Conditions: Carcinoma, Basal Cell Recurrent Skin Cancer Skin Neoplasms Basal Cell Nevus Syndrome
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 10
Healthy volunteers: no

Brief summary:
This pilot trial studies how well sonidegib and buparlisib work in treating patients with basal cell carcinoma that has spread to other places in the body. Sonidegib and buparlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

Estimate the overall response rate (ORR) of sonidegib (erismodegib) in combination with buparlisib (hereby referred to as "LB therapy") for patients with locally advanced or metastatic basal cell carcinoma (BCC) in Smoothened inhibitor-naive patients (Cohort 1) and those whose disease is refractory or relapsed on Smoothened inhibitor monotherapy (Cohort 2).

NOTE: This study does not compare the treatment effect between these 2 dissimilar participant groups.

SECONDARY OBJECTIVES:

* Estimate the median duration of response, on or after LB therapy.
* Assess the safety and tolerability of LB therapy.
* Assess the histopathologic effect of LB therapy in tumor biopsies obtained at baseline and following 12 weeks of treatment.
* Assess the effect of LB therapy on gene expression including Hedgehog pathway and phosphatidylinositol 3-kinase (PI3K) pathways.
* Assess correlation between gene mutations in Smoothened, suppressor of fused homolog (Sufu), patched (PTCH), glioma-associated oncogene homolog (Gli)1, 2 and gene expression profiles and response to LB therapy.

OUTLINE:

Patients receive sonidegib orally (PO) once daily (QD) and buparlisib PO QD on days 1 to 28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months.

Arms:
arm 1: Participants with locally advanced or metastatic basal cell carcinoma (BCC) and naive to treatment with Smoothened inhibitors receive sonidegib and buparlisib in repeating 28-day cycles in the absence of disease progression or unacceptable toxicity. arm 2: Participants with locally advanced or metastatic basal cell carcinoma (BCC) that is refractory or relapsed after treatment with Smoothened inhibitors receive sonidegib and buparlisib in repeating 28-day cycles in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Buparlisib intervention 2: Sonidegib
Intervention descriptions: intervention 1: Administered orally at starting dose of 80 mg/day intervention 2: Administered orally at starting dose of 200 mg/day

Protocol document:
Prot_SAP_000.pdf: 
 
 
1 
Investigator Initiated Study IRB-29839 
 
An open-label pilot study to evaluate the efficacy and safety of a 
combination treatment of Sonidegib and BKM120 for the treatment 
of advanced basal cell carcinomas 
 
 
 
 
Version 05 September 2016 
                                     
 
NCT02303041 
                                                DATE: 12Dec2018 
 
 
 


 
 
2 
 
 
 
Coordinating Center 
Stanford Cancer Center 
875 Blake Wilbur Drive 
Stanford, CA 94305 
And 
450 Broadway, MC 5334 
Redwood City, CA 94603 
 
Protocol Director and Principal Investigator 
Anne Lynn S Chang, MD, Director of Dermatological Clinical Trials 
450 Broadway St, MC 5334 
Redwood City, CA 94603 
alschang@stanford.edu 
 
Co-Investigator 
Anthony Oro, MD PhD 
450 Broadway St, MC 5334 
Redwood City, CA 94603 
oro@stanford.edu 
 
Biostatistician 
Shufeng Li, MS 
450 Broadway St, MC 5334 
Redwood City, CA 94603 
lishufeng@gmail.com 
 
Study Coordinator 
Ann Moffat 
450 Broadway St, MC 5334 
Redwood City, CA 94603 
amoffat@stanford.edu 
 
 
 
 
 


 
 
3 
 
Table of Contents 
1 Background ................................................................. 7 
1.1 Disease Background ..................................................... 7 
1.2 Hedgehog Pathway and mechanism of action ............................... 7 
1.3 PI3K Pathway and mechanism of action ................................... 9 
1.4 Sonidegib Compound Information ............  Error! Bookmark not defined. 
 
1.4.1 Preclinical Studies for Sonidegib ....................................................................11 
 
1.4.2 Muscular system...............................................................................................13 
 
1.4.3 Skeletal system ................................................................................................13 
 
1.4.4 Reproductive system ........................................................................................14 
 
1.4.5 Gastro-intestinal system ...................................................................................14 
 
1.4.6 Renal system ....................................................................................................15 
 
1.4.7 Clinical experience with Sonidegib..................................................................15 
 
1.5 Buparlisib (BKM120)..............................................................................................20 
 
1.5.1 Preclinical studies of Buparlisib.......................................................................20 
 
1.5.2 Clinical experience with Buparlisib .................................................................25 
 
1.6 Study Rationale .......................................................................................................32 
2 
Study objectives .........................................................................................................33 
3 
Exploratory Investigational plan ................................................................................34 
3.1 
Overall study design ...........................................................................................34 
3.2 
Study population..................................................................................................34 
3.2.1 
Patient population.........................................................................................34 
3.2.2 
Inclusion and exclusion criteria....................................................................35 
4 
Treatments ............................................................................................................... 40 
 
4.1 Dose modification, interruption or discontinuation of treatment .............................40 
4.1.1 
Monitoring of buparlisib suspected toxicities ..............................................55 
4.1.2 
Known Undesirable Side Effects of buparlisib ............................................55 
 
4.2 Treatment Administration.........................................................................................65 
4.2.1 
Buparlisib Administration ............................................................................65 
4.2.2 
Sonidegib Administration ............................................................................66 
4.2.3 
Concomitant therapy ....................................................................................67 
 
4.3 Visit schedule and assessments ................................................................................74 
4.3.1 
Evaluation and Visit Schedule (Table 20).................................................... 74 
4.3.2 
Efficacy assessments ....................................................................................77 
4.3.3 
Safety assessments .......................................................................................77 
4.3.4 
Treatment compliance ..................................................................................78 
4.3.5 
Novartis instructions for rapid notification of serious adverse events .........80 
5 
Investigational agent sampling and shipping information .........................................84 
5.1 
Investigational treatment .....................................................................................84 
5.2 
How supplied .......................................................................................................85 
5.2.1 
Buparlisib .....................................................................................................85 
5.2.2 
Sonidegib...................................................................................................85 


 
 
4 
5.3 
Storage and Preparation ...................................................................................85 
5.4 
Disposal and destruction...................................................................................86 
6 
Data management ...................................................................................................86 
6.1 
Data collection .................................................................................................86 
6.1.1  
Variables....................................................................................................87 
6.2 
Analysis of the primary and key secondary variable(s) ...................................87 
7 
Statistical methods...................................................................................................87 
7.1 
Statistical Methods ...........................................................................................87 
7.1.1 
Statistical model, hypothesis, and method of analysis...............................87 
7.1.2 
Handling of missing values/censoring/discontinuations ...........................87 
8 
References .............................................................................................................88 
9 
APPENDICES........................................................................................................91 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
5 
 
 
List of abbreviations 
AE 
Adverse Event 
AKT 
See PKB (protein Kinase B) 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CK 
Creatinine Kinase / Phosphokinase 
CK-MB 
Creatinine Kinase – Muscle and Brain isoenzyme 
CR 
Complete Response 
CRD 
Clinical Research and Development 
CS 
Cowden Syndrome 
CT 
Computed Tomography 
CTC 
Circulating Tumor Cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Drug Safety Monitoring Board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EGFR 
Epidermal Growth Factor Receptor 
18F-FDG      [18F]-Fluorodeoxyglucose  
FPG  
 Fasting Plasma Glucose 
GCP  
 Good Clinical Practice 
     GI                 Gastrointestinal 
     HIV              Human Immunodeficiency Virus 
     ICH              International Conference on Harmonization 
     HDL             High density lipoprotein 
     IEC               Independent Ethics Committee   
    IRB               Institutional Review Board  
     LDL              Low density lipoprotein 
    LVEF            Left Ventricular Ejection fraction  
    MRI              Magnetic Resonance Imaging  
MTD             Maximum Tolerated Dose  
MUGA          Multiple Gated Acquisition Scan 
PD 
Pharmacodynamic 
PET 
Positron Emission Tomography 
PI3K 
Phosphatidylinositol 3’- kinase 
PK 
Pharmacokinetic 
PKB 
Protein Kinase B (or AKT) 
PT 
Prothrombin Time 


 
 
6 
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  
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
7 
 
 
1 
Background 
1.1        Disease Background 
Basal cell carcinoma (BCC) is the most common human malignancy with an estimated 
2 million cases diagnosed annually (American Cancer Society 2010).  Most of these forms 
of skin cancer are highly curable if found and treated early.  However, a fraction of these 
are highly aggressive and difficult-to-treat with conventional therapies. These can become 
life-threatening and even metastasize to distant organs.  These BCCs are collectively 
termed advanced BCCs (aBCCs). Recently, the Smoothened inhibitor (SI) class of drugs 
has emerged as a highly targeted therapy for BCCs resulting in the ability to shrink BCCs 
while causing minimal collateral damage.  (Sekulic et al., 2012) However, less than 50% 
of aBCCs respond to (SIs).   Of those that respond, approximately 20% become resistant to 
SIs after 1 year.  (Chang and Oro, 2012) Recently, our group has identified one mechanism 
of SI drug resistance, specifically increase in the PI3 kinase pathway (Chang et al., 2013, 
in press) Hence, we propose a preliminary proof-of-principle clinical trial to describe the 
overall response rate of aBCCs to combination SI and PI3K inhibitor treatment.  We also 
will characterize the mean duration of response on this combination therapy.  These data 
will be critical for future clinical studies using greater sample size. 
 
1.2        Hedgehog Pathway and mechanism of action 
Smoothened (Smo) is a G protein-coupled receptor-like molecule that positively regulates 
the Hedgehog (Hh) signal transduction pathway.    Hh pathway activation (Figure 1) at or 
upstream of Smo is linked to the pathogenesis of several types of cancer.  In particular, 
activating mutations in Hh pathway genes have been identified in patients with 
medulloblastoma (MB), basal cell carcinoma (BCC), and rhabdomyosarcoma.  Aberrant 
 
Figure 1. 
Schematic representation of the Hh pathway depicting mechanism of 
action of Sonidegib (http://www.novartisoncology.us/research/pipeline/ 
Sonidegib.jsp) 
upregulation of the Hh pathway without known mutation is linked to the pathogenesis of 
many other cancer types including pancreatic breast, esophageal, gastric, colorectal, 
glioblastoma, ovarian, sarcoma, acute and chronic leukemias, multiple myeloma, 
lymphoma and small-cell lung cancer (SCLC). Antagonists of Smo are hypothesized to 
block the growth of tumors that are dependent on Hh pathway activation. Furthermore, 
preclinical and emerging clinical data suggests Hh signaling may play an important role in 
many hematological cancers, such as acute and chronic leukemia, multiple myeloma and 
lymphomas. 
Sonidegib is a potent, selective and orally bioavailable Smo antagonist.  Treatment with 
sonidegib results in tumor regression in vivo in several genetically defined MB models. 
Efficacy in these tumor models is dose-related and correlates with inhibition of Hh 
pathway signaling, as measured by decreased Gli1 mRNA.  Treatment with sonidegib in 


 
 
8 
combination with other therapeutic agents also shows in vivo efficacy in many tumor 
models including of pancreatic cancer, glioma, and SCLC. 
Sonidegib is a potent antagonist of Hedgehog (Hh) - and Smoothened (Smo)-dependent 
signaling.  Smo is a GPCR-like molecule that positively regulates the Hh signal 
transduction pathway. Hh signaling plays critical roles in the development and homeostasis 
of many human organs and tissues, including the skeletal system, gastrointestinal tract, 
kidney, and eye (McMahon, Ingham and Tabin 2003).  In the resting state, the 12-pass 
transmembrane protein Patched (Ptch) inhibits activity of the divergent GPCR Smo. The 
Hh family protein ligands Sonic Hedgehog (SHH), Desert Hedgehog (DHH) and Indian 
Hedgehog (IHH) can all bind to and inactivate Ptch, leading to release of Smo repression.  
Active Smo signals via a cytosolic complex of proteins including Suppressor of Fused 
(SuFu) to the Gli1 family of transcription factors.  Active Gli1 signaling can cause cell 
proliferation and differentiation. 
Genetic activation of the Hh pathway at or upstream of Smo is linked to proliferation of 
several tumor types.  Patients with a germline mutation in Ptch have activated Hh signaling 
and develop Gorlin’s Syndrome, or basal cell nevoid syndrome (BCNS). Gorlin’s patients 
present with skeletal and dental anomalies due to developmental patterning defects, 
together with a high incidence of BCC, pediatric MB, ovarian cysts and ovarian carcinoma. 
Moreover, somatic mutations in Ptch and Smo have been detected in human MB and BCC. 
Activating mutations in Ptch and Smo are found in 20% of sporadic pediatric MB (Lee et 
al 2003, Thompson et al 2006), and in >70% of sporadic BCC (Gailani et al 1996, Xie et 
al 1998). Smo antagonists exert dose-dependent anti-tumor activity in vivo in several 
genetically defined MB models that are driven by mutations in Ptch (Romer et al 2004). 
Hedgehog overexpression, accompanied by increased expression of Hh target genes, is 
detected in a broad spectrum of human tumor biopsies and cell lines, including small cell 
lung   cancer,   gastric   cancer,   prostate   cancer   and   pancreatic   cancer. Growth   of 
Hh-overexpressing tumors in xenograft models has been shown to be inhibited by 
treatment with cyclopamine, a small molecule antagonist of Smo (Watkins et al 2003, 
Thayer et al 2003, Karhadkar et al 2004, Berman et al 2003, Rubin and De Sauvage 2006, 
Clement et al 2007). 
Since sonidegib may inhibit the growth of a wide range of cancers with aberrant 
upregulation of  Hh signaling,   the first-in-human   study   is   a   phase 1,   multicenter,   
open-label, dose-escalation study of oral sonidegib in patients with advanced solid tumors.  
Given the germline mutation in Ptch in Gorlin patients, a proof of concept in Gorlin 
patients presenting with BCCs has been conducted. 
 
1.3        PI3K Pathway and mechanism of action 
The phosphatidylinositol-3-kinase (PI3K) signaling regulates diverse cellular functions, 
including cell proliferation, survival, translational regulation of protein synthesis, glucose 
metabolism, cell migration, and angiogenesis.  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. 


