manage as for Grade 3 
hyperglycemia (see below) 
● If asymptomatic, maintain dose and re-check FPG within 24 
hours. If grade worsens or improves then follow specific grade 
recommendations. If FPG remains at Grade 2:  
 
○ 
maintain dose level and monitor FPG at least weekly until 
FPG resolves to ≤ Grade 1 
 
○ 
initiate or intensify medication with appropriate anti-
diabetic treatment such as metformin; consider adding a second oral 
agent if not improvement after several days.  
 
○ 
instruct patient to follow dietary guidelines according to 
local and/or institutional standards for management of diabetes 
mellitus (such as those provided by the American Diabetes 
Association) during the study 
 
○ 
if FPG does not resolve to ≤ Grade 1 within 14 days after 
institution of appropriate anti-diabetic treatment reduce BKM120 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/hyperosmolar disturbances as clinically 
appropriate 
● continue to omit BKM120 
● monitor FPG at least twice weekly until FPG resolves to 
≤ Grade 1  
● If FPG resolves to < Grade 1 in 7 days or less, then re-start 
BKM120 and  1 dose level 
● If FPG remains greater than Grade 1 severity for more than 7 
days, then discontinue patient from BKM120  


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for 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 (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 and following 
guidance for management of Grade 3 fasting plasma glucose (FPG) 
Grade 4 (> 500 mg/dL) (≥ 27.8 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/hyperosmolar disturbances as clinically 
appropriate 
● discontinue patient from BKM120 
● instruct patient to follow dietary guidelines according to local 
and/or institutional standards for management of diabetes mellitus 
(such as those provided by the American Diabetes Association) 
during the study 
● consider use of oral anti-hyperglycemic therapy such as 
metformin 
● check FPG at least weekly for 8 weeks, then continue checking at 
least every 2 weeks if clinically indicated 
For non-fasting plasma glucose >500 mg/dL (> 27.8 mmol/L) 
accompanied by signs/symptoms of hyperglycemia (for example, 
mental status changes, excessive thirst, polyuria), or presence of 
blood or urine ketones, discontinue BKM120 and following guidance 
for management of Grade 4 fasting plasma glucose (FPG). 
CARDIAC 
Cardiac - Left Ventricular systolic dysfunction 
Asymptomatic,  
resting ejection fraction 40-50%; 
or 10-20% drop from baseline 
Maintain dose level, and continue BKM120 with caution 
Repeat LVEF within 4 weeks or as clinically appropriate 
Symptomatic,  
responsive to intervention,  
ejection fraction 20-39% 
or > 20% drop from baseline 
● Omit BKM120 until resolved* (as defined below), then  1 dose 
level 
● LVEF measurement to be repeated, if not resolved* within 21 
days, permanently discontinue patient from BKM120 treatment 
Refractory or poorly controlled,  
ejection fraction < 20% 
● Permanently discontinue patient from BKM120 
*the event is considered resolved when the patient is asymptomatic, has a resting ejection fraction ≥ 40% and 
≤20% decrease from baseline. 
Cardiac – QTc prolongation  


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
QTcF > 500 ms (≥ 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 or >60ms from baseline 
● If QTcF remains > 500 ms or >60ms from baseline, repeat ECG 
as clinically indicated, but at least once a day until the QTcF returns 
to < 480 ms. Seek cardiologist input. 
● Once QTcF prolongation has resolved, BKM120 may be restarted 
at a one lower dose level 
Second Occurrence: 
● Permanently discontinue patient from BKM120 
Other Cardiac Events 
 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Permanently discontinue patient from BKM120 
OTHER 
Mood alteration/Psychiatric Disorders 
* Note: For all grades, if question 9 on the PHQ-9 has a positive response (as indicated by selecting "1", "2", or 
"3"), omit study drug and refer patient for psychiatric consult regardless of the total questionnaire score or 
CTCAE grading to confirm if study drug should be interrupted or permanently discontinued. 
Grade 1* 
● Maintain dose level 
● Consider psychiatric consultation at the investigator’s discretion 
and introduce optimal management (e.g. as per local guidelines 
and/or psychiatric/expert consultation) 
 
Grade 2* 
● Omit dose until resolved to ≤ Grade 1 or baseline status 
● Consider psychiatric consultation at the investigator’s discretion 
and introduce optimal management (e.g. as per local guidelines 
and/or psychiatric/expert consultation) 
 
● First event:  if the condition resolved to Grade ≤ 1 or to baseline 
status, continue to co-medicate and then maintain the dose level  
● Second and further events:  if the condition resolved to Grade ≤ 1 
or to baseline status, continue to co-medicate and then ↓ 1 dose level 
Grade 3* 
Omit dose until resolved to ≤ Grade 1 or baseline status 
● Psychiatric consultation is required and introduce optimal 
management  
● if the condition resolved to Grade ≤1 or to baseline status, 
continue to co-medicate and then  1 dose level 
Grade 4* 
Permanently discontinue patient from BKM120 
● Psychiatric consultation is required  
● Introduce optimal management (e.g. as per local guidelines) 
Rash 
Grade 1 
Maintain dose level. Consider to initiate appropriate skin toxicity 
therapy (such as antihistamines, topical corticosteroids)  
Grade 2 
First occurrence: Omit dose until resolved to grade ≤ 1 then:  
● If resolved in ≤ 2 weeks, maintain dose level.  
● If resolved in more than 2 weeks,  1 dose level.  
Second occurrence:  1 dose level. 
Initiate/intensify appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids) 


 
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Worst toxicity (CTCAE 4.03 Grade)** 
Dose Modifications for BKM120 
Grade 3 
First occurrence: omit dose until resolved to CTCAE Grade ≤ 1; then 
 1 dose level. 
Second occurrence: permanently discontinue patient from BKM120. 
Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation.  
According to the investigators discretion, a paired skin biopsy could 
be obtained (from both an affected and an unaffected skin area for 
local histopathology assessment) if clinical appropriate. 
 