 
 
9 
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. 
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.  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 (eg, HER2, EGFR, RAS, Src-family proteins) or 
b. Loss-of-function mutations or epigenetic alterations affecting negative regulators 
ofPI3K signaling (eg, loss of PTEN expression or function) 
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 buparlisib (BKM120) treatment potentially addresses an unmet medical need in 
such patients.  A schematic representation of these PI3K components is shown in Figure 2. 
In 2010, Buonamici, et al demonstrated that the PI3K signally pathway is increased in 
medulloblastomas resistant to SIs.  Concurrent administration of BKM appeared to delay 
the onset of resistant.  Recently, our group interrogated BCCs with demonstrated resistance 
to vismodegib, an SI.  In both these tumors, the levels of PI3K were increased compared to 
normal skin (Figure 3), in press.    Furthermore, this combination SI and PI3K inhibitor 
therapy is currently in phase 1 studies for safety in patients with solid tumors.  In our 
patient population, a significant number of patients are resistant to SI monotherapy or 
develop resistance after SI treatment.  Few good options exist for these patients.  Our data 
suggests that combination therapy with SI inhibitor and PI3K inhibitor is likely to delay 
resistance in these patients and is the subject of this proposal. 
Figure 2 
Schematic representation of the PI3K pathway 
Figure 3. PI3K signaling pathway is increased in both resistant tumors from a patient 
treated with a SI, vismodegib. 
1.4        Sonidegib Compound Information 
Sonidegib is a potent and highly specific oral selective, Smo antagonist from a 
novel structural classN-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-
methyl-4’-(trifluoromethoxy)-1,1’-[biphenyl]-3-carboxamide diphosphate and has 
been shown to potentially inhibit Hh and Smo-dependent proliferation in vivo.  This 
compound has been studied extensively in non-clinical models and is currently 
being evaluated in clinical trials. 
 
1.4.1       Preclinical Studies for Sonidegib 
1.4.1.1    Pharmacodynamics of Sonidegib 
 


 
 
10 
Sonidegib potently inhibits both human and mouse Smo at low nanomolar concentrations 
(11 and 12 nM, respectively) in competitive binding in vitro assays. In a single dose 
pharmacokinetic–pharmacodynamic (PK-PD) study, 20 mg/kg Sonidegib resulted in >90% 
inhibition Gli1 mRNA expression in tumor samples that was sustained for over 24 hrs.  
Daily multiple doses of Sonidegib (20 mg/kg QD) caused >90% tumor regression in 
genetically defined in vivo MB xenograft models characterized by heterozygous deletion of 
PTCH. 
1.4.1.1.1 Nonclinical pharmacokinetics and metabolism of Sonidegib 
Sonidegib   (free   base   or   diphosphate   salt)   and   [14C] sonidegib   were   used   in   
the pharmacokinetic (PK) studies.  Total radioactivity in rat blood, plasma and excreta 
samples was determined using a liquid scintillation counter (LSC).   Parent drug in plasma 
was determined by high-performance liquid chromatography with tandem mass 
spectrometry (LC-MS/MS).  The lower limit of quantification (LLOQ) for sonidegib was 1 
ng/mL in the 4 week rat or dog GLP toxicity study.  The LLOQ was 0.05ng/mL in the 13 
and 26 week rat and dog GLP studies using a 0.05 mL aliquot of plasma.  Metabolite 
concentrations and metabolite patterns in plasma and excreta were obtained by HPLC with 
radioactivity detection.  Metabolite structural elucidation was carried out using LC-MS or 
LC-MS/MS.  
Quantitative whole body autoradiography (QWBA) was also performed on rat tissues. 
In all species investigated, bioavailability of the compound was high (from 68.5% in 
mouse to ~100% monkey) with the Tmax occurring between 1.7 – 48 h.   In the rat, 
following a single oral dose, absorption of sonidegib-related radioactivity was high but was 
eliminated very  slowly  from  the  circulation  (T1/2  169  h)  compared  to  sonidegib 
(T1/2  10.6  h). LGE899, the major metabolite of sonidegib, exhibited a half-life of 155 
hours, suggesting that the remaining circulating radioactivity was essentially associated to 
this metabolite. 
After an IV dose in male rats, mini-pigs, and dogs using [14C] sonidegib, and after an IV 
dose in mice and monkeys using unlabeled sonidegib, the plasma clearance (CL) was low 
to moderate compared to their respective hepatic blood flows.  The estimated plasma 
volume of distribution at steady state (Vss) was moderate to high (greater than total body 
water) in all species, indicating wide tissue distribution, which was consistent with the rat 
ADME tissue distribution results (Section 4.2.3 of IB).  The terminal elimination T1/2 of 
sonidegib in plasma was moderate in mouse (~3-5h) and longer in the rat, dog, and 
monkey (Section 4.2.5 of Investigator Brochure). 
Clearance of Sonidegib is primarily hepatic by CYP3A4. Sonidegib was extensively 
metabolized, with the major metabolic pathway being via mono- or dioxygenation, 
demethylation, and oxidation leading to carboxylic acid formation, dealkylation, and 
dehydrogenation monohydroxylation.   The elimination of metabolites was mainly through 
the bile. 
Studies with human liver microsomes demonstrated that Sonidegib is a competitive 
inhibitor of CYP2B6 (IC50 ~0.5 µM; Ki 0.045 µM), and CYP2C9 (IC50~5 µM; Ki 1.7 µM), 
but showed very  little  or  no  inhibition  of  CYP1A2,  2A6,  2C8,  2C19,  2D6,  2E1 or  
3A4/5  at concentrations  of  up  to  100  µM. No apparent time-dependent inhibition of the 
major CYP450 enzymes was observed.  Sonidegib is neither a substrate nor an inhibitor of 
P-glycoprotein (Pgp) or multi-resistance protein 2 (MRP2); but it has demonstrated 
inhibitory effects on breast cancer resistance protein (BCRP), with an estimated IC50 value 


 
 
11 
of 1.5 mM. The potential of Sonidegib and its metabolites to undergo covalent binding to 
cellular macromolecules was found to be low. 
The toxicokinetics of sonidegib have been investigated in male and female rats (4-, 13-, 
and26-week studies).  In all studies, the exposure increased with dose, there was also 
evidence of sonidegib accumulation following repeated dosing (1.6- to 5.6–fold).  There 
was a general under-proportionality of exposure with increasing doses in the 4 week rat 
study (doses of 20, 100, and 600 mg/kg/day) and over-proportional increases in exposure 
with increasing doses in the 13 and 26 week studies (doses up to 20 mg/kg/day).  In the 4 
week rat study, there was evidence of a sex difference, with females having higher 
exposure (particularly at the higher doses and after multiple doses), but there was no 
evidence of a sex difference in either the 13 or 26 week studies. 
Juvenile rats (14 days post-partum) were dosed with sonidegib at 1, 3, 10, and 30 mg/kg/ 
day for 5 weeks.  On day one, the AUC0-24 increase was roughly dose-proportional from 
3 to 30 mg/kg/day and slightly greater than dose-proportional from 1 to 3 mg/kg/day. In 
week 5, a slight tendency for a greater than dose-proportional increase in AUC0-24 was 
observed. The female showed slightly higher exposure compared with the male rats. No 
obvious accumulation was seen after 5 weeks of dosing except that a 40-80% increase of 
exposure (AUC) was observed at 30 mg/kg dose for both gender and at 10 mg/kg for 
female.  The dose normalized AUC at 10 and 30 mg/kg after single or multiple dosing are 
similar to those achieved in adult rats at 20 mg/kg dose.  The toxicokinetics in the dog (4, 
13, and 26 week studies) were similar to the rat.  In general, increasing doses showed 
under-proportional increases   in   exposure   after   single   doses   in   the   4   week 
toxicology   study,   and over-proportional exposure with multiple dosing in the 13 and 26 
week studies.  There was no difference in exposure between male and female dogs, and 
there was evidence of accumulation (2- to 46-fold) following repeated dosing. 
1.4.1.1.2 Safety pharmacology and toxicology of Sonidegib 
The majority of adverse effects observed in toxicity studies in growing rats and dogs can 
be attributed to the pharmacologic action of sonidegib, and the effects in both species were 
similar.  The most striking effects of sonidegib, which are consistent with literature reports 
on other Hh pathway inhibitors, were on bone and consisted of thinning or closure of 
growth plates in the sternum and femur and decreasing proliferating chondrocytes in the 
chostochondral junction of ribs.  In addition, decreases in bone alkaline phosphatase were 
observed in dogs (Investigator Brochure].  The observations were more pronounced in rats, 
which is a species where the growth plate does not close.  Similar observations have been 
reported for other Smo inhibitors in animal studies (eg, GliLuc transgenic mice, IHH 
transgenic mice) including thinning and early closure of the growth plate, shortened bones, 
inhibition of tooth growth and abnormal bone structures, particularly the femur and tibia 
(Maeda 2007, Kimura 2008).  This is likely due to the role of the Hh pathway in bone 
development, particularly in the early stages of bone formation and growth (Kimura 2008). 
These effects are not likely to occur in the adult cancer patient population intended for the 
clinical studies due to the maturity of their skeletal system.  However, it anticipated that 
Smo inhibition may likely affect the development of bones and teeth in growing children. 
Hence, monitoring for these effects will be required during therapy with Smo inhibitors in 
children. Preclinical cardiovascular safety pharmacology data do not indicate a clinical risk 
for QTc prolongation.  There is also no indication of effects on the central nervous and 
respiratory systems from the preclinical data.  Please refer to the Investigator’s Brochure 
for more details on the non-clinical toxicity and safety of sonidegib. 


 
 
12 
 
1.4.2       Muscular system 
In the phase 1 trial (LDE225X2101), dose-limiting skeletal muscle toxicities characterized 
by CTCAE Grade 3 or Grade 4 creatinine kinase (CK) elevation associated with muscle 
pain and elevated plasma myoglobin have been observed in a dose and exposure dependent 
manner.  No evidence of cardiac muscle toxicity has been observed.  The majority of cases 
of CTC Grade 3/4 elevated CK, occurred 3 to 6 weeks after continuous daily treatment 
with sonidegib.  Following the discontinuation of sonidegib, the majority of DLTs resolved 
over a period of approximately 4-8 weeks.  Re-challenge with sonidegib at a lower dose 
appeared not to cause subsequent CK elevation.   The DLTs were described in some cases 
as rhabdomyolysis, however, no impairment in renal function was been observed in any of 
the affected patients. 
In the CLDE225A2112 drug-drug interaction study, one patient developed rhabdomyolysis 
with renal failure, which necessitated treatment with hemodialysis, as described in Section 
5.2.1.8. Muscular activities such as strenuous exercise that can result in significant 
increases in plasma CK levels should be avoided while on sonidegib treatment. Patients 
who are taking statins appear to be at increased risk of developing Grade  
3/4 CK elevation and therefore statins should be avoided while taking sonidegib.  If it is 
essential that the patient stays on a statin to control hyperlipidemia, only pravastatin may 
be used with extra caution. 
Patients should be assessed for the development of muscle symptoms such as myalgia, 
myopathy and/or muscle spasms.  Serum creatinine and plasma levels of CK, CK-MB, and 
myoglobin should be closely monitored during the first 8 weeks and throughout treatment 
with sonidegib.  If clinically significant increases in CK levels are detected, serum 
creatinine must be checked and the patients must be monitored for signs and symptoms of 
rhabdomyolysis.   Management using supportive therapy including adequate hydration 
may be   considered   according   to   standard   medical   practice, institutional   and   
applicable protocol-specific guidelines. 
1.4.3       Skeletal system 
In the GLP toxicology studies of sonidegib conducted in growing rats and dogs there was 
thinning or closure of growth plates in the sternum and femur and decreased proliferation 
of chondrocytes in the costochondral junction of ribs.  These effects are more likely to 
occur in children where the growth plate is open.  However, the effect of sonidegib on 
mature bones is not known, since the toxicology studies were conducted in growing 
animals.  It is possible that treatment with sonidegib could have effects on bone 
metabolism in addition to its effect on the growth plate.  In the clinical setting, apparent 
growth plate thinning was observed in 2 pediatric patients (aged 4 and 11 years) after 
approximate 9 month treatment with single agent sonidegib for medulloblastoma.  
Therefore, pediatric patients should be observed using imaging techniques (such as knee 
and wrist x-rays), assessment of changes in serum bone markers including bone-specific 
alkaline phosphatase, osteocalcin and N-terminal propeptide (type 1 collagen, as well as 
any other protocol-specific guidance in order to assess the potential effects on bone. 
 
 
 


 
 
13 
1.4.4       Reproductive system 
The effects of sonidegib on the male and female reproductive tract of young rats and dogs 
included delayed or arrested maturation of the testes, prostate, ovary and uterus in young 
dogs and uterine atrophy in rats.  Protocol-specific guidelines regarding the participation of 
women of child-bearing potential, the use of contraceptives, and the prohibition of 
treatment of pregnant and lactating women are provided in the study protocol.  Patients 
should be informed that treatment with sonidegib carries the potential risk of causing 
infertility. However, a single oral dose of sonidegib employed to study the 
pharmacokinetics in healthy subjects is not expected to have effects on male reproductive 
tissues or to impair fertility of male subjects. 
Sonidegib has been found to be teratogenic.  The investigator is therefore advised to make 
patients aware of this risk.  To minimize the risk of teratogenic effects, sonidegib should 
not be given to pregnant or lactating women.  In addition patients intended to be treated 
with sonidegib should be made aware of this risk and instructed to apply appropriate 
barrier contraceptive methods during treatment with sonidegib. 
1.4.5       Gastro-intestinal system 
GI mucosal toxicity was observed in preclinical toxicology studies.   In preclinical studies, 
observations included extreme distention of the stomach and duodenum in rats that died 
early or were euthanized moribund at the highest doses (600 mg/kg). These findings were 
associated with visible hemorrhage in the stomach wall, loss of mucosa with inflammation, 
and ulcerations of the non-glandular mucosa.   Emesis and diarrhea were also observed at 
high doses (1000 mg/kg) in preclinical studies in dogs.  These effects are considered 
unlikely to be related to the pharmacologic mechanism of action of sonidegib and are 
instead hypothesized to reflect the very high oral doses of sonidegib given to animals, 
coupled with the low solubility and incomplete absorption from the GI tract, resulting in 
direct irritation of the mucosa. 
In on-going clinical studies, nausea, vomiting, and diarrhea have been reported as AEs.  
Patients should be monitored for symptoms and signs of such toxicity and care should be 
taken to ensure that patients in whom such symptoms arise do not develop dehydration. 
Management using supportive therapy with anti-emetics and/or anti-diarrheal medications 
may be considered according to standard medical practice, institutional and applicable 
protocol-specific guidelines. 
 
1.4.6       Renal system 
Rats treated with high doses (600 mg/kg) of sonidegib developed acute tubular necrosis 
and prominent mineralization of the tubular epithelium. 
The renal function of patients receiving sonidegib should be closely monitored, including 
serum creatinine, urine output, urine color and specific gravity.  Attention should be given 
to the prevention and treatment of dehydration, particularly if the patient reports muscle 
symptoms or there is laboratory evidence of an increased CK. 
 