Grade 4 
Permanently discontinue patient from BKM120. 
Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation. 
According to the investigators discretion, a paired skin biopsy could 
be obtained (from both an affected and an unaffected skin area for 
local histopathology assessment) if clinical appropriate. 
 
Fatigue (asthenia) 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then: 
● If resolved in ≤ 7 days, maintain dose level 
● If resolved in > 7 days,  1 dose level 
Pneumonitis  
please see Table 4-8, Section 4.1.2.4.1 for additional follow up for 
selected toxicities 
Other non- hematological adverse events 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ Grade 1, then  1 dose level 
Grade 4 
Permanently discontinue patient from BKM120 
Note: Omit dose for ≥ Grade 3 vomiting or Grade 3 nausea only if the 
vomiting or nausea cannot be controlled with optimal antiemetic 
 
Mucositis  
Grade 1 / Tolerable Grade 2 
Maintain dose level. 
Non-alcoholic or salt water mouth wash (see also section for 
additional follow up for selected toxicities) 
Intolerable Grade 2 or Grade 3 
First occurrence: hold until resolved to grade ≤ G1 and  1 dose level 
(if stomatitis is readily manageable with optimal management, re-
introduction at the same level might be considered at the discretion of 
the investigator).  
Second occurrence: hold until resolved to grade ≤ G1 and  1 dose 
level. 
Grade 4 
Permanently discontinue patient from BKM120. 
** Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
These changes must be recorded on the Dosage Administration Record eCRF. 
4.3 
Monitoring of BKM120 Suspected Toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event, 
clinically significant laboratory value(s) or abnormal test procedure result(s), must be followed 
as outlined in Table 4-5, at least once a week for 4 weeks, and subsequently at 4-week intervals, 
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delay of > 28 days from the intended day of the next scheduled dose and has had more than two 
dose reductions, 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 4.2.5.1  
4.4 
Known Undesirable Side Effects of BKM120 
4.4.1 
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 symptoms 
CTCAEhy Grade ≥ 2 should immediately be examined by a psychiatrist and closely followed 
medically. Medical treatment with mood stabilizers (2nd generation antipsychotics) such as 
olanzapine and quetiapine may be applied as per investigator’s discretion and following 
consultation of a psychiatrist. 
4.4.1.1 
Management of Mood Alteration 
Guidelines for the treatment of BKM120 induced psychiatric disorders 
Psychiatric adverse events will be closely monitored and evaluated at each planned 
visit until recovery to Grade ≤ 1 or baseline status. The grading of psychiatric adverse 
events/mood alterations must be based on the clinical interpretation of severity 
according to the NCI- CTCAE (v 4.03) guidelines. 
For patients who experience new or worsening of existing psychiatric AEs of Grade 
≥1, psychiatric consultation should be considered as described in Table 4-5. 
Patient self-reported mood questionnaires (GAD-7 and PHQ-9) will be used for 
screening and during the study treatment phase to aid the investigator in identifying 
new or worsening of events. For additional information regarding safety assessments 
based on patient self-reported mood questionnaires, please refer to Section Patient 
self-rating mood questionnaires. 
If question 9 in the PHQ-9 has a positive response (as indicated by selecting "1", "2", 
or "3"), omit treatment with BKM120 and refer the patient to the on-site psychiatrist 


 
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or a local psychiatrist for psychiatric consultation for optimal management regardless 
of the total questionnaire score or CTCAE grading to confirm if study drug should be 
interrupted or permanently discontinued. In this specific case, the psychiatric advice 
can overrule the patient’s PHQ-9 self-assessment. During the study, subjects will be 
monitored at regular scheduled visits (eg, Day 15 of Cycle 1, Day 1 and Day 15 of 
Cycles 2, Day 1 of each subsequent cycle, and at the End of Treatment visit) by the 
investigator/site staff through personal interaction and the two self-reported 
questionnaires. For patients who fax or email their questionnaires; the study nurse 
will promptly review the questionnaires as they become available. Additional 
assessments may be done according to the clinical judgment of the investigator if 
desired. 
 
Table 4-6 GAD-7 anxiety scale 
 


 
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Table 4-7 PHQ-9 depression scale 
 
 
 


 
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4.4.2 
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 4-5. 
4.4.2.1 
Management of Hyperglycemia 
In addition to the dose modification and hyperglycemia treatment guidelines in Table 4-5: 
• Under the supervision of an endocrinologist, an insulin regimen should be initiated 
according to institutional standard of care or the Treat-To-Target Algorithm for Lantus® 
(Riddle, Rosenstock, and Gerich 2003). 
 
• For any hyperglycemia ≥ grade 1, the patient should continue to follow dietary guidelines 
provided by the American Diabetes Association (American Diabetes Association 2004). 
 
• For each patient, a maximum of 2 dose reductions will be allowed after which the patient 
should be discontinued from the study. In addition, a patient must discontinue treatment with 
BKM120, if after treatment is resumed at a lower dose, hyperglycemia recurs at a worse 
severity. 
 
• For each patient, once a dose level reduction has occurred, the dose level may not be re-
escalated in that patient during future treatment cycles with BKM120. 
 