1.4.7       Clinical experience with Sonidegib 
 
 


 
 
14 
1.4.7.1 Pharmacokinetics and pharmacodynamics of Sonidegib  
 
The PK summary of sonidegib in adult patients with advanced solid tumors assessed in 
study (LDE225X2101] can be found in the Investigational Brochure in Table 5-3.  The 
available preliminary PK data demonstrate that the median peak plasma concentrations of 
sonidegib occurs at 4 hours (range: 2-24 hours) after dosing.  Plasma exposure to sonidegib 
(Cmax and AUC) after single dose administration increases dose proportionally from 100-
800 mg and appears to plateau at higher dose levels (1500 mg to 3000 mg).  On cycle 1 
Day 15 Cmax and AUC increase linearly with doses up to 400 mg/ day, and in a less than 
dose-proportional manner with higher doses (800 to 3000mg/ day).    Sonidegib  exposure  
at  400 mg  BID demonstrates ~30% higher mean AUC on day 15 compared with exposure 
at 800 mg QD, and AUC at 750mg BID is approximately 18% greater than the AUC 
achieved at 1500 mg QD.  The median accumulation index is 3-fold (range: 0.5-12), and 6-
fold (range: 2.22-22.1.) for Cmax and AUC, respectively, on cycle 1 Day 15 compared with 
the single PK run-in dose. Due to the long apparent terminal half-life of sonidegib, an 
accurate terminal half-life cannot be calculated using a non-compartmental approach.   The 
estimated effective half-life, calculated on the basis of the accumulation index across dose 
groups, is greater than 4 days (range: 1-14 days).   Successive measurements of plasma 
trough concentrations (Cmin) over time suggest that steady-state appears to be achieved 
after 28 days of daily dosing. Trough levels on day 15 (pre-dose) correlate well with AUC 
and Cmax on day 15 during daily administration of sonidegib.  The inter-patient coefficient 
of variation in sonidegib AUC is 40 to 58% across the dose range of 100 mg to 3000 
mg/day.  Exploratory analyses suggest that the odds of observing a CK DLT increase with 
AUC on day 15.   In addition, the probability of a CK DLT is expected to be low (< 0.16) 
for exposure levels (AUC day 15) below 41 µM*hr (equivalent to an average steady state 
concentration of approximately 1. 7 µM). 
Analyses of skin punch biopsies taken at baseline and at the end of the first treatment cycle 
(day 28) have shown evidence of potent target modulation, as measured by Gli1 mRNA, in 
a dose- and exposure-dependent manner.  The available data shows that sonidegib caused 
up to 95%  mean  reduction  in  Gli1  expression  in  skin  compared  with  baseline values. 
The maximum observed inhibition of the target in skin (as measured by Gli1 expression) 
was observed at 1500 mg QD.  Based on the limited data on PD effect in tumor biopsies 
(n=4 paired samples), where up to 99% reduction in Gli1 expression was observed, skin is 
a good surrogate tissue for assessing target inhibition.  On the whole, the changes in Gli1 
expression in skin appeared to be highly variable, particularly within the 800 mg QD 
cohort, where a relatively large number of paired samples were obtained compared with 
the other doses. 
Sonidegib,  at  800  mg  QD,  demonstrated  a  mean  reduction  in  Gli1  mRNA  in  skin  
of approximately  74%  (n=13,  range:  8.3%  -  95.8%)  compared  with  baseline  values  
after 28 days of therapy. At 200 mg QD, approximately 68% (n=4, range: 25.9%  - 89.3%) 
reduction in Gli1 expression in skin was observed, with 87% reduction in the MB patient 
who achieved objective partial response. 
The FDA has not yet approved the drug for treatment of this indication, and IND 
application is currently in process. 
 
 
 


 
 
15 
1.4.7.2 Clinical experience with Sonidegib 
 
Sonidegib is currently undergoing phase 1, 2, and 3 evaluation in clinical trials, to assess 
the safety,   tolerability,   PK,   PD   and   potential   efficacy   of   continuous   once   daily 
oral administration in patients with malignant solid tumors as part of monotherapy and 
combination studies.  Data provided here are obtained from an active clinical trial 
database; therefore, they are preliminary and subject to change upon final QC review when 
the study is completed. 
1.4.7.2.1 Human safety and tolerability data of Sonidegib 
As of November 29, 2013, a total of 701 cancer patients have been treated with sonidegib, 
including  60  pediatric  patients,  in  11  Novartis  sponsored  clinical  studies. 
There were 6 studies   conducted   with   316   healthy   or   hepatically   impaired   
volunteers receiving single-dose sonidegib. In addition, there are Investigator Initiated 
Trials (IIT) being conducted under their own respective INDs.  Data from these IITs are 
not included in this IB, except for SUSAR reports attributed to patients in IITs. 
The dose limiting toxicities observed in the first-in-human adult study in patients with 
advanced solid tumors (CLDE225X2101) were creatinine phosphokinase elevation, AST 
increase, and myoglobin increase.  The most common treatment emergent toxicities 
reported in this study were nausea, muscle spasms, increased blood creatinine 
phosphokinase, vomiting, decreased appetite, dysgeusia, fatigue, asthenia and myalgia. 
Common toxicities observed in on-going studies are summarized in Section 5.2 of the 
Investigator’s Brochure. In general, the safety profile in pediatric patients appeared to be 
similar to adult patients. Clinical response (CR and PR) was observed in basal cell 
carcinoma, and medulloblastoma in both adult and pediatric patients. In general, the safety 
profile in pediatric patients appeared to be similar to adult patients. Clinical response (CR 
and PR) was observed in basal cell carcinoma, and medulloblastoma in both adult and 
pediatric patients. 
The pharmacokinetic data in patients with advanced solid tumors showed that the median 
Tmax occurs at 2-13 hours after single or repeated oral dosing of 100 to 3000 mg/day. 
Mean plasma exposure to sonidegib appeared to increase approximately dose 
proportionally up to 400 mg, but less than proportionally above 400 mg.   The median 
effective elimination half-life of sonidegib calculated based on drug accumulation in 
patients was 11 days. The median terminal half-life estimated after a single dose in healthy 
subjects was 10 days. 
DLTs occurred during Cycle 1 at the 800 mg and 1000 mg QD and 750 mg BID dose 
levels. The most common DLT was Grade 4 increase in CK, which typically occurred 
between Days 24-30 of the study. 
 
In addition to the increases listed in in Table 1 below, 14 additional patients had Grade 3/4 
increases in CK, consisting of 1 patient at 800 mg QD, 1 patient at 1000 mg QD.  3 
patients 
 
 


 
 
16 
 Table 1. 
Incidence of dose limiting toxicities in Study CLDE225X2101 
 
Dose of 
Sonidegib 
No. 
patients 
treated 
Elevated plasma CK 
No. patients with 
CTCAE Grade 3 
No. patients with 
CTCAE Grade 4 
Total (CTCAE 
Grade 3 or 4) 
100 mg QD 
5 
0 
0 
0 
200 mg QD 
6 
0 
0 
0 
400 mg QD 
4 
0 
0 
0 
800 mg QD 
21 
0 
1 
1 
1000 mg QD 
7 
0 
1 
1 
1500 mg QD 
8 
0 
0 
0 
3000 mg QD 
4 
0 
0 
0 
250 mg BID 
12 
0 
0 
0 
400 mg BID 
6 
0 
0 
0 
750 mg BID 
5 
0 
3 
3 
Total 
78 
0 
5 
5 
 
at 1500 mg QD, 3 patients at 3000 mg QD, 2 patients at 250 mg BID, 2 patients at 400 
mg BID, and 2 patients at 750 mg BID.  These DLTs occurred after cycle 1, however, 
they were considered as part of the clinical review that occurred as a part of each dose 
escalation decision.    Consistent  with  the  findings  during  Cycle  1,  Grade 3  and  4 
CK  elevations occurring in later cycles were not observed at dose levels below 800 mg 
on the QD schedule. These data supported the choice of 800 mg QD and 250 mg BID as 
the MTDs. 
Overall 102 of 103 patients (99.0%) experienced an AE during the study, and the majority 
of patients (78 patients, 75.7%) had AEs, which were suspected to be related to study 
drug. Approximately 60% of the patients experienced Grade 3 or Grade 4 AEs, and 
approximately one-half of patients experienced an SAE.  Fourteen patients died during 
the study or within28 days after the last dose of sonidegib.  Twelve of the patient deaths 
were related to disease progression.  The other 2 deaths on study were cardiac arrest and 
sudden death, both were considered to be unrelated to sonidegib. Other than DLTs, there 
were no clinically significant changes in laboratory values, vital signs, or ECG parameters 
during the study. 
As seen in Table 2 below, the most common preferred terms were nausea (47 patients, 
45.6%), muscle spasms, increased blood creatinine phosphokinase (35 patients each, 
34.0%), vomiting, (33 patients, 32.0%), decreased appetite, dysgeusia (31 patients each,  


 
 
17 
30.1%), fatigue (29 patients, 28.2%), asthenia and myalgia (24 patients each, 23.3%). 
Other AEs were reported in less than 20% of patients. 
Table 2.  Adverse events suspected to be related with sonidegib, occurring in >/=5% of 
                patients in Study CLDE225X2101 October 2012 
 
800 mg QD* (n=26) 
All doses** (n=103) 
Any grades n(%) 
Any grades n(%) 
Nausea 
10 (38.5) 
47 (45.6) 
Dysgeusia 
5 (19.2) 
31 (30.1) 
Weight decrease 
5 (19.2) 
18 (17.5) 
Decreased appetite 
5 (19.2) 
31 (30.1) 
Vomiting 
10 (38.5) 
33 (32.0) 
Diarrhea 
3 (11.5) 
17 (16.5) 
Constipation 
3 (11.5) 
18 (17.5) 
Muscle spasms 
9 (34.6) 
35 (34.0) 
Myalgia 
5 (19.2) 
24 (23.3) 
Blood CK increased 
8 (30.8) 
35 (34.0) 
AST increased 
3 (11.5) 
14 (13.6) 
ALT increased 
2 (7.7) 
10 (9.7) 
Fatigue 
6 (23.1) 
29 (28.2) 
Asthenia 
7 (26.9) 
24 (23.3) 
Alopecia 
4 (15.4) 
13 (12.6) 
Lethargy 
3 (11.5) 
7 (6.8) 
Anemia 
3 (11.5) 
18 (17.5) 
Pyrexia 
3(11.5) 
15 (14.6) 
Abdominal Pain 
2 (7.7) 
13 (12.6) 
Insomnia 
2 (7.7) 
13 (12.6) 
Dyspnoea 
5 (19.2) 
13 (12.6) 
Dizziness 
4 (15.4) 
12 (11.7) 
Abdominal pain upper 
4 (15.4) 
11 (10.7) 
Back pain 
2 (7.7) 
11 (10.7) 
Cough 
1 (3.8) 
11 (10.7) 
Oedema peripheral 
1 (3.8) 
10 (9.7) 
Headache 
3 (11.5) 
10 (9.7) 
Hypoalbuminaemia 
2 (7.7) 
9 (8.7) 
Blood bilirubin 
increased 
1 (3.8) 
8 (7.8) 
Pain in extremity 
1 (3.8) 
8 (7.8) 
Dyspnoea exertional 
3 (11.5) 
8 (7.8) 
Urinary tract infection 
1 (3.8) 
7 (6.8) 
Musculoskeletal pain 
0 (0.0) 
7 (6.8) 
Hyperbilirubinaemia 
2 (7.7) 
6 (5.8) 
Arthralgia 
0 (0.0) 
6 (5.8) 
Muscular weakness 
2 (7.7) 
6 (5.8) 
Somnolence 
1 (3.8) 
6 (5.8) 
Pruritus 
2 (7.7) 
6 (5.8) 
* Recommended phase 2 dose in adults 


 
 
18 
** All doses, including BID and QD schedule 
1.4.7.2.2 Clinical efficacy data of Sonidegib 
Responses (confirmed, RECIST v1.0) were observed in 8 patients, 1 patient (1.0%) with CR 
and 7 patients (6.8%) with PR (see Table 3 below).  SD was the best response in 24 patients 
 
Table 3.  Summary of best overall response by treatment – CLDE225X2101 
100 
mg 
QD 
200 
mg 
QD 
400 
mg 
QD 
800 
mg 
QD 
1000 
mg 
QD 
1500 
mg 
QD 
3000 
mg 
QD 
250 
mg 
BID 
400 
mg 
BID 
750 
mg 
BID 
All 
N=6 
n (%) 
N=6 
n (%) 
N=5 
n (%) 
N=26 
n (%) 
N=11 
n (%) 
N=9 
n (%) 
N=10 
n (%) 
N=14 
n (%) 
N=8 
n (%) 
N=8 
n (%) 
N=103 
n (%) 
CR 
0 
(0) 
0 
(0) 
0 
(0) 
0 
(0) 
0 
(0) 
0 
(0) 
0 
(0) 
0 
(0) 
1  
(12.5) 
0 
(0) 
1  
(1.0) 
PR 
1 
(16.7) 
1 
(16.7) 
0 
(0) 
3 
(11.5) 
1 
(9.1) 
0 
(0) 
0 
(0) 
1 
(7.1) 
0 
(0) 
0 
(0) 
7 
(6.8) 
SD 
1 
(16.7) 
2 
(33.3) 
2 
(40.0) 
6 
(23.1) 
1 
(9.1) 
3 
(33.3) 
2 
(20.0) 
4 
(28.6) 
2 
(25.0) 
1  
(12.5) 
24 
(23.3) 
PD 
3 
(50.0) 
3 
(50.0) 
3 
(60.0) 
11 
(42.3) 
6 
(54.5) 
3 
(33.3) 
3 
(30.0) 
6 
(42.9) 
4 
(50.0) 
2 
(25.0) 
44 
(42.7) 
Unknown 
1 
(16.7) 
0 
(0) 
0 
(0) 
6 
(23.1) 
3 
(27.3) 
3 
(33.3) 
5 
(50.0) 
3 
(21.4) 
1  
(12.5) 
5 
(62.5) 
27 
(26.2) 
Best overall response is based on investigator’s assessment of disease status using RECIST. 
 
 
(23.3%), and PD was the best response in 44 patients (42.7%).   Consistent with 
the mechanism of action of sonidegib, all responding patients had diagnoses of 
basal cell carcinoma (BCC) or medulloblastoma, cancers known to be driven by 
activation of the Hedgehog pathway.  Of 16 patients with BCC, 1 patient achieved 
a CR and 5 patients achieved PR, for a response rate of 38% in this subset. Of the 
9 patients with medulloblastoma, 2 patients achieved a PR, for a response rate of 
22%.  In addition one patient with medulloblastoma, whose only site of disease 
was bone metastases, had a metabolic PR by [18F]-FDG PET.  The disease in this 
patient could not be evaluated by CT. 
1.5        Buparlisib (BKM120) 
NVP-BKM120 (buparlisib, BKM120) is a potent and highly specific oral panclass 
I PI3K inhibitor that is a 2, 6-dimorpholino pyrimidine derivatives. This 


 
 
19 
compound has been studied extensively in non-clinical models and is currently 
being evaluated in clinical trials. 
1.5.1       Preclinical studies of Buparlisib 
Buparlisib 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 
using 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 4: 
Table 4.  Inhibitory activities (IC50) of buparlisib against other PI3K or related 
kinases 
Buparlisib significantly inhibits p110α and the most common p110α mutations 
(H1047R, E454K, E542K), p110β, p110δ and p110γ but not the related proteins 
Vps34, mTOR or PI4Kβ.  Hence buparlisib is classified as a pure pan-class I  
PI3K inhibitor.  Enzymatic characterization of the inhibitory properties of the 
compound revealed that buparlisib is a mixed inhibitor of PI3Kα with a strong 
competitive component (largest on Vmax).  The cocrystal X-ray structure of 
buparlisib with PI3Kγ confirmed that buparlisib 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 buparlisib on the mTORC1 complex, the compound was tested in 
TSC1 null cells.  These cells  express  a  constitutively  activated  mTORC1  
complex  that  uncouples  the  mTOR pathway from the PI3K upstream input 
(Kwiatkowski 2003).  When exposed to TSC1 null MEFS, buparlisib reduced the 
S235/236P-RPS6 levels with an IC50 of 1785 nM, in agreement with the data 
obtained in the mTOR biochemical assay.  In contrast, and as expected the allosteric 
mTORC1 inhibitor RAD001 displayed sub-nanomolar inhibitory activity in this 
assay. 
In contrast to molecules with distinct mechanism of action (BCR-Abl inhibitor STI571, 
mTORC1 allosteric inhibitor RAD001), buparlisib is able to decrease the phosphorylation 
status of various either direct (GSK3β, FKHRL1/FOXO3a) or indirect downstream Akt 
effectors (p70S6K, through mTOR) in the PTEN null U87MG cell line, as efficiently as 
prototypical PI3K inhibitors such as LY294002 and Wortmannin. 
Forkhead transcription factors (such as FKHRL1) are re-located from the nucleus to the 
cytosol upon phosphorylation by Akt. Treatment of U2OS cells stably expressing GFP - 
FKHRL1 chimera to GFP with buparlisib produced a strong nuclear localization of the 
fluorescence signal, in agreement with the reduction of the phosphorylated FKHRL1 
levels.    Signaling pathways from membrane receptors to nuclear transcription factors 
involve many different players such as kinases or molecular adaptors.  To test whether 
buparlisib does influence other signaling molecules outside of the PI3K pathway, induction 
of various pathways (mitogenic with EGF and PDGF, stress pathways with anisomycine 
and interleukine pathways with IL-4) were interrogated in the presence of the compound.  
In all cases, buparlisib showed specific PI3K pathway attenuation, as demonstrated by 
specific attenuation of S473P-Akt levels, without affecting the non PI3K driven read –outs 
such as activated receptors (EGFR, PDGFR), MAPK kinases (ERK, JNK and p38) or Jak 
cytosolic tyrosine kinases responsible for Stat transcription factor phosphorylation. 


 
 
20 
1.5.1.1 Preclinical Safety of Buparlisib 
 
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.  In the isolated rabbit heart, effects pointing 
towards a shortened repolarization were seen only at 10 µM.  Buparlisib inhibited hERG 
channel activity significantly at concentrations ≥ 100 µM (IC50: 190 µM). 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, observed in two dog 
telemetry studies. 
Repeated-dose studies (up to 13 weeks of duration) were performed in rats and dogs. 
In rats, clinical pathology and histopathology findings showed a decrease in lymphocyte 
counts in the peripheral blood, decreases in germinal center development in different 
lymph nodes, and lymphocytolysis in the thymus.  In dogs, similar findings occurred.  In 
both species, erythropoiesis was affected, as evidenced by reduced erythrocyte counts, 
accompanied by bone marrow depression observed in rats. 
The pancreas was seen to be affected by treatment with buparlisib, particularly in dogs, 
where acinar cell toxicity was seen in the exocrine part of this organ.  In addition, in one of 
the  four  recovery  animals  minimal  acinar  cell  atrophy was  observed  after  four weeks 
treatment-free period.  In rats, in the 4-week study, no pancreas toxicity was observed 
(however, in the 2-week dose range finding study, at higher doses, there were 
histopathological findings of the endocrine as well as the exocrine pancreas). 
Male sexual organs and associated tissues were found to be targets of toxicity in both rats 
and dogs.  Changes included minimal to slight germ cell depletion, formation of spermatic 
giant cells and abnormal spermatids, and cellular debris in epididymal tubules.  Testicular 
toxicity did not fully reverse after the 4-week treatment-free period in rats (highest dose) 
although a clear trend towards recovery was seen.   In individual female rats, minimal to 
slight cyst formation occurred in the Graafian follicles; in addition, an increased incidence 
of diestrus stage of the estrous cycle was seen.   In dogs, there was no effect on female 
sexual organs. 
Insulin/glucose homeostasis was impacted in various species (mice, rats, dogs), as 
expected from the mode of action of buparlisib.  However, in both rats and dogs, at the 
doses used in the 4-week studies, these effects were minimal. 
After up to 2 weeks of treatment with up to 2.5 mg/kg/day, decreased levels of glutamate, 
dopamine, serotonin and epinephrine as well as elevated levels of glutamine, GABA 
(gamma-amino butyric acid) and HIAA (5-hydroxyindoleacetic acid, a serotonin 
breakdown product) were seen in rats.  The increased levels of HIAA and decreased levels 
of serotonin indicates an increased serotonin breakdown, pointing to a potential 
perturbation of the serotonin release and/or re-uptake.  Generally, the decreased levels of 
glutamate, dopamine, serotonin and epinephrine points to an exhaustion of these 
neurotransmitters.   No such effects were seen in cerebrospinal fluid (CSF) or plasma of 
those animals. 
Both in vitro and in vivo, buparlisib elicited a genotoxic potential.  While no evidence for a 
direct DNA interaction was found in an Ames test and two chromosome aberration tests in 
vitro, a potential for genotoxicity was concluded based on the observation of an aneugenic 
potential, seen in this latter experiment.  In line with this result, buparlisib treatment 
resulted in an elevated frequency of micronucleated polychromatic erythrocytes in the 
bone marrow of rats.  Data indicate the absence of a relevant photoxic potential of 
buparlisib. 


 
 
21 
In conclusion, the majority of the observed effects were related to the pharmacological 
activity  of  buparlisib  as  an  inhibitor  of  PI3K,  such  as  a  potential  influence on 
glucose/insulin homeostasis and the risk of increased blood pressure.  Main target organs 
of toxic effects were bone marrow and lymphoid tissue, pancreas, and male as well as, to a 
lesser extent, female reproductive organs.  Further, neurotransmitter fluctuations were seen 
in the brain of rats, not visible in plasma or cerebrospinal fluid. 
Please refer to the Investigator’s Brochure for additional information on the preclinical 
testing of buparlisib. 
 
1.5.1.2  Pharmacodynamics of Buparlisib 
 
Buparlisib 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.  Buparlisib does not inhibit the related kinases mTOR 
or Vps34, nor does it inhibit other receptors and ion channels profiled (IC50 >10 µM). 
Buparlisib demonstrates significant tumor growth inhibition in relevant tumor xenografts 
in mice and rats when administered orally, including models of renal cell cancer  
(RENCA, 786-0, Caki-1), glioblastoma multiforme (U87MG), prostate cancer (PC3M), 
lung cancer (A549, NCI-H1975), ovarian cancer (A2780), colorectal cancer (HCT116, 
HCT-15) and melanoma (A2058, A375).   In vivo PK/PD analyses of tumor tissues shows 
a good correlation between exposure, PI3K pathway blockade (S473P-Akt levels), and 
anti-tumor activity. 
 
1.5.1.2.1 Nonclinical pharmacokinetics and metabolism of Buparlisib 
Buparlisib showed favorable pharmacokinetic properties in all animal species tested. The 
absorption of [14C]-buparlisib-related radioactivity was >84% in the rat.  Oral 
bioavailability was 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. Buparlisib was 
found to cross the blood brain barrier in rats with a tissue-to-plasma ratio of approximately 
2 (Novartis internal data).   Buparlisib is moderately bound to plasma protein in all species 
examined (about 80%). 
In vitro metabolism studies using human liver microsomes showed that oxidative phase 1 
metabolism of buparlisib was predominantly mediated by CYP3A4 (estimated fm > 0.9). 
Formation   of   a   buparlisib   N-glucuronide   conjugate   (phase 2   metabolism) via   the 
UDP-glucuronosyltransferase-1 family, polypeptide A4 (UGT1A4) was also observed in 
human   liver   microsomes   supplemented   with   uridine   5'-diphosphoglucuronic   acid 
(UDPGA).  Buparlisib and metabolites have a low potential for covalent binding to 
protein. Buparlisib was determined to be a weak reversible inhibitor of CYP3A4 (IC50 = 8 
µM, Ki = 13.4 µM unbound) at concentrations reached in the clinic.  Buparlisib very 
weakly inhibited the CYP2C family (2C8, 2C9 and 2C19) with IC50 values ranging from 
35-65 µM (34-59 µM unbound).  Buparlisib did not show time-dependent inhibition of 
CYP450 enzymes. In GLP toxicology studies, buparlisib 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 


 
 
22 
excretion was minor.  There was no noticeable drug accumulation in dog or male rats after 
13 weeks of daily dosing.  There was a slight accumulation in female rat (< 2 fold). 
Further information concerning the pharmacokinetic and pharmacodynamics properties of 
buparlisib may be found in the Investigator Brochure. 
 
1.5.1.2.2 Safety pharmacology and toxicology of Buparlisib 
Safety  pharmacology  studies  in  rats  revealed  no  effects  on  neuronal  (behavior) or 
respiratory functions.  Cardiac safety studies, conducted in vitro and in vivo did not 
indicate a prominent electrophysiological risk.  No relevant electrophysiological effect was 
seen in dogs.  The only effect considered relevant was a trend towards an increase in 
systolic and diastolic blood pressure, which was observed in two dog telemetry studies. In 
rats and dogs, clinical pathology and histopathology findings showed quantitative 
reductions of lymphoid and erythroid counts and lymphoid tissue hypoplasia. 
The pancreas was seen to be affected by treatment with buparlisib, particularly in dogs, 
where acinar cell toxicity was seen in the exocrine part of this organ.  At higher doses in 
the 2-week dose-range-finding study in rats, there were histopathological findings in both 
the endocrine as well as the exocrine pancreas. 
Male sexual organs and associated tissues were found to be targets of toxicity in both rats 
and dogs.  Changes included minimal to slight germ cell depletion, formation of spermatic 
giant cells and abnormal spermatids, and cellular debris in epididymal tubules.  Testicular 
toxicity did not fully reverse after the 4-week treatment-free period in rats (highest dose), 
although a clear trend towards recovery was seen.   In individual female rats, minimal to 
slight cyst formation occurred in the Graafian follicles.   In dogs, there was no effect on 
female sexual organs. 
Glucose homeostasis was affected in various species (mice, rats, dogs), as expected from 
the mode of action of buparlisib.  However, these effects were minimal in both rats and 
dogs at the doses used in the 4-week studies. 
Other safety considerations include: 
After up to 2 weeks of treatment with up to 2.5 mg/kg/day of buparlisib, 
alterations in the levels of multiple brain neurotransmitters were seen in rats. 
No evidence for a direct DNA interaction was found in an Ames test and two 
chromosome aberration tests in vitro with buparlisib.   However, evidence of a 
genotoxic potential with buparlisib has been seen in vitro and in vivo and is likely 
due to an aneugenic effect. 
No phototoxic potential or any effect on wound healing has been identified with 
buparlisib in pre-clinical studies. 
In conclusion, the majority of the observed effects were related to the pharmacological 
activity of buparlisib as an inhibitor of PI3K, such as a potential influence on glucose 
homeostasis and the risk of increased blood pressure. 
Please refer to the Investigator’s Brochure for additional information on the preclinical 
testing of buparlisib. 
1.5.1.2.3 Pharmacodynamic biomarkers of Buparlisib 
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 


 
 
23 
as further suppression of downstream signaling (eg, phosphorylation of S6) was obtained 
soon after buparlisib administration.  PI3K is known to serve a pivotal role in the 
regulation of glucose homeostasis, and preclinical studies in which oral glucose and 
intraperitoneal insulin tolerance tests were performed suggesting post-treatment induction 
of insulin insensitivity/resistance.  Therefore, throughout the trial the circulating levels of 
several markers for glucose metabolism (eg, glucose, insulin, C-peptide) will be assessed 
as an additional measure of PI3K signaling modulation. 
 
1.5.2 
Clinical experience with Buparlisib 
1.5.2.1   Pharmacokinetics and pharmacodynamics of Buparlisib 
 
Pharmacokinetic data observed so far showed that buparlisib is rapidly absorbed after oral 
administration with mean peak plasma concentrations (Cmax) ranging between 0.5 to 4 h 
post dose (tmax).  The median tmax at the MTD dose (100 mg daily) was about 1 hour. After 
reaching Cmax, buparlisib plasma concentrations decreased in a bi-exponential manner. 
Apparent total body clearance from plasma (CL/F) was low: ~5.0 L/h, indicating that 
buparlisib is a low clearance drug.  Buparlisib accumulated ~3-fold in achieving steady-
state, consistent with an effective half-life of ~40 h.  Steady-state can be expected to be 
reached after approximately 7-10 days of daily dosing in most patients. Approximate dose-
proportional increase in Cmax and AUC was found in the dose range of 12.5-150 mg. 
Intersubject variability in Cmax and AUC differed at each dose level but was relatively low 
and generally around 40%.  Doses of 50mg/day and above led to steady-state drug 
exposure (AUC0-24,.SS) > 10,000 ng*h/mL, a target efficacious exposure level estimated 
preclinically. 
Due to the difficulty to obtain fresh tumor tissue during treatment, pharmacodynamic 
measurements were limited to surrogate tissues such as skin and blood.  The parameters 
assessed have been selected for their relevance to PI3K/mTOR signaling modulation: 
phosphorylated S6 ribosomal protein in the skin (S6 is a well-known downstream target of 
mTOR/PI3K  pathway)  and  C-peptide  and  glucose  levels  in  the  blood  (PI3K/ mTOR 
signaling has a critical role in glucose metabolism).  A formal analysis of these 
assessments is currently ongoing.  Consistent suppression of S6 activation in skin was 
evident at the highest doses tested (100 and 150mg/day) with 30 to 80% decrease from 
baseline levels. Occasional increases of C-peptide have been seen at all doses, while 
hyperglycemia was one of the DLTs suggesting potential impairment of glucose transport 
and utilization by the tissues (insulin resistance).  More information is provided in the 
Investigator’s Brochure. 
 