• Based upon the results of preliminary clinical data and actual laboratory values (e.g., glucose, 
insulin) generated, the treatment recommendations for study drug induced hyperglycemia may 
be modified as needed.  
4.4.3 
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 


 
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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. 
4.4.3.1 
Management of Cardiac Events  
At the screening visit a 12-lead electrocardiogram (ECG), and an echocardiogram or MUGA 
(ECHO/MUGA) will be performed to assess eligibility. Repeat ECGs will be performed at 
screening and as clinically indicated. An ECHO/MUGA will be repeated at Cycle 4 and then 
every 4th cycle thereafter. 
4.4.4 
Lung Toxicity/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 pneumonitis grade 2 eight 
weeks after the first dose of BKM120 at 100 mg 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 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). 
4.4.4.1 
Management of Pneumonitis 
All patients participating in clinical trials with BKM120 will be routinely asked about 
and observed for the occurrence of adverse events which could include new or 
changed pulmonary symptoms (consistent with lung abnormalities). CT scans and 
pulmonary function tests should be done, as clinically indicated, or if there are 
symptoms that indicate that the patient has developed pneumonitis. In case of a 
documented pneumonitis, the guidelines (including dose modifications) in Table 4-8 
should be followed. Consultation with a pulmonologist is highly recommended for 
any pneumonitis case during the study treatment. 


 
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Table 4-8 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, (or as per 
local practice) 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, (or as 
per local practice) 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 3) 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 
28 days. 
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, (or as per local 
practice) until return to within 
normal limits. Bronchoscopy with 
biopsy and / or BAL is 
recommended. 
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Hold treatment with BKM120 until 
recovery to ≤ Grade 1. May restart 
study treatment within 28 days at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing, if possible, includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat at least 
every 6 weeks, (or as per local 
practice) 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. 
4.4.5 
Liver Toxicity 
4.4.5.1 
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 or bilirubin* values. 
 
Monitoring Cycle 3 and more: monthly or more frequently if clinically indicated. In case of 
any occurrence of ALT/ AST or bilirubin* increase ≥ grade 2 the liver function tests must be 
monitored weekly or more frequently if clinically indicated until resolved to ≤ grade 1. 
 
In case of any occurrence of ALT/ AST or bilirubin* increase ≥ grade 3  the liver function tests 
must be monitored weekly or more frequently if clinically indicated until resolved to ≤ grade 
1; hereafter the monitoring should be continued every other week or more frequently if 
clinically indicated until the end of treatment with study medication. 


 
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Patients who discontinued study treatment should be monitored weekly, including LFTs* or 
more frequently if clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE 
grade change over 4 weeks). 
4.4.5.2 
Management of Hepatotoxicity (ALT and/or AST >3.0x ULN and total 
bilirubin >2.0x ULN)  
Criteria for interruption and re-initiation of BKM120 treatment in case of the occurrence of 
AST, ALT or bilirubin increase are detailed in Section 4.2, Table 4-5. Patients with clinically 
significant liver test abnormalities should perform liver-directed medical history, physical 
examination and other tests as medically indicated to assess potential relationship with study 
treatment and rule out other underlying causes (e.g. disease progression/obstruction, 
infection/hepatitis or other liver diseases, sepsis, metabolic diseases including diabetes, 
concomitant medications including herbals, alcohol, drug-drug interaction, cardiovascular 
disease/ischemia, other organ injuries, etc.). Any pre-existing liver conditions or risk factors 
should be reported in the respective medical history and concomitant medication CRF pages 
(if not done already). All patients with ALT or AST >3.0 x ULN and total bilirubin > 2.0 x 
ULN in the absence of cholestasis (elevation of alkaline phosphatase [ALP] in patients 
without bone metastasis or if bone metastasis are present elevation of 5’-nucleotidase and 
ALP liver fraction) must be immediately withdrawn from BKM120, and every attempt should 
be made to carry out locally the liver event follow-up assessments as described below:  
• Inform the sponsor about the event immediately after its occurrence by reporting the event 
immediately in the clinical database if it meets the criteria for an AE or SAE.  
• Evaluate if associated with the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash or eosinophilia, or other organ involvement.  
• Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), and blood count with differential to assess eosinophilia.  
• Perform liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease including metastasis or new lesions, obstruction/compression, etc.  
• Perform viral hepatitis and other serology tests:  
o Hepatitis C (HCV) serology and viral RNA, Hepatitis B (HBV) serology and viral 
DNA, Hepatitis A (HAV) Immunoglobulin M (IgM) and HAV total  
o Hepatitis E (HEV) serology: IgM and IgG, viral RNA  
o Herpes Simplex Virus (HSV), Cytomegalovirus (CMV), Epstein-Barr viral (EBV) 
serology  
• Verify and record the use of concomitant medications, acetaminophen, herbal remedies, and 
other over the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.  
• Consultation with a specialist(s) or a hepatologist(s) is recommended. 


 
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• Liver biopsy as clinically indicated to assess pathological change and degree of potential 
liver injury  
• LFTs should be followed-up weekly until resolve to ≤ grade 1, baseline or stabilization (no 
CTCAE grade change over 4 weeks) and outcome documented on the respective AE and lab 
chemistry pages. 
4.4.6 
Skin Toxicity/Hypersensitivity  
Buparlisib should be discontinued in cases of CTCAE grade 3/4 hypersensitivity reaction and 
medical intervention according to the local standards instituted. 
4.5 
Study Termination 
A patient is considered terminated from the study when the decision to permanently stop the 
study medication and survival follow-up is made. Subjects can terminate their participation in 
this study at any time without penalty or loss of benefits to which the subject is otherwise 
entitled. A subject’s participation may be terminated by the Principal Investigator due to any of 
the following:  
1. adverse event(s) 
2. protocol violation 
3. subject withdrew consent 
4. lost to follow-up 
5. administrative problems 
6. Death 
7. If a patient requires a dose delay of > 28 days from the intended day of the next 
scheduled dose and has had more than two dose reductions, then the patient should be 
discontinued from the study. 
 