1.5.2.2 
Clinical Experience with Buparlisib 
 
As of September 2013, a total of 1469 patients were enrolled into twenty two Novartis 
sponsored clinical studies of buparlisib, including 3 blinded phase 2 and phase 3 studies: 
Phase 1 single agent studies CBKM120X2101 (First in man dose escalation in 
solid tumors) and CBKM120X1101 (Japanese dose escalation in solid tumors), 
CBKM120Z2102 (Chinese dose escalation in solid tumors), CBKM120C2110  
(bioavailability of BMK120 tablet formulation in healthy subjects), 
CBKM120C2104 (Single dose in hepatic impairement), CBKM120C2106 (two 
doses  of  50mg  in  healthy  subjects),  CBKM120C2111  (two  doses  of  30mg 


 
 
24 
in healthy subjects) and CBKM120C2102 (one dose of 100mg in healthy subjects) 
 
Phase 2 single agent studies CBKM120C2201 (endometrial cancer) and 
CBKM120D2201 (non-small cell lung cancer) 
Phase 1 combination studies CBKM120B2101 (buparlisib plus GSK1120212), 
CBKM120X2107 (buparlisib plus trastuzumab), CBEZ235A2118  
(buparlisib plus paclitaxel),  and  CMEK162X2101  (buparlisib  plus  MEK162), 
CBKM120E2101 (buparlisib plus radiation and temozolimide for gliobastoma), 
CLDE225X2114 (dose escalation of buparlisib plus sonidegib), CSTI571X2101 
(buparlisib plus imatinib), CINC424A2104 (buparlisib plus INC424) and 
CBEZ235D2101 (buparlisib plus BEZ235) 
Phase 2 combination study CBKM120F2202 (buparlisib plus paclitaxel in breast 
cancer) 
Phase 3 combination studies CBKM120F2302 (buparlisib/placebo plus 
fulvestrant in breast cancer) and CBKM120F2303 (buparlisib plus fulvestrant in 
breast cancer) 
1.5.2.2.1 Human safety and tolerability data of Buparlisib 
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 
buparlisib given as single agent, once daily was established at 100 mg/day.  Fortythree 
additional patients were treated in the expansion cohort at 100 mg/day.  At the cutoff date 
of 4th July 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 buparlisib is described in Table 5 below. 
 
Table 5.          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%) 
Anxiety 
14 (17.3%) 
1 (1.2%) 


 
 
25 
Depression 
14 (17.3%) 
1 (1.2%) 
A  second  single  agent  trial,  CBKM120X1101  was  a  phase 1  dose  escalation  study 
in Japanese patients with advanced solid tumors with dose levels ranging from 25 to 100 
mg/day.  Enrolment of 15 patients has been completed, including 9 patients at 100 mg/day. 
One DLT (G4 hepatic function abnormal) was observed in the 100mg/day group.  The 
most common G3 or G4 adverse events occurring in at least 2 patients were hepatic 
function abnormal  in  6  patients  including  transaminase  increase  in  2  patients,  G3  
anemia in 2 patients, hypokalemia in 2 patients.  The recommended phase 2 dose (RP2D) 
for Japanese has been determined at 100 mg/day, as in the western population. 
Buparlisib  in  combination  with  trastuzumab  is  currently  investigated  in  a  phase  
1b/1 CBKM120X2107 study in patients with HER2+ MBC who acquired trastuzumab 
resistance. The phase 1b part of the study has been presented.   In this study trastuzumab is 
given at fixed dose of 2 mg/kg/week (with a 4 mg/kg/week loading dose).   In the dose 
escalation phase, 17 patients with MBC have been enrolled at the cutoff date of September 
30th, 2011: 5 patients at 50 mg/day and 12 patients at 100 mg/day.  The recommended 
phase 2 dose for buparlisib was declared at 100 mg/day.  The median age was 47 years 
(range 28 -70). Most of the patients have been heavily treated (range of prior 
chemotherapy lines 1-8). With the completion of escalation phase, buparlisib in 
combination with trastuzumab has shown an acceptable safety profile.  Grade 3 adverse 
events reported with a suspected relationship to buparlisib were asthenia, ALT increase, 
hypersensitivity hyperglycemia, mood altered, affective disorder, photosensitivity reaction 
and rash in 1-2 patients each. No drug related G4 toxicity has been observed so far.  The 
trial is currently recruiting the phase 2 part. 
Details on liver toxicity, mood alterations, pneumonitis and hyperglycemia as side effects 
of buparlisib are presented below. 
 
Liver Toxicity of Buparlisib  
 
Liver function test (LFT) alterations observed during ongoing studies were mostly 
transaminase enzyme increases (ALT and/or AST).  Only a few of the patients with LFT 
alterations had other simultaneous observations like bilirubin increase or clinical symptoms 
related to impaired liver function.  To be noted, no case fitting Hy’s law has been observed 
so far. 
Liver toxicity observed at 100 mg/day, regardless of study drug relationship, in ongoing 
buparlisib studies are summarized in Table 6. 
 
Table 6. Numbers  of  patients  with  liver  toxicity  occurred  at  100  mg/day  in 
ongoing buparlisib studies 
Study Number (N = patient treated with 
100 mg/d buparlisib) 
All grades 
Grade 3-4 
CBKM120X2101 (N = 55) 
22 (40%) 
13 (23%) 
CBKM120X1101 (N = 9) 
4 (44%) 
4 (44%) 
CBKM120C2201 (N = 50) 
10 (20%) 
6 (12%) 


 
 
26 
CBKM120X2107 (N = 12) 
2 (16%) 
2 (16%) 
CBEZ235A2118 (N = 6, buparlisib-treated only) 
0 (0%) 
0 (0%) 
Based on these findings, conservative selection criteria and guidelines to monitor and to 
follow patients with LFT alterations (including dose and schedule modifications) are 
currently implemented in study protocols investigating buparlisib. 
 
 
Mood alteration of Buparlisib 
 
Recently, a number of publications demonstrated that the modulation of AKT/GSK3 
signaling pathway by neurotransmitters is important for the regulation of behavior. 
Preclinical studies conducted in rats to investigate the effect of buparlisib on different 
neurotransmitters have shown that repeated administration of buparlisib resulted in an 
enhanced decrease in glutamate, dopamine, serotonin and epinephrine as well as in an 
enhanced increase in GABA and HIAA. 
Reversible mild to moderate mood disorders observed at 100 mg/day, regardless of study 
drug relationship, in ongoing buparlisib studies are summarized in the Investigator’s 
Brochure. (see also Table 7 below) 
 
Table 7. Numbers of patients with mood disorders occurred at 100 mg/day in ongoing 
buparlisib studies 
Study Number (N = patient treated with 
100 mg/d buparlisib) 
All grades 
Grade 3-4 
CBKM120X2101 (N = 55) 
11 (20%) 
2 (3%) 
CBKM120X1101 (N = 9) 
4 ( 44%) 
0 (0%) 
CBKM120C2201 (N = 50) 
6 (12%) 
0 (0%) 
CBKM120X2107 (N = 12) 
7 (58%) 
2 (16.7%) 
CBEZ235A2118 (N = 6, buparlisib-treated only) 
0 (0%) 
0 (0%) 
 
These adverse events are currently under investigation.  Nevertheless, until a more 
complete understanding of this AE is compiled and in order to lower the risk, protocol 
guidelines disqualify patients with an active and/or history of major psychiatric disorder. In 
addition, throughout the trial patients must be closely monitored using self-rating 
questionnaires (ie, PHQ-9 and GAD-7), when required a psychiatrist should be consulted 
and the use of standard available medication should be considered as per investigator’s 
discretion. 
Across the ongoing studies of buparlisib, 4 patients experienced other psychiatric toxicities 
related to buparlisib: confusional state in 3 patients (Grade 3 in 1 patient) and mental status 
change in 1 patient (Grade 3).  With regards to the confusional state, in one case it has been 
considered as a symptom related to mood disorders, cholangitis and brain metastases, and 
in the remaining two cases, the confusional state occurred in a context of infection and 


 
 
27 
gastrointestinal disorders.  In two out of the three cases, the event improved/resolved after 
study drug interruption.  Further information is being collected for the latest reported case. 
 
Lung Toxicity and Pneumonitis in buparlisib 
Lung  changes  compatible  with  pneumonitis  have  not  been  observed  in  the 
preclinical setting.  Among the current studies, lung toxicity has been observed in 2 
patients and reported as pneumonitis, including a fatal outcome reported in one patient in a 
complex clinical context, combining progression of lung lesions and aspergillosis infection 
The currently available data do not enable a clear assessment about the causal relationship 
of pneumonitis  with  buparlisib  treatment. Newly appearing or significant changes in 
pulmonary symptoms (which cannot be explained by the underlying disease), should be 
carefully followed with appropriate management as per institutional guidelines and the 
guidelines provided in the protocol. 
 
Hyperglycemia events in buparlisib 
The PI3K/Akt pathway plays a significant role in regulating glucose metabolism, 
particularly by regulating glucose transport into adipocytes and muscle tissue.  Therefore, 
hyperglycemia is considered as an “on target” effect of buparlisib. Regular monitoring of 
insulin C-peptide is implemented in buparlisib protocols to evaluate this 
pharmacodynamics effect.   Transient increases of plasma glucose levels have been 
reported commonly in patients treated with buparlisib.   Hyperglycemia observed at 100 
mg/day, regardless of study drug relationship, in ongoing buparlisib studies are 
summarized in Table 8. 
 
Table 8.          Number of patients with hyperglycemia occurred at 100 mg/day in 
   
ongoing BKM studies  
Study Number (N = patient treated with 
100 mg/d buparlisib) 
All grades 
Grade 3-4 
CBKM120X2101 (N = 55) 
17 (30.9%) 
2 (3.6%) 
CBKM120X1101 (N = 9) 
2 (22.2%) 
1 (11.1%) 
CBKM120C2201 (N = 50) 
31 (62.0%) 
12 (24.0%) 
CBKM120X2107 (N = 12) 
4 (33.3%) 
2 (16.7%) 
CBEZ235A2118 (N = 6, buparlisib-treated only) 
2 (33.3%) 
1 (16.7%) 
 
The highest rate of hyperglycemia (62.0%) was reported in CBKM120C2201, a phase  
2 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 (150 mg/day) in the 
CBKM120X2101 study.  Detailed guidelines to monitor and manage patients who develop 
hyperglycemia are provided in the Investigator’s Brochure.  Specifically, with regards to 
appropriate concomitant medication, considering that in vitro studies have shown that 
buparlisib may inhibit insulin-stimulated glucose uptake, the first recommended approach 


 
 
28 
is to use oral anti-diabetics (eg, metformin) who increases muscle and fat glucose uptake.  
The addition of insulin can be considered based on the guidelines of American Diabetes 
Association included as reference in the current protocol. 
 
1.5.2.2.2 Human pharmacokinetic and metabolism data of buparlisib 
 
Preliminary clinical  pharmacokinetic  data  of  buparlisib  after  single  and  multiple daily 
dosing is available from the first-in-human trial CBKM120X2101.   Buparlisib 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. 
Buparlisib was rapidly absorbed, with the median time to reach the peak plasma 
concentration (Tmax) ranging from 1.0 to 1.75 hours following administration.  Tmax was 
independent of dose and was not altered after multiple oral doses.  Variability in systemic 
drug exposure was moderate at all dose levels.  At 100 mg the variability in systemic drug 
exposure  and  Cmax  (CV  %)  at  steady-state  was  moderate,  about 36%  and  25%, 
respectively. 
During once daily dosing, plasma buparlisib concentrations were found to accumulate in 
reaching steady-state.    After  one  week  of  oral  daily  dosing  (day  8),  both  Cmax and 
AUC0-24h were approximately 3-fold higher than after a single dose (day 1).  The mean 
accumulation ratio (Racc) of buparlisib at 100 mg was 2.7 and 3.3 on days 8 and 28, 
respectively, indicating the absence of significant drug accumulation after day 8.  The 
decay in buparlisib plasma concentration over time was bi-exponential, with an apparent 
long terminal half-life.  The mean T1/2,acc (effective half-life, obtained from drug 
accumulation) calculated from exposure data at day 28 ranged between 38 and 49 hours 
across all dose levels.   T1/2,acc was found to be independent of dose.   Based on the 
effective half-life, steady state buparlisib plasma levels can be expected to be reached after 
1 week of daily dosing. 
Furthermore the preliminary PK data within the  Japanese population CBKM120X1101 show 
no significant differences in Cmax or AUC0-24h 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, buparlisib was administered with GSK1120212 (a MEK 
inhibitor). Single dose pharmacokinetics of buparlisib 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 
buparlisib systemic drug exposure. After 28 days of once daily combination treatment of 
buparlisib with GSK1120212 (1.5-2.0 mg), exposure of buparlisib at system steadystate 
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 buparlisib 
increased up to 2-fold in the presence GSK1120212.  This dose and time dependent effect 
of GSK1120212  on  buparlisib  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 buparlisib clearance on CYP3A4 
activity.  Similar changes in the pharmacokinetics of buparlisib could be expected to occur 
when other inducers of CYP3A4 are combined with buparlisib treatment (see concomitant 
medication).  The pharmacokinetics of GSK1120212 was not altered by buparlisib. 
In study CBKM120X2107 a daily dosing regimen of buparlisib was tested in combination 
with weekly infusions of trastuzumab in patients with relapsed HER2-overexpressing 


 
 
29 
breast cancer.  Preliminary pharmacokinetic data indicated that the systemic drug exposure 
(Cmax and AUC) of oral buparlisib in combination with trastuzumab was similar to the 
single agent data.  Trastuzumab trough levels were consistent with those previously 
reported to be therapeutic (ie, generally greater than 20 µg/ml). 
1.5.2.2.3 Clinical efficacy data on buparlisib 
Sixty-six patients were evaluable for response in study CBKM120X2101 where all patients 
in the expansion cohort were required to have mutated and/or amplified PIK3CA and/or 
mutated PTEN or null/low PTEN protein expression: partial tumor responses (PR) were 
observed in 3 patients, one of which was a RECIST v1.0 confirmed PR in a patient with 
triple negative breast cancer and the other 2 not confirmed (1 patient with metastatic breast 
cancer and 1 patient with parotid carcinoma). 
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 1 
study of buparlisib in the 100 mg/day cohort.  A metabolic response (61% decrease in 
SUV) was observed after 2 cycles, followed by a RECIST partial response (66% tumor 
shrinkage) after 4 cycles.  This patient continues to receive treatment beyond 32 cycles. 
The  second  patient  was  a  52  year-old  female  with  moderately  differentiated ductal 
metastatic breast cancer, assessed as ER positive, HER2 negative, PI3KCA mutated 
(E545K& H1047Y), PTEN IHC positive. She had been previously treated with several 
antineoplastic agents.  When she received buparlisib at 100 mg/day (January 2010), she 
had measurable metastases in the brain, lung and liver.  At the second radiological 
assessment after receiving 4 cycles of buparlisib treatment, a 45% reduction of the sum of 
the lesions was recorded.  The TTP for this patient was 24 weeks. 
The third patient was a 45 year-old man with Grade 4 parotid gland ductal carcinoma, 
PI3KCA wild type, PTEN IHC positive.  He had been previously treated with doxorubicin 
and adriamycin.  After disease progression was observed on this regimen he was enrolled 
in the 100mg/day cohort (July 2010) in the CBKM120X2101 study.  At the first 
radiological assessment after receiving 2 cycles of buparlisib treatment, a 33% reduction of 
the sum of the lesions was recorded.  The TTP for this patient was 16 weeks. 
As of the data cut-off 04July2011, preliminary analysis shows forty-five percent of patients 
(30 of 66 evaluable) had stable disease as best response, with 20 patients (30%) with a 
disease stabilization of 3 months or longer.  A trend towards better activity (longterm 
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, of the two 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 


 
 
30 
pathway.  These data are promising and continued exploration of the activity of buparlisib 
in patients with activated PI3K pathway is warranted. 
More specifically, in CBKM120X2101, 25.3% (21/83) of patients had metastatic breast 
cancer.  At the cut-off date of 4th July 2011, twenty breast cancer patients were evaluable 
for objective tumor response by RECIST 1.0.  Two breast cancer patients (11%), described 
above exhibited partial responses.  For these 2 patients, the treatment duration was 27+ 
(ongoing) and 5 months, respectively.   An additional 8 breast cancer patients (40%) had 
stable disease.  Median progression-free survival was 60 days and the 6-month PFS rate 
was 3 3%. 
Please  refer  to  the  Investigator’s  Brochure  for  additional  information  on  the 
available clinical experience with buparlisib. 
 
1.5.2.2.4 Clinical safety data on combination of sonidegib plus buparlisib 
The combination maximum tolerated dose (MTD) and/or recommended dose expansion 
(RDE) of sonidegib + buparlisib when co-administered orally, was determined in Study 
LDE225X2114, an ongoing phase 1b, multi-center, open label, dose escalation study of 
oral sonidegib in combination with buparlisib in patients with advanced solid tumors 
(metastatic breast cancer, advanced pancreatic adenocarcinoma, metastatic CRC and 
recurrent GBM). The RDE was determined based on observed rates of dose limiting 
toxicities (DLTs) during the first 6 weeks (42 days) of the combination treatment of 
sonidegib and buparlisib, using a Bayesian Logistic regression Model (BLRM) with 
Overdose Control (EWOC).  The dose escalation  phase  was  completed  in  December 
2013  with  46  patients  enrolled  across 5 cohorts.  The RDE was declared as 400 mg 
sonidegib QD + 80 mg buparlisib QD. 
In a recent randomized double-blind study of sonidegib in patients with locally advanced 
(La) or metastatic (m) basal-cell carcinoma (BCC), 230 patients were randomized in a 2:1 
fashion to receive either 200 mg QD or 800 mg QD of sonidegib. The primary endpoint of 
objective response rate was met in both arms with both doses achieving meaningful disease 
control and sustained duration  of  responses.    The 200mg arm had a more  favorable risk-
benefit profile with respect to toxicities. Therefore, the doses of sonidegib and buparlisib 
for the current study will be 200mg QD of sonidegib and 80mg QD of buparlisib. 
1.6        Study Rationale 
Mutations in hedgehog pathway genes are clearly associated with development of BCCs 
and recent, exciting early phase clinical studies in locally advanced or metastatic BCCs 
using drugs  which  target  the  hedgehog pathway have  shown  potent  and  dramatic anti-
tumor results (Sekulic et al;   2012, Von Hoff, et al, 2009).   Another example of a 
Smoothened inhibitor is Sonidegib, which appears to be well-tolerated and possess anti-
tumor activity in advanced solid tumors in a phase 1 and 2 clinical trials which are 
ongoing. 
Nevertheless, a significant subset of BCC patients with locally advanced or metastatic BCC 
treated with Smoothened inhibitors do not respond to the drug, and their tumors become 
progressive (by estimate, approximately 50% of individuals treated with GDC0449 did not 
respond  to  the  study drug)  (Von  Hoff  et al,  2009;    Sekulic  et al,  2012).    In  addition 
approximately 20% of advanced BCCs which initially respond develop resistance to SI 
monotherapy (Chang and Oro, 2012).   Several mechanisms for resistance to Smoothened 
inhibitors have been postulated.  In particular, gene expression data from resistant tumors 
(Chang et al., 2013) have suggested that increased phosphatidylinositol-3-kinase (PI3K) 


 
 
31 
signaling may be a potential resistance mechanism in BCCs.  The role of this pathway in other 
solid tumors has been reported as well (Zhu et al, 2010;   Buonamici, et al., 2010). Subsets of 
cancers have been reported to become dependent on PI3K pathway signaling (“pathway 
addicted”, Weinstein et al, 2008) as a result of mutations of the PIK3CA gene itself or of 
regulators of PI3K (eg, PTEN, HER2) NVP-BKM120 (buparlisib) is an oral 
phosphatidylinositol-3-kinase (PI3K) inhibitor.   The PI3K/AKT pathway regulates cell 
proliferation, growth, survival and apoptosis.   Experiments in mice with mutations of the 
hedgehog pathway  leading to medullo-blastoma found that tumor resistance to Smoothened 
antagonists could be delayed or prevented with the concomitant use of buparlisib (Buonamici, 
et al, 2010).  This effect appeared to be more pronounced when combination therapy was 
initiated at the start of treatment before development of resistance. 
As more and more patients with BCCs are treated with Smoothened inhibitors, the presence of 
resistant tumor populations has become a critical issue.  This pilot study will provide vitally 
important information regarding the potential of dual treatment with PI3K inhibitor 
(buparlisib) PLUS Smoothened inhibitor (Sonidegib) to address resistance. 
It  is  currently  unclear  whether  the  clinical  efficacy  of  combination  therapy  (termed  
LB therapy) is more pronounced if it is instituted at the outset versus after resistance is 
clinically apparent. 
2 
Study objectives 
Primary Objective 
To estimate the overall response rate (ORR) of sonidegib in combination with buparlisib  
(hereby referred to as “LB therapy”) for patients with locally advanced or metastatic BCC in 
Smoothened inhibitor naive patients (Cohort 1) and those whose disease is refractory or 
relapsed on Smoothened inhibitor monotherapy (Cohort 2).  
 
Secondary Objectives 
To estimate the median duration of response, on or after LB therapy 
To assess the safety and tolerability of LB therapy 
To assess the histopathologic effect of LB therapy in tumor biopsies obtained at 
baseline and following 12 weeks of treatment 
To assess the effect of LB therapy on gene expression including Hedgehog 
pathway and PI3K pathways. 
To assess correlation between gene mutations in Smoothened, Sufu, PTCH, 
Gli1,2 and gene expression profiles and response to LB therapy 
 
3 
Exploratory Investigational plan 
3.1        Overall study design 
This is an open-label, single-center 2-cohort pilot study, as shown in Figure 4.  All patients 
will receive LB therapy until evidence of progression, intolerable toxicities or withdrawal 
from the study. 
 
3.2 
Study population 
Figure 4.   Study Design 
3.2.1       Patient population 


 
 
32 
Adult patients with locally advanced or metastatic BCC. 
The study will accrue 12 patients with locally advanced or metastatic basal cell carcinoma 
who are naïve to Smoothened inhibitors (COHORT 1) and 12 patients are refractory or 
resistant to non-Sonidegib SI (COHORT 2).  This is an exploratory descriptive study. 
 
3.2.2       Inclusion and exclusion criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and 
must meet all inclusion and exclusion criteria.   Results of all baseline evaluations, which 
assure that all inclusion and exclusion criteria have been satisfied, must be 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. 
3.2.2.1 Inclusion criteria 
 
Patients eligible for enrollment into the treatment phase of this study must meet all of the 
following criteria: 
1. 
Able to understand and sign informed consent 
2. 
Age ≥ 18 years 
3. 
ECOG performance status ≤ 2 
4. 
Patients with metastatic BCC, histologic confirmation of distant BCC metastasis 
5. 
Patients with metastatic disease, target lesion must be measurable using CT or 
MRI 
6. 
Patients with locally advanced BCC are required to have disease that is considered 
inoperable due to significant functional compromise or to have a medical 
contraindication to surgery 
7. 
Patients with nevoid BCC syndrome (Gorlin syndrome) may enroll in this study 
but must meet the criteria for locally advanced or metastatic disease listed above 
8. 
COHORT 2 ONLY:   A Smoothened inhibitor must have been previously 
administered as monotherapy) 
9. 
Adequate bone marrow function as shown by: 
a. ANC ≥ 1.5 x 109/L, 
b. Platelets ≥ 80 x109/L, 
c. Hb > 9 g/dL or values ≥ LLN for site-specific lab 
10. Total calcium (corrected for serum albumin) within normal limits  
(biphosphonate use for malignant hypercalcemia control is not allowed) 
11. Magnesium ≥ the lower limit of normal 
12. Potassium within normal limits for the institution 
13. Alanine  aminotransferase  (ALT)  and  aspartate  aminotransferase  (AST) within 
normal range (or ≤ 3.0 x upper limit of normal (ULN) if liver metastases are 
present) 
14. 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) 
15. Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min 
16. Serum amylase ≤ ULN 
17. Serum lipase ≤ ULN 


 
 
33 
18. Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) 
19. Negative serum pregnancy test within 72 hours before starting study treatment in 
women with childbearing potential 
20. INR ≤ 2 
 
3.2.2.2 
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 a known hypersensitivity to buparlisib or to its excipients 
3. 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 not receiving corticosteroid therapy 
4. Patients with acute or chronic liver, renal disease or pancreatitis 
5. Patients with baseline creatinine kinase (CK) > upper limit of normal (ULN) 
6. 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) 
≥ CTCAE Grade 3 anxiety 
Meets the cut-off score of ≥ 12 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-
7 mood scale, respectively, or selects a positive response of “1, 2, or 3” to 
question number 9 regarding potential for suicidal thoughts in the PHQ-9  
(independent of the total score of the PHQ-9) 
7. Patients with diarrhea ≥ CTCAE Grade 2 
8. Patient has active cardiac disease including any of the following: 
Persistent Left ventricular ejection fraction (LVEF) < 50% as determined by prior 
Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO) 
QTc > 450 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 
9. 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 


 
 
34 
10. Patient  has  poorly  controlled  diabetes  mellitus  (defined  as  HgA1c  >  ULM), 
steroid-induced diabetes mellitus or insulin dependent diabetes mellitus. 
11. Other concurrent severe and/or uncontrolled concomitant medical conditions (eg, 
active or uncontrolled infection) that could cause unacceptable safety risks or 
compromise compliance with the protocol 
Significant  symptomatic  deterioration  of  lung  function.    If  clinically  indicated, 
pulmonary function tests including measures of predicted lung volumes, DLco, O2 
saturation at rest on room air should be considered to exclude pneumonitis or 
pulmonary infiltrates. 
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of buparlisib (eg, ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption  syndrome,  or  small  bowel  resection).  Patients with 
unresolved diarrhea will be excluded as previously indicated 
13. Patients who have been treated with any hematopoietic colony-stimulating growth 
factors (eg, 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. 
14. 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 16 for a list of prohibited QT-prolonging drugs with risk of 
Torsades de Pointes. 
15. Patients receiving chronic treatment with steroids or another immunosuppressive 
agent. 
Note: Topical applications (eg, rash), inhaled sprays (eg, obstructive airways 
diseases), eye drops or local injections (eg, intr-articular) are allowed. Oral or 
systemic liver enzyme inhibitors such as topical antifungal creams are allowed. 
Patients with previously treated brain metastases, who are on stable low dose 
corticosteriods treatment (eg, dexamethasone 2 mg/day, predisolone 10 mg/day) 
for at least 14 days before start of study treatment are eligible. 
16. 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,   and ephedra   (ma   huang),   dehydroepiandrosterone (DHEA), 
gingko biloba, yohimbe, saw palmetto, and ginseng.  Fruits include the CYP3A 
inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits. 
17. 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 15 for a list of prohibited inhibitors and inducers of  
CYP3A (Please note that co-treatment with weak inhibitors of CYP3A is allowed). 
18. 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 
19. 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 
20. Use of statin drugs or other medications known to associate with rhabdomyolysis. 
These drugs must be discontinued at enrollment. 