The reasons in which a subject is terminated from the study must be documented in the 
patient’s chart or records. 


 
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4.6 
Visit Schedule and Assessments 
4.6.1 
Visit Schedule 
Table 4-9 Evaluation and Visit Schedule 
Examination 
Screeni
ng/ 
Baselin
e 
Cycle 1 
Cycle 2 
 
Cycle 3- Cycle n11  
Follow-
up 
Day of Cycle 
-21 
1 
158 
1 
15
8 
3 
4 
5 
6 
7 
8 
9 
etc 
EOT 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Pathology 
Review9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
Test (within 72 hours 
of first treatment for 
WOCBP) 
X 
As clinically indicated.  
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
X8 
X 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Genomic Analysis 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
(including skin rash 
assessment) 
X 
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 
X 
 
Neuro-psychiatric 
assessment (PH1-9 
& GAD-7)1 
X 
X 
X 
X 
X 
X  X 
X 
X 
X 
X 
X 
X 
X 
 
MUGA/ECHO2 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
12-lead ECG 
X 
 
X 
As clinically indicated 
 
Radiological tumor 
assessment/respons
e assessment (Chest 
CT scan)3 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematology4 
X 
X 
X8 
X 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry5 
X 
X 
X8 
X 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation Profile6 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Fasting plasma 
glucose7 
X 
X  
X8 
X 
X8 
X  X 
 
X 
X 
X  X 
X 
X 
X  
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
Medications 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hepatotoxicity 
follow-up testing 
procedures 
As clinically indicated 
 


 
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1 PHQ-9 and GAD-7 questionnaires will be completed in clinic at each visit through the end of Cycle 2. Symptomatic 
patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis On Day 1 starting at Cycle 3 and for 
all subsequent cycles while active on the treatment portion of the study. Questionnaires on day 15 of cycles 1 and 2, as 
well as any other questionnaires required at times other than the scheduled visits can be completed by the patient at 
home and faxed to the Investigator or the authorized study member for evaluation to fax number (317-274-8007) or sent 
via PDF. 
2 MUGA/ECHO Baseline, Cycle 4 then every 4th cycle.  
3 Radiological tumor assessment should be performed at screening and every 8 weeks from start of treatment until 
progression of disease as per RECIST 1.1, or end of treatment. All assessments should be performed within ±7 days of 
the scheduled day of assessment. Other scans, as appropriate for measurements will be performed at the same time 
interval. 
4 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.   
5Serum chemistry - K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin (direct and indirect), creatinine, amylase, GGT, 
lipase, alkaline phosphatase (fractionated if alkaline phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric 
acid, total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein are required at 
baseline and at end of treatment. Subsequent assessments always include K+, Na+, Ca++, ALT, AST, total bilirubin 
(direct and indirect), creatinine, alkaline phosphatase, bicarbonate, phosphorus, glucose, urea or BUN, albumin, and 
total protein BUT, lipase, total cholesterol, HDL, LDL, triglycerides should be obtained on the first day of odd numbered 
cycles only. C1D1 assessments may be performed up to 72 hours prior to the scheduled visit. All other draws should 
occur within 24 hours of the intended visit. 
6 Coagulation - PT or INR, PTT, and C1D1 assessments may be performed up to 72 hours prior to the scheduled visit. 
Additional assessments will be performed on Day 1 of Cycle 2 (≤ 72 hours prior to dosing) and repeated every other 
cycle. A repeat coagulation profile panel is required at the time of study treatment discontinuation. Patient entering the 
study while receiving anti-coagulation therapy or those who have the initiation of an anti-coagulation therapy should 
have their coagulation test performed on a weekly basis. 
7 Patients must be fasting overnight for at least 8 hours. Additional measurements may be performed as clinically 
indicated. 
8 May be performed at outside institution with results transmitted via fax (to fax number 317-274-8007) or via PDF. 
9Pathology will undergo central review by IU Department of Pathology to confirm eligibility which will include obtaining 
blocks or primary or metastatic lesion s which can be obtained prior to the 21-day screening window. 
10Genomic analysis consists of collecting peripheral whole blood prior to the first dose of chemotherapy. DNA and 
RNA will be extracted from a core tumor specimen as part of standard of care prior to enrollment. See Section 4.2.6, 
Collection of Genomics Data. 
11 Assessments for Cycles 3 and beyond will occur on Day 1. 
4.6.2 
Efficacy Assessments 
4.6.2.1 
Anti-Tumor Effect 
Imaging will be obtained at baseline and at the end of every two cycles. Tumor responses will 
be assessed by Response Evaluation Criteria in Solid Tumors Guideline (RECIST v1.1) 
(Eisenhauer, et al 2009). 
4.6.2.2 
Measurement Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1) 
Measurable: 
• 
Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
o 10 mm by CT, MRI or PET scan (slice thickness no greater than 5 mm) 
o 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
o 20 mm by chest X-ray 


 
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• 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT, MRI 
or PET scan (slice thickness recommended to be no greater than 5 mm). At baseline 
and in follow-up, only the short axis will be measured and followed.  
2) 
Non-measurable: 
All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurable lesions. 
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging. 
4.6.2.3 
Specifications by Methods of Measurements 
1) 
Measurement of Lesions: 
 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the treatment start 
and never more than 4 weeks before the beginning of the treatment. 
 
2) 
Method of Assessment: 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
• 
 
Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and ≥10mm diameter as assessed using calipers (e.g. skin nodules). 
For the case of skin lesions, documentation by color photography including a ruler 
to estimate the size of the lesion is suggested. As noted above, when lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the 
study. 
• 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated lung.  
• 
 
CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability 
of lesions on CT scan based on the assumption that CT slice thickness is 5mm or 
less.  
• 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. 


 
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• 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  
• 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response.  
• 
 
Cytology, histology: These techniques can be used to differentiate between PR 
and CR in rare cases if required by protocol. 
4.6.2.4 
Tumor Response Evaluation 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
• 
When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and will 
be recorded and measured at baseline. 
• 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  
• 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. 
If lymph nodes are to be included in the sum, then as noted above, only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of 
the disease. 
4.6.2.5 
Response Criteria 
For other details and special circumstances of the RECIST 1.1 guidelines, refer directly to 
reference. 
• 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
• 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.  
• 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance 
of one or more new lesions is also considered progression). 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 


 
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Time Point Response of Target Lesions 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not Evaluated 
No 
PR 
PR 
Non-PD 
or Not All Evaluated 
No 
PR 
SD 
Non-PD 
or Not All Evaluated 
No 
SD 
Not All Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
4.6.2.6 
Definitions of Endpoints 
• 
Progression-Free Survival (PFS): Duration of time from start of treatment to time 
of documented progression or death 
• 
Overall Response Rate (ORR): Number of patients who achieve either a partial or 
complete response divided by the number of patients 
• 
Duration of Response (DoR) (Among Responders, PR + CR): A measurement 
from the earliest time when response criteria are met until death or progression.  
Patients still meeting the criteria for response at the end of the study are treated as 
censored. 
• 
Overall Survival (OS): Time from the date of enrollment to the date of death due 
to any cause or the last date the patient was known to be alive (censored observation) 
at the date of data cutoff for the final analysis 
• 
Disease Control Rate (DCR):  Number of patients who achieve either a partial or 
complete response or stable disease for at least 4 months divided by the number of 
patients. 


 
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4.6.3 
Safety Assessments 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine 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. 
4.6.4 
Treatment Compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to return 
all unused study medication. 
4.6.5 
Adverse Events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is 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, 


 
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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 [Investigators’ Brochure]. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
4.6.5.1 
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 patient’s 
general condition 
• 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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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 [Investigator’s Brochure] 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. 
4.6.5.2 
Novartis Instructions for Rapid Notification of Serious Adverse Events 
The principal investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). 
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.  


 
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For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
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+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 


 
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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. 
4.6.6 
Laboratory Evaluations 
4.6.6.1 
Pregnancy Test 
A serum pregnancy test (β-HCG) is required for all women of child-bearing potential at 
screening, within 72 hours prior to the first dose of BKM120. Note: Postmenopausal women 
must have been amenorrheic for ≥ 12 months in order to be considered “of non-childbearing 
potential”. This should be documented appropriately in the patient’s medical history. Additional 
pregnancy tests should be performed as clinically indicated.  
4.6.6.2 
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. 
4.6.6.3 
Coagulation Profile 
The coagulation profile includes prothrombin time or INR, and activated partial thromboplastin 
time. 


 
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4.6.6.4 
Serum Chemistry 
Biochemistry includes the following parameters: K+, Na+, Ca++, Mg++, LDH,ALT, AST, total 
bilirubin (direct and indirect), creatinine, amylase, GGT, lipase, alkaline phosphatase 
(fractionated if alkaline phosphatase is grade 2 or higher), bicarbonate, phosphorus, uric acid, 
total cholesterol, HDL, LDL, triglycerides, glucose, urea or BUN, albumin, and total protein 
are required at baseline and at end of treatment.  Subsequent assessments always include K+, 
Na+, Ca++, ALT, AST, total bilirubin (direct and indirect), creatinine, alkaline phosphatase, 
bicarbonate, phosphorus, glucose, urea or BUN, albumin, and total protein BUT, lipase, total 
cholesterol, HDL, LDL, triglycerides should be obtained on the first day of odd numbered 
cycles only. C1D1 assessments may be performed up to 72 hours prior to the scheduled visit. 
All other draws should occur within 24 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. 
4.6.6.5 
Urinalysis 
Urinalysis includes macroscopic (protein, glucose, ketones, blood, and specific gravity) and 
will be performed at screening visit and EOT visit. A microscopic (WBC/HPF, RBC/HPF, and 
any additional findings) exam need only be performed if the urinalysis result is abnormal.  
This must be supplemented with laboratory quantification of any potentially relevant 
abnormalities. 
4.6.6.6 
Hepatotoxicity 
Hepatotoxicity follow-up testing will be performed when needed (refer to Section 4.4.5.2 
Management of hepatotoxicity [ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN]). 
4.6.6.7 
Viral hepatitis serology and other tests for hepatotoxicity follow-up 
Viral hepatitis serologic tests are performed confirm patient’s eligibility when needed per 
clinical judgment and specific patient’s clinical circumstances.  
During study treatment, viral hepatitis serologic and other tests will be performed as per the 
guidelines of management of hepatotoxicity (ALT or AST >3.0x ULN and total bilirubin > 2.0x 
ULN) in patients receiving BKM120. Refer to Section 4.4.5.2 Management of hepatotoxicity 
(ALT and/or AST >3.0x ULN and total bilirubin >2.0x ULN) for details.  
Viral hepatitis serology includes the following:  
• Hepatitis A IgM antibody and hepatitis A serology total  
• Hepatitis B surface antigen, Hepatitis B Core Antibody (IgM) and viral DNA 
• Hepatitis C serology and viral RNA  
• Hepatitis D RNA (where needed)  
• Hepatitis E IgM and IgG antibody and viral RNA  