 
 
35 
21. 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 
22. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or 
who have not recovered from side effects of such therapy. 
23. Patients who are currently taking therapeutic doses of warfarin sodium or any other 
coumadin-derivative anticoagulant.  Low molecular weight heparin is allowed. 
24. Women who are pregnant or breast feeding or adults of reproductive potential not 
employing an effective method of birth control.  Double barrier contraceptives must be 
used through the trial by both sexes.   Oral, implantable, or injectable contraceptives 
may be affected by cytochrome P450 interactions, and are therefore not considered 
effective for this study.  Women of child-bearing potential, defined as sexually mature 
women who have not undergone a hysterectomy or who have not been naturally 
postmenopausal for at least 12 consecutive months ( ie, 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 (eg, 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 
the study and through 20 months after the final dose of study treatment..  For 
males with partners with childbearing potential, highly effective contraception 
is required for 6 months.  The highly effective contraception is defined as 
either: 
I. 
True abstinence: When this is in line with the preferred and usual lifestyle of 
the subject.       Periodic   abstinence   (eg,   calendar,   ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
II. 
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. 
III. 
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. 
IV. 
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 


 
 
36 
Oral contraception, injected or implanted hormonal methods are not allowed as 
buparlisib potentially decreases the effectiveness of hormonal contraceptives. 
Fertile males, must use highly effective (double barrier) methods of contraception 
(eg, spermicidal gel plus condom) for the entire duration of the study, and 
continuing using contraception and refrain from fathering a child for 6 months 
following the study drug.  A condom is required to be used also by vasectomized 
men as well as during intercourse with a male partner in order to prevent delivery 
of the study treatment via seminal fluid.  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. 
Note:   Hormonal contraception methods (eg, oral, injected, implanted) are not 
allowed as it cannot be ruled out that the study drug decreases the effectiveness of 
hormonal contraception. 
Note: Woman are considered post-menopausal and not child bearing potential if 
they have  had  12  months  of  natural  (spontaneous)  amenorrhea  with  an 
appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or 
six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ mL and 
estradiol< 20 pg/mL   or   have   had   surgical   bilateral   oophorectomy   (with   or 
without hysterectomy) at least six weeks ago.  In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential 
25. Known diagnosis of human immunodeficiency virus (HIV) infection, Hepatitis B or 
Hepatitis C 
26. History of another malignancy within 3 years, except cured basal cell carcinoma of 
the skin or excised carcinoma in situ of the cervix 
27. Patient is unable or unwilling to abide by the study protocol or cooperate fully with 
the investigator 
 
 
 
4 
Treatments 
4.1        Dose modification, interruption or discontinuation of treatment 
If an adverse event is clearly associated to one of study drugs, the dose adjustment 
directed for that study drug will be followed; however, if the causality is not clear, 
then it may be necessary to adjust both study drugs.    Dosing adjustments will be 
discussed with the sponsor.  If a patient experiences a DLT then treatment with 
Sonidegib plus buparlisib must be stopped and the patient may be discontinued from 
the study.   However, following resolution of the DLT to CTCAE Grade 1 or to the 
patient’s baseline value, the patient may continue to receive study treatment with a  
50% dose reduction  for  either  sonidegib, buparlisib or both, if appropriate, at the 
discretion of the investigator and after discussion with the Sponsor. 
If a patient requires a dose delay of > 21 days due to an sonidegib- or buparlisib-
related toxicity, then the patient must be discontinued from the study; however, if the 
patient is obtaining clinical benefit (ie, SD, PR, or CR), the patient may continue 
treatment at the same or at a reduced dose following discussion between the 
investigator and Novartis.  All patients will be followed for AEs and SAEs for 30 
days following the last dose of sonidegib and/or buparlisib.  If the administration of 


 
 
37 
study treatment was interrupted for reasons other than toxicity, then treatment with 
Sonidegib and buparlisib may be resumed at the same dose. 
Patients who experience hematologic, renal, hepatic, or muscle toxicities should 
receive follow up and dosing modifications for sonidegib as per Table 9 and 10 
below.   Specific instructions for follow-up and dosing modifications for sonidegib 
are described in detail in Table 9.  Patients who experience muscle toxicity, 
regardless of whether the toxicity meets the criteria described for a DLT, should be 
receive follow-up and dosing modifications specified in Table 9 below. 
Table 9.  Recommended dose modifications and dose delays 
for suspected sonidegib** treatment-related toxicities 
Worst toxicity CTCAE grade* (value) 
During a cycle of therapy 
Hematologic 
Neutropenia (ANC) 
Worst toxicity CTCAE grade* (value) 
During a cycle of therapy 
Grade 1 (ANC < LLN - 1500/mm3) 
Maintain dose level 
Grade 2 (ANC < 1500 - 1000/mm3) 
Maintain dose level 
Grade 3 or 4 
(ANC < 1000 - 500/mm3 or < 
500/mm3) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, implement 50% dose 
reduction 
If resolved in > 7 days, discontinue 
drug  
If a Grade 4 event, consider 
hospitalization if appropriate 
Thrombocytopenia (PLT) 
Grade 1 (PLT < LLN - 75,000/mm3) 
Maintain dose level 
Grade 2 (PLT < 75,000 - 50,000/mm3) 
Maintain dose level 
Grade 3 or 4 (PLT < 50,000 - 25,000/mm3 
or < 25,000/mm3) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, implement 50% dose 
reduction 
If resolved in > 7 days, discontinue 
drug  
If a Grade 4 event, consider 
hospitalization if appropriate


 
 
38 
Febrile Neutropenia 
Grade 3 (ANC < 1.0 x 109/L, fever ≥ 
38.5°C) 
Omit dose until resolved, then implement 50% dose 
reduction 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
 Consider hospitalization  
 Discontinue drug 
 
Table 9.  Recommended dose modifications and dose delays 
for suspected sonidegib** treatment-related toxicities 
Worst toxicity CTCAE grade* (value) 
During a cycle of therapy 
Muscle Toxicity 
Elevated creatinine phosphokinase (CK) 
Asymptomatic (no new-onset muscle 
pain/spasm or worsening of pre-existing 
muscle pain/spasm) CTCAE Grade 1 or 
2 CK 
elevation 
For CTCAE Grade 1 CK elevation, continue 
treatment on same dose and continue monitoring as 
per schedule of assessments 
For CTCAE Grade 2 CK elevation, continue on 
same dose level of sonidegib.  CK should be 
measured weekly until resolution to ≤ Grade 1. 
Symptomatic (new-onset or worsening of 
pre-existing muscle pain/spasm) with 
CTCAE Grade 1 or 2 CK elevation 
For CTCAE Grade 1 CK with muscle pain/spasm 
≥ CTCAE Grade 1, continue treatment at same dose 
and measure CK weekly until CK returns to normal 
or baseline value or muscle pain/spasm resolves 
For CTCAE Grade 2 CK with muscle pain/spasm 
≥ CTCAE Grade 1, continue treatment at same dose 
level of sonidegib.  CK should be measured weekly 
until CK is ≤ CTCAE Grade 1 
CTCAE Grade 3 or 4 CK elevation (with 
or without muscle pain/spasm) 
Omit sonidegib dose, check blood myoglobin and 
monitor renal function.  Measure CK weekly until 
resolution to Grade ≤ 1 
Consider performing electromyography, MRI scan 
of symptomatic muscle group(s) and muscle biopsy 
If renal function is not impaired and resolution to 
≤ CTCAE Grade 1 occurs within 21 days, consider 
resuming treatment at a reduced dose; CK should be 
measured weekly for 2 months after re-
administration of sonidegib 
Patients who experience renal impairment (serum 


 
 
39 
creatinine > 2x ULN) should be permanently 
discontinued from the study 
If a Grade 4 event, consider hospitalization if 
appropriate
 
Table 9.  Recommended dose modifications and dose delays for 
suspected sonidegib** treatment-related toxicities 
Worst toxicity CTCAE grade* (value) 
During a cycle of therapy 
Muscle pain/spasm (new onset or   
worsening of preexisting muscle 
pain/spasm)                                                     
 For CTCAE Grade 1 muscle pain/spasm, continue 
treatment on the same dose and planned assessments 
For CTCAE ≥ Grade 2 muscle pain/spasm, measure 
CK weekly until muscle pain resolves to ≤ Grade 1.  If 
CK is elevated, follow guidance for CK elevation as 
described above.  Continue treatment with sonidegib 
For new-onset CTCAE Grade 3 muscle pain/spasm, 
interrupt sonidegib.  Collect blood sample for CK 
measurement at the time of dose interruption.  Provide 
symptomatic treatment.  Measure CK weekly until the 
muscle pain/spasm resolves to ≤ Grade 1 and resume 
therapy at a reduced dose.  Measure CK weekly for 2 
months after re-administration. 
Renal 
 Serum creatinine 
Serum creatinine <1.5 x ULN 
Maintain dose level 
Serum creatinine 1.5-3 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 implement 50%   
dose reduction (consider checking serum CK, if not  
already done) 
Grade 3  
Serum creatinine > 3.0 - 6.0 x ULN 
Omit dose until resolved to ≤ Grade 1 then implement   
50% dose reduction 
Grade 4 
Serum creatinine > 6.0 x ULN 
Omit dose and discontinue study drug. Consider   
hospitalization if appropriate 
Hepatic 
Bilirubin 
Total bilirubin <1.5 x ULN 
Maintain dose level 


 
 
40 
Total bilirubin 1.5-3 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 implement 50% dose 
reduction 
Grade 3 
Total bilirubin > 3.0 - 10.0 x ULN 
 Omit dose until resolved to ≤ Grade 1, then implement   
 50% dose reduction 
Grade 4 
Total bilirubin > 10.0 x ULN 
Discontinue study drug.  
Consider if hospitalization is appropriate.  
 
Table 9.  Recommended dose modifications and dose delays 
for suspected sonidegib** treatment-related toxicities 
Worst toxicity CTCAE grade*(value) 
During a cycle of therapy 
AST or ALT 
Grade 1 (> ULN - 3.0 x ULN) 
Maintain dose level 
Grade 2 (> 3.0 - 5.0 x ULN) 
Maintain dose level 
Grade 3 (> 5.0 - 20.0 x ULN) 
Omit dose until resolved to ≤ Grade 1 or baseline 
then:  
If resolved in ≤ 7 days, then maintain dose 
level  
If resolved in > 7 days, then implement 50% 
dose reduction 
Grade 4  (> 20.0 x ULN) 
Omit dose until resolved to ≤ Grade 1 or baseline, 
then implement 50% dose reduction.  Consider if 
hospitalization is appropriate 
Cardiac 
Cardiac - prolonged QTc interval 
Grade 3 (QTcF > 500 msec or 
>60 ms from baseline on at least 
2 separate ECGs taken within 1 
hour) 
 
First Occurrence: 
Omit dose 
Perform an analysis of serum potassium and 
magnesium, and if below lower limit of normal, correct 
with supplements to within normal limits. Concomitant 
medication usage must be reviewed. 
Perform a repeat ECG within one hour of the first 
QTcF of > 500 ms 
If QTcF remains > 500 ms, repeat ECG as clinically 
indicated but at least once a day until the QTcF returns to 
< 480 ms. 
Once QTcF prolongation has resolved, study 
treatment may be restarted with a 50% dose reduction 
Second Occurrence: 
discontinue patient from study drug 


 
 
41 
Cardiac - prolonged QTc interval 
Grade 4 
Discontinue patient from study drug 
 
 
 
 
Table 9.  Recommended dose modifications and dose delays 
for suspected sonidegib** treatment-related toxicities 
 
Worst toxicity CTCAE grade* (value) 
During a cycle of therapy 
 
Other Cardiac Events 
Grade 1 
Maintain dose level 
Grade 2 
Implement 50% dose reduction of buparlisib 
Grade 3 
Omit dose and discontinue study drug 
Grade 4 
Omit dose and discontinue study drug. Consider if 
hospitalization if appropriate 
Other adverse events** 
Grade 1 
Maintain dose level 
Grade 2 
Implement 50% dose reduction 
 
Grade 3 
Omit dose and discontinue study drug 
Grade 4 
Omit dose and discontinue study drug 
Consider if hospitalization if appropriate 
All dose modifications should be based on the worst preceding toxicity. 
If the dose-limiting toxicity recurs in a patient following dose reduction, then further therapy 
with sonidegib will not be continued. 
If a patient requires a dose interruption of > 21 days from the intended day of the next 
scheduled dose because of a sonidegib-related toxicity, then the patient must be discontinued 
from the study. 
*Common Toxicity Criteria for Adverse Events (CTCAE Version 4.0). 


 
 
42 
** If the investigator deems that a recommended dose reduction or the recommendation to 
maintain the same dose level is not in the best interest of the patient, this decision may be 
discussed with Novartis on a case-by-case basis. 
 
Criteria for follow-up and dosing modifications for buparlisib are described in detail in 
Table 10. 
For overlapping toxicities of sonidegib and buparlisib, specifically hematologic, 
renal and hepatic  toxicities,  BOTH  sonidegib  and  buparlisib  will  be  reduced 
or  discontinued depending on toxicity grade per the guidelines  listed below for 
each  drug (Tables 9 and 10). 
 
Table 10.  Recommended dose modifications and dose 
delays for suspected buparlisib treatment-related 
toxicities 
Worst toxicity CTCAE grade* 
(value) 
During a cycle of therapy 
Hematologic 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1500/mm3) 
Maintain dose level 
Grade 2 (ANC < 1500 - 1000/mm3) 
Maintain dose level 
Grade 3 or 4 (ANC < 1000 - 500/ mm3 or 
< 500/mm3) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, implement 50% dose 
reduction 
If resolved >7 days, discontinue drug 
If a Grade 4 event, consider hospitalization if appropriate 
Thrombocytopena 
Grade 1 (PLT < LLN - 75 x 109/L) 
 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain dose level 
 
Maintain dose level 


 
 
43 
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 implement 50% dose 
reduction 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 1, then implement 
50% dose reduction.  Consider if hospitalization is 
appropriate 
Renal 
Serum creatinine 
Serum creatinine <1.5 x ULN 
Maintain dose level 
Serum creatinine 1.5-3 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 implement 50% 
dose reduction (consider checking serum CK, if not 
already done) 
 
 
Table 10.  Recommended dose modifications and dose delays for suspected buparlisib 
treatment-related toxicities 
Worst toxicity CTCAE grade* 
(value) 
During a cycle of therapy 
Grade 3  
Serum creatinine > 3.0 - 6.0 x ULN 
Omit dose until resolved to ≤ Grade 1 then implement 
50% dose reduction 
Grade 4 
Serum creatinine > 6.0 x ULN 
Omit dose and discontinue study drug. Consider 
hospitalization if appropriate 
Hepatic 
Bilirubin 
 (*for patients with Gilbert syndrome these dose modifications apply to changes in direct 
bilirubin only) will be fractionated if elevated 


 
 
44 
Total bilirubin <1.5 x ULN 
Maintain dose level 
Total bilirubin 1.5-3 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 implement 50% dose 
reduction 
Grade 3 
Total bilirubin > 3.0 - 10.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then 
implement 50% dose reduction 
Grade 4 
Total bilirubin > 10.0 x ULN 
Discontinue study medication 
Consider if hospitalization is appropriate 
AST or ALT 
Grade 1 (> ULN - 3.0 x ULN) 
Maintain dose level 
Grade 2 (> 3.0 - 5.0 x ULN) 
  Maintain dose level 
Grade 3 (> 5.0 - 20.0 x ULN) 
Omit dose until resolved to ≤ Grade 1 or baseline then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then implement 50% dose 
reduction 
Grade 4 (> 20.0 x  
ULN) 
Discontinue study drug 
Consider if hospitalization is appropriate 
AST or ALT and concurrent Bilirubin 
AST or ALT > 3.0 x ULN and 
total bilirubin > 2.0 x ULN 
Discontinue study drug 
*(LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x 
ULN), alkaline phosphatase (fractionated if alkaline phosphatase is Grade 2 or higher) and 
GGT). Monitoring (*for patients with Gilbert Syndrome: total and direct bilirubin must be 
monitored, intensified monitoring applies to changes in direct bilirubin only; the monitoring 
includes the following LFTs: albumin, ALT, AST, total bilirubin (fractionated if total 
bilirubin > 2.0 x ULN), alkaline phosphatase (fractionated if alkaline phosphatase is Grade 2 
or higher) and GGT). 
In case of any occurrence of ALT/AST/ bilirubin* increase ≥ Grade 2 the liver function tests 
must be monitored weekly or more frequently if clinically indicated until resolved to ≤ 
Grade 1 
In case of any occurrence of ALT/ AST/ bilirubin* increase ≥ Grade 3  the liver function 
tests must be monitored weekly or more frequently if clinically indicated until resolved to ≤ 
Grade 1; hereafter the monitoring should be continued every other week or more frequently 
if clinically indicated until the end of treatment with study medication. 