 
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Obtain fractionated bilirubin, serum Alkaline Phosphatase (ALP), creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), and blood count with differential to assess eosinophilia. 
Novartis Confidential Page 18 BKM120 liver toxicity standard language based on protocol 
CBKM120F2303 Amendment 3 Additional viral serology tests may include:  
• Cytomegalovirus IgM antibody  
• Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody 
or monospot testing)  
• Herpes Simplex Virus 
Table 4-10 Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Viral hepatitis serologic tests and other tests 
for hepatotoxicity follow-up * 
HAAb, HBsAg, HBsAb HBcAb, HCV RNA 
or HDV RNA (where needed), HEAb, 
CMVAb, EBcAb, ALP, CPK, LDH, WBC 
(eosinophilia), and others. 
* Hepatotoxicity follow-up testing/procedures will be performed locally (refer to Section 
4.4.5.2 Management of hepatotoxicity [ALT and/or AST >3.0x ULN and total bilirubin >2.0x 
ULN] and Section 4.6.6.7 Viral hepatitis serology and other tests for hepatotoxicity follow-
up). 
4.6.6.8 
Collection of Genomics Data 
A genomic analysis will be performed and analyzed if there are statistically objective responses 
to identify markers for patients who respond and do not respond to therapy. For each patient, 
DNA & RNA will be extracted from a core tumor specimen collected as part of standard of care 
prior to enrollment. Blocks or 5 (10 micron thick) slides should be requested and/or sent to Dr. 
Milan Radovich’s lab for future research studies located at:  
 
Walther Hall, Room R3 C240 
980 W. Walnut Street 
 Indianapolis, IN 46202. 
 
In addition, DNA extracted from 9mL of peripheral whole blood will be collected (in a BD 
Vacutainer EDTA tube) prior to the first dose of therapy for all patients. Extractions will be 
performed in using a Qiagen DNA/RNA All Prep Kit (Qiagen, Valencia CA). For DNA 
sequencing, we will employ high-coverage whole-exome chemistry to ensure capture of both 
structural and nucleotide-level mutations. Briefly, the whole exome sequencing will be 
performed on our group’s own Ion Proton Sequencers. The Ion Proton has been previously 
demonstrated to produce high-quality exomes for germline variation detection. 100ng of 
genomic DNA for both tumor and blood normal will undergo library preparation for the Ion 
Proton Sequencer using the Ion Ampliseq Exome Kit (Life Technologies).  This amplification-
based method of exome enrichment covers 97% of all consensus coding sequence with >90% 
of on-target bases covered and >90% coverage uniformity. Sequencing for this project will 


 
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utilize the Ion Proton PII chip yielding an estimated 400 million high quality 100bp reads per 4 
hour run. In addition, we will also utilize the Ion Hi-Q sequencing chemistry, which uses a new 
polymerase that results in a 90% reduction in the indel error rate for increased accuracy. All 
samples will be sequenced to an average of 100X coverage. Each sequencing run will be 
evaluated for technical quality control metrics including: efficient ion sphere loading, 
percentage of polyclonality, and mean raw accuracy. Following technical quality control, raw 
sequencing reads will be mapped to the human genome (hg19) using the highly efficient TMAP 
algorithm with output in standard BAM format. High confidence SNPs and indel variants will 
be called using the Ampliseq variant caller which incorporates local re-alignment as well as 
filtering for homopolymer induced false-positive indels. A minimum of 10 sequencing reads 
will be needed for a SNP or indel to be called, and only bases with quality values ≥ 20 will be 
considered. Final variant calls will be reported in standard VCF format. For additional quality 
review, we will estimate the average transition/transversion (Ti/Tv) ratio per sample. For RNA-
sequencing of tumor RNA, libraries will be prepared using the Ion Total RNA-Seq Kit v2 (Life 
Technologies), followed by emulsion PCR, templating, and sequencing as described above. 
After quality filtration, we estimate generation of 400 million 100bp fragment sequencing reads 
per sample. For bioinformatics analysis, reads will be mapped to the human genome using the 
STAR algorithm; differential expression using Cufflinks, and visualization using Partek 
Genomics Suite (Partek, Inc). For calling expressed gene fusions, we will use the Tophat-Fusion 
(Broad Institute) and FusionMap (Amgen) algorithms. Of importance, all genomic data will be 
stored on the HIPAA-compliant IU Scholarly Data Archive, and all analyses will be performed 
on secure HIPAA-compliant servers. 
4.6.7 
Vital Signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. Blood pressure, pulse and respiration rate should be measured on 
patients after at least 3 minutes in the sitting position as per the visit schedule.  
4.6.8 
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. 
4.6.9 
Neuropsychiatric Assessments 
Patient self-rating mood questionnaires for anxiety and depression (PHQ-9, GAD-7) will be 
applied at: 
• Screening 
• Days 1 and 15 of Cycle 1 
• Day 1 and 15 of Cycle 2 


 
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• Day 1 of Cycle 3 and subsequent cycles (only for patients who have not shown mood 
alterations during the first 2 cycles, patients who did should continue to fill out the questionnaire 
on a weekly base). 
Questionnaires on day 15 of cycles 1 and 2, as well as any other questionnaires required at times 
other than the scheduled visits can be completed by the patient at home and faxed to the 
Investigator or the authorized study member for evaluation. 
• End of Study treatment 
Additional assessments may be done according to the clinical judgment of the Investigator. 
Symptomatic patients (≥ CTCAE grade 1) must continue with questionnaires on a weekly basis 
while active on the treatment portion of the study. 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. 
4.6.10 
ECG/ECHO 
A standard 12 lead ECG is to be performed at screening, C1D15 and as clinically indicated. 
An echocardiogram (ECHO) or MUGA will be performed to assess eligibility. ECHO/MUGA 
will be repeated at Cycle 4 and then every 4th cycle thereafter. 
4.6.11 
Performance Status 
Performance status will be assessed at screening and per the visit schedule. The Eastern 
Cooperative Oncology Group (ECOG) Performance Status Scale will be used for this study. 
See Appendix A for details. 
4.6.12 
Drug Levels and Pharmacokinetic Assessments 
• None will be made.  
5 
Data Management 
5.0 
Data Collection 
This study will utilize electronic Case Report Form completion in the OnCore® database. A 
calendar of events and required forms are available in OnCore® at https://cancer.iu.edu/oncore. 
The OnCore® database is a comprehensive database used by the Clinical Trials Research Office 
(CRO) and supported by the Indiana University Cancer Center. OnCore® properly used is 
compliant with Title 21 CFR Part 11. 
Access to data through OnCore® is restricted by user accounts and assigned roles. Once logged 
into the OnCore® system with a user ID and password, OnCore® defines roles for each user 
which limits access to appropriate data. User information and password can be obtained by 
contacting the CRO at 317-274-0930. 
All source documents are to remain in the patient’s clinic file. All documents should be kept 
according to applicable federal guidelines. Clinical trial data in OnCore® are periodically 
monitored by the IU Simon Cancer Center Clinical Trials Monitoring Committee. 


 
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6 
Patient Consent and Peer Judgment 
The protocol and informed consent form for this study must be approved in writing by the 
appropriate Institutional Review Board (IRB) prior to any patient being registered on this study. 
Changes to the protocol, as well as a change of principal investigator, must also be approved by 
the Board. Records of the Institutional Review Board review and approval of all documents 
pertaining to this study must be kept on file by the investigator (housed in the Clinical Research 
Office) and are subject to FDA inspection at any time during the study. Periodic status reports 
must be submitted to the Institutional Review Board at least yearly, as well as notification of 
completion of the study and a final report within 3 months of study completion or termination. 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
7 
Statistical Methods 
7.0 
General Considerations 
Statistical analysis of this study will be the responsibility of the Department of Biostatistics at 
Indiana University School of Medicine. Parameter estimates and relevant summary statistics 
will be reported for both efficacy and safety outcomes. Continuous variables will be 
summarized by means, medians, minima, maxima and standard deviations. Categorical 
variables will be summarized by frequencies and percentages. Missing data will not be imputed. 
Additional exploratory analysis will be conducted when appropriate. Changes from the analysis 
plan will not require an amendment to the protocol unless it changes a significant feature in the 
protocol. The statistical analysis methods are outline below. 
7.1 
Study Design 
This is a single arm, open label, two-stage, phase II clinical trial. No randomization or blinding 
is involved.   
7.2 
Analysis Population 
7.2.1 
Enrolled Population 
The enrolled population comprises all patients who meet the eligibility criteria and are 
registered onto the study. 
7.2.2 
 Safety Population 
The safety population comprises all patients who have received at least one dose of the study 
medication. This set will be used for safety analysis. 
7.2.3 
Efficacy Population 
The efficacy population comprises all patients with disease that is radiographically evaluable at 
initial and at least one follow-up time point. This population will be used for efficacy analysis. 


 
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7.3 
Sample Size, Accrual and Study Duration 
The primary end point of the study is objective response rate (CR+PR) according to RECIST 
1.1 criteria for BKM120 monotherapy in patients with advanced thymomas. All sample size 
estimates are based on the objective response rate. 
 
A two-stage Minimax design will be used with two-sided alpha = .10 and power of 90%.  The 
study will try to rule out a 10% objective response rate (p0= 0.10) and target a modest response 
rate of 30% (p1= 0.30). The study will initially enroll 16 evaluable patients with thymoma; if 0 
to 1 of the 16 patients demonstrate a partial response then no further patients will be accrued. If 
2 or more of the first 16 patients have a response, then accrual would continue until a total of 
25 evaluable patients have been treated. A temporary pause in the accrual to the trial may be 
necessary to ensure that enrollment to the second stage is warranted. If there are 2 to 4 patients 
with a response in the total of 25 evaluable patients, then this would be an uninterestingly low 
rate, while if there were 5 or more patients of the 25 who have a response, this would be 
sufficiently interesting to warrant further study of this agent in later trials. Under the null 
hypothesis (10% response rate), the probability of early termination in this cohort is 52%. 
 
It is anticipated that approximately 2 patients per month overall may enroll on this trial. Thus, 
accrual should be completed in approximately 12-18 months. In order to allow for a small 
number of in-evaluable patients, the accrual ceiling will be set at 27.  
7.4 
Patient Characteristics 
Baseline patient characteristics will be tabulated, such as demographics (age, race, gender), and 
ECOG performance score. 
7.5 
Significant Protocol Violations 
Significant protocol violations such as with respect to eligibility criteria and treatment plan will 
be tabulated. 
7.6 
Concomitant Medications 
Drugs that might affect the study medication, as described in Section 4.0.2, will be tabulated. 
7.7 
Exposure and Compliance 
Exposure to the study medication will be summarized by frequencies and rates of the doses 
given. Reasons of not completing all doses will be tabulated. 
7.8 
Efficacy Analysis 
The main analysis of the primary endpoint, objective response rate (ORR) after two months, 
will be based on the safety population (see section 7.12.2 below). The primary efficacy 
endpoint, ORR (defined as the proportion of patients with the best overall response of PR or 
CR), together with corresponding 95% exact binomial confidence interval, will be calculated.  


 
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A similar analysis will be done for the secondary objective of disease control rate (DCR), 
defined as the proportion of patients with the best overall response of PR or CR or SD of at 
least 4 months). 
Progression free and overall survival will be determined using Kaplan-Meier curves.  Medians 
and other quartiles for each endpoint will be estimated in addition to the corresponding two-
sided 95% confidence intervals.  The results of this analysis may be compared in an informal 
manner to any similarly defined curves available from other published studies in comparable 
patients with the same disease.  We will also repeat all analysis using the efficacy population 
as supportive analyses. 
7.9 
Safety Analysis 
Toxicities according to CTCAE 4.0 will be summarized by frequencies and rates calculated as 
the proportion of patients in the safety population experiencing SAEs, discontinuations due to 
AEs, and AEs.  Two sets of tables will be generated: one for the overall toxicities and one for 
toxicities related to the study medication (possibly related, probably related and definitely 
related). Toxicities will be grouped by system using MedRA preferred terminology. Grade 1 to 
4 will be reported individually and also as grade 3/4.  Deaths will be reported individually.  AE 
related to neuropsychological events (depression and anxiety) will also be tabulated. 
7.10 
Statistical Analysis of Genetic Data 
Statistical analysis will include identification of differentially expressed genes, and pathways 
between tumors than exhibited greater response (CR+PR+SD) compared to those that did not 
(PD) using two-sample t-tests; association of expressed genes and signatures with response 
and survival outcome (multivariable logistic and cox regression, respectively); identification 
of significantly mutated genes associated with response and survival outcome (MutSigCV, 
which determines significance by testing whether the observed mutations in a gene 
significantly exceed the expected counts based on a background model); and association of 
mutational context spectra with response and survival outcomes (Non-Matrix Factorization). 
In addition, data will also be integrated using a variety of tools designed for multi-platform 
approaches. This includes network & pathway analyses (IPA and GeneGo); CNV and 
mutation integrated clusters (IntClust); mutually exclusive modules in cancer (MEMo); drug 
association databases (Metacore, IPA); and multi-platform cluster of clusters (C-of-C). 
7.11 
Interim Analysis 
Efficacy interim analyses will be performed at described above based on the standard two-
stage design. 
7.12 
Reporting and Exclusions 
7.12.1 
Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with BKM120. 


 
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7.12.2 
Evaluation of Response 
All patients included in the study who received any study drug must be assessed for response 
to treatment, even if there are major protocol treatment deviations or if they become ineligible 
after enrollment. Each patient will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database]. 
 
All of the patients who meet the eligibility criteria and are enrolled (with the exception of those 
who received no study medication) should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. Precise definitions for categories 4-9 are 
protocol specific and included in section 4.2.2. 
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. The 95% confidence intervals should also be provided. 
8 
Data and Safety Monitoring Plan (DSMP) 
Investigators will conduct continuous review of data and patient safety. Monthly review 
meetings are required and will include the principle investigator, clinical research specialist 
and/or research nurse (other members per principle investigator’s discretion). Monthly 
meeting summaries should include review of data and patient safety by including for each 
dose level: the number of patients, significant toxicities as described in the protocol, dose 
adjustments and responses observed. Summaries are to be submitted to DSMC@iupui.edu 
weekly and reviewed monthly.  
 
Study Auditing and Monitoring  
All trials conducted at the IUSCC are subject to auditing and/or monitoring. Reports will be 
reviewed by the full DSMC at the time of study review (Reference Risk Table in full DSMC 
Charter).  
 
Early Study Closure  
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks 
(or benefits) to the patient warrant early closure of the study, this recommendation should be 
made in writing to the Data Safety Monitoring Committee. Alternatively, the DSMC may 
initiate suspension or early closure of the study based on its review. 


 
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The DSMC has streamlined the reporting process by utilizing reports from OnCore®. This has 
allowed direct view of reports within the Clinical Trials Management System (CTMS); thus 
discontinuing paper reports. SAE reports are entered into OnCore® monthly and reviewed by 
the DSMC chair and/or coordinator monthly. Findings will be reported to the full DSMC at 
the time of study review.  
 
Reporting Death  
Death will be reported per local IRB reporting guidelines (Section 5.8 of the Unanticipated 
Problems and Noncompliance SOP).  
 
Study Accrual Oversight  
Accrual data will be entered into the IU Simon Cancer Center OnCore® system. The Protocol 
Progress Committee (PPC) reviews study accrual twice per year while the PAC coordinator 
reviews accrual quarterly.  
 
Protocol Deviations  
Protocol deviations are entered into OnCore® and reviewed by the DSMC chair and/or 
coordinator monthly. Findings will be reported to the full DSMC at the time of study review.  
9 
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APPENDICES 
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.