 
 
45 
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) during a cycle of therapy 
 
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 blood finger stick every day 
and if blood glucose levels are worsening for 2 consecutive days FPG assessment is 
recommended. 
Check FPG at least weekly for 8 weeks, then continue checking at least every 2 weeks. 
 
First occurrence: 
If signs and symptoms of hyperglycemia (e.g. mental status changes, excessive thirst, polyuria), 
omit buparlisib immediately and manage as per Grade 3 hyperglycemia. 
If asymptomatic, maintain dose and recheck FPG within 24 hours. If grade worsens to grade 3 
or 4 follow specific Grade recommendations. If grade improves to grade 1 follow Grade 
recommendations.  If FPG remains at Grade 2, reduce study drug dose to 50% of prior dose and 
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 blood finger stick every day 
and if blood glucose levels are worsening for 
2 consecutive days FPG assessment is recommended. Check FPG at least weekly for 8 weeks, 
then continue checking at least every 2 weeks. 
 
Second occurrence: 
Discontinue study drug 
 
Table 10.  Recommended dose modifications and dose delays 
for suspected buparlisib treatment-related toxicities 
Worst toxicity CTCAE grade* (value) 
During a cycle of therapy 
 
Grade 3 
(> 250-500 mg/dL) 
First Occurrence:  Immediately omit buparlisib, 
initiate or intensify medication with appropriate 


 
 
46 
(> 13.9-27.8 mmol/L) 
anti-diabetic treatment, recheck FPG within 
24 hours.  If Grade worsens to grade 4 then follow 
grade 4 recommendations. If Grade improves to 
grade 1 or 2 follow grade 1 or 2 guidelines.  If FPG 
remains at Grade 3*: 
Administer intravenous hydration and intervention 
for electrolyte/ ketoacidosis/hyperosmolar 
disturbances as clinically appropriate  
Discontinue study drug 
Monitor FPG at least twice weekly until FPG 
resolves to ≤ Grade 1 
Initiate or continue anti-diabetic  treatment as 
appropriate 
Instruct patient to follow dietary guidelines 
according to local and/ or institutional standards for 
management of diabetes mellitus (such as those 
provided by the American Diabetes Association) 
during the study Consider use of oral anti-
hyperglycemic therapy such as metformin 
Check FPG at least weekly for 8 weeks, then 
continue checking at least every 2 weeks 
For non-fasting plasma glucose >250-500 mg/dL (> 
13.9 - 27.8 mmol/L) accompanied by 
signs/symptoms of hyperglycemia (for example, 
mental status changes, excessive thirst, polyuria), 
or presence of blood or urine ketones, omit 
buparlisib and following guidance for management 
of Grade 3 fasting plasma glucose (FPG) 
 
 
Table 10.  Recommended dose modifications and dose delays 
for suspected buparlisib** treatment-related toxicities 
Worst toxicity CTCAE grade* (value) 
During a cycle of therapy 
Grade 4 
(> 500 mg/dL) (>27.8 mmol/L) 
Discontinue study drug 
Consider hospitalization if appropriate. 
Initiate or intensify medication with appropriate anti-
diabetic treatment, re-check within 24 hours, if grade 
improves then follow specific grade 


 
 
47 
recommendations.  If FPG is confirmed at Grade 4: 
Administer intravenous hydration and intervention 
for electrolyte/ ketoacidosis/hyperosmolar 
disturbances as clinically 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 
if clinically indicated 
For non-fasting plasma glucose > 500 mg/dL (> 27.8 
mmol/L) accompanied by signs/symptoms of 
hyperglycemia (for example, mental status changes, 
excessive thirst, polyuria), or presence of blood or 
urine ketones, discontinue buparlisib and following 
guidance for management of Grade 4 fasting plasma 
glucose (FPG). 
 
Cardiac 
 
Cardiac - Left Ventricular systolic dysfunction 
Grade 1 or 2 
Asymptomatic, resting ejection 
fraction 40-50%; or 10-20% drop from 
baseline 
 
Reduce buparlisib dose by 50%   
Repeat LVEF within 4 weeks or as clinically 
appropriate 
Table 10.  Recommended dose modifications and dose delays for 
suspected buparlisib** treatment-related toxicities 
Worst toxicity 
CTCAE grade* (value) 
During a cycle of therapy 
Grade 3 
Symptomatic, ejection fraction 
responsive to intervention, ejection 
fraction 20-39% or > 20% drop from 
baseline 
Discontinue buparlisib 
LVEF measurement to be repeated within 4 weeks or 
as clinically appropriate 


 
 
48 
Grade 4 
Refractory or poorly controlled heart 
failure due to drop in ejection fraction; 
intervention such as ventricular assist 
device, intravenous vasopressor 
support or heart transplant indicated; 
ejection fraction < 20% 
Discontinue buparlisib 
Hospitalize if appropriate 
*the event is considered resolved when the patient is asymptomatic, has a resting ejection fraction 
≥40% and ≤20% decrease from baseline. 
Cardiac – QTc prolongation 
Cardiac - prolonged QTc interval ≥ 
Grade 3 (QTcF > 500 msec  
or 
>60 ms from  
baseline on at least 2 separate ECGs 
taken within 1 hour) 
Refer to Table 9 Recommended dose modifications for 
sonidegib. 
Other Cardiac Events 
Grade 1 
Maintain dose level 
Grade 2 
Implement 50% dose reduction of buparlisib 
Grade 3 
Omit dose and discontinue study drug 
Table 10.  Recommended dose modifications and dose delays for 
suspected buparlisib treatment-related toxicities 
Worst toxicity CTCAE grade* (value) 
During a cycle of therapy 
Grade 4 
Omit dose and discontinue study drug 
Consider hospitalization if appropriate 
Other 
Mood alteration 
* Mood questionnaire scores should be considered when assigning the AE Grade but psychiatric 
consult, if required, may determine the grade 


 
 
49 
Grade 1  
Mild mood alteration (or Grade 2 
anxiety if present at baseline) 
Maintain dose level 
Note:  If question 9 (suicidal ideation) on the PHQ-9 
has a positive response, or worsens in severity, the 
patient should be referred for psychiatric consult 
regardless of the total questionnaire score 
Grade 2 
Moderate mood alteration (for 
Anxiety only, if worsened from 
baseline) and if there is no concurrent 
medical condition that accounts for an 
acute increase the PHQ score. 
Institute appropriate co-medication under the guidance 
of the psychiatrist. Maintain dose level. 
If the condition does not resolve to ≤ Grade 1 within 14 
days despite medical treatment; then implement 50% 
dose reduction (continue to co-medicate) 
Note:  If question 9 (suicidal ideation) on the PHQ-9 
has a positive response, or worsens in severity, the 
patient should be referred for psychiatric consult 
regardless of the total questionnaire score 
Grade 3 
Severe agitation; hospitalization not 
indicated 
Discontinue study medication 
Note: If question 9 on the PHQ-9 has a positive 
response, or worsens in severity, the patient should be 
referred for psychiatric consult regardless of the total 
questionnaire score 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
Discontinue study medication. Consider hospitalization 
if appropriate 
Note: If question 9 on the PHQ-9 has a positive 
response, or worsens in severity, the patient should be 
referred for psychiatric consult regardless of the total 
questionnaire score 
Table 10.  Recommended dose modifications and dose delays 
for suspected buparlisib treatment-related toxicities 
Worst toxicity 
CTCAE grade* (value) 
During a cycle of therapy 
Rash 
Grade 1 
Macules /papules covering <10% 
BSA with or without symptoms (e.g. 
pruritus, burning) 
Maintain dose level.  Consider to initiate appropriate 
skin toxicity therapy (such as antihistamines, topical 
corticosteroids) 


 
 
50 
Grade 2 
Macules/papules covering 10-30% 
BSA with or without symptoms; 
limiting instrumental ADLs 
Reduce study drug dose to 50% of prior dose.  
Initiate/intensify appropriate skin toxicity therapy 
(such as antihistamines, topical corticosteroids) 
Grade 3 
Macules/papules covering >30% 
BSA with or without associated 
symptoms, limiting self-care ADLs 
Discontinue study drug 
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 
Discontinue buparlisib. 
Consider if hospitalization is appropriate 
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. 
 
 
 
 
 
 
 
 
 
 
Table 10.  Recommended dose modifications and dose delays for suspected buparlisib** 
treatment-related toxicities 
Worst toxicity CTCAE grade* 
(value) 
During a cycle of therapy 
Fatigue (asthenia) 
Grade 1 
Fatigue relieved by rest 
Maintain dose level 
Grade 2 
Fatigue not relieved by rest; limiting 
instrumental ADL 
Reduce study drug dose by 50% of prior 


 
 
51 
Grade 3 
Fatigue not relieved by rest; limiting 
self care ADL 
Discontinue study drug 
Grade 4 
Discontinue buparlisib. 
Consider if hospitalization is appropriate 
Pneumonitis 
Please see Section 4.1.2.3.2; Table 14; and/or buparlisib Investigator Brochure Section 
6.2.6.1.1. 
Other adverse events 
Grade 1 
Maintain dose level 
Grade 2 
Implement 50% dose reduction 
Grade 3 
Omit dose and discontinue study drug 
Grade 4 
 
 
 
 Omit dose and discontinue 
study drug Consider if 
hospitalization if appropriate 
 
 
Other notes: 
Table 10.  Recommended dose modifications and dose delays 
for suspected buparlisib treatment-related toxicities 
Worst toxicity CTCAE grade* (value) 
During a cycle of therapy 
Note:  Omit dose for ≥ Grade 3 vomiting or Grade 3 nausea only if the vomiting or nausea 
cannot be controlled with optimal antiemetic 
All dose modifications should be based on the worst preceding toxicity. 
If the dose-limiting toxicity recurs in a patient following dose reduction, then further therapy 
with sonidegib will not be continued. 
If a patient requires a dose interruption of > 21 days from the intended day of the next 
scheduled dose because of a sonidegib-related toxicity, then the patient must be discontinued 
from the study. 
** Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 


 
 
52 
 
4.1.1       Monitoring of buparlisib suspected toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value, must be followed at least 
once a week for 4 weeks, and  subsequently  at  4-week  intervals,  until resolution  
or  stabilization  of  the  event, whichever comes first.  If a patient requires a dose 
delay of > 21 days from the intended day of the next scheduled dose, then the 
patient should be discontinued from the study.  If the patient requires more than 1 
dose reductions, the patient should be discontinued from the study (ie, patients 
cannot be treated below a 50% dose reduction).   All patients must be followed for 
adverse events and serious adverse events for 28 days following the last dose of 
buparlisib.  All SAEs must be reported to Novartis as detailed in Section 4.3.4.2. 
4.1.2       Known Undesirable Side Effects of buparlisib 
 
 
 
4.1.2.1 
Neuropsychiatric events 
 
In an ongoing phase 1a study of buparlisib in patients with solid tumors  
(CBKM120X2101), neuro-psychiatric adverse events, including reversible and 
generally mild to moderate mood alterations, described as anxiety, agitation with 
crying episodes and depression have been reported in patients treated with 
buparlisib.  In this study, three out of five patients with moderate to severe mood 
alterations had a history of depression and/or anxiety.  All patients with a 
documented medical history of depression/anxiety also developed mood alterations 
while treated with buparlisib at the 100 mg dose level 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  CTCAE  Grade ≥  2  should  
immediately  be  examined  by a psychiatrist  and  closely  followed  medically.    
Medical  treatment  with  mood stabilizers (2nd generation antipsychotics) such as 
olanzapine and quetiapine may be applied as per investigator’s discretion and 
following consultation of a psychiatrist. 
 
4.1.2.1.1 Management of mood alteration 
Patient self-rating mood questionnaires GAD-7 (anxiety) (see Table 11) and PHQ-9 
(depression) (see Table 12) will be used: 
to support assessment of eligibility at Screening 
to monitor for newly occurring or worsening mood alterations during the study.  
The following grading system will be used for this study: 


 
 
53 
At Screening, a patient as judged by the investigator or who meets the cut-off score of ≥ 12 
in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively, or select a 
positive response of ‘1, 2, or 3’ to question number 9 regarding suicidal thoughts or 
ideation will be excluded from the study. 
During the study, patients who meet the cut-off score of ≥ 10 (≥ CTCAE Grade 2 mood 
alteration) in either questionnaire or indicate a positive response by selecting ‘1, 2, or 3’ to 
question number 9 on the PHQ-9 must see a psychiatrist for advice on the most appropriate 
medical  treatment  must  see  a  psychiatrist  for  diagnosis  and determination  of  most 
appropriate medical treatment.  For anxiety, this applies only if status has worsened from 
baseline.  Patients who experience ≥ Grade 2 mood alteration will be followed by patient 
self-rating mood scale and will be seen weekly by the psychiatrist until resolved ≤ Grade 1 
or baseline (for anxiety), if there is no concurrent medical condition that accounts for an 
acute increase the PHQ score.  Questionnaire responses will be checked by the psychiatrist 
at the weekly visits (until resolution to Grade 1 or baseline (for anxiety). 
 
 
Table 11.  
GAD-7 anxiety scale 
Over the last 2 weeks, how often have you 
been bothered by the following problems?  
(Use "./"to indicate your answer" 
Not at all  
Several 
days  
More than 
half the 
days  
Nearly 
every day 
1. Feeling  nervous, anxious or on edge  
0  
1  
2  
3 
2. Not being able to stop or control worrying  
0  
1  
2  
3 
3. Worrying too much about different things  
0  
1  
2  
3 
4. Trouble relaxing  
0  
1  
2  
3 
5. Being so restless that it is hard to sit still 
0  
1  
2  
3 
6. Becoming easily annoyed or irritable  
0  
1  
2  
3 
7. Feeling afraid as if something  awful might 
happen  
0  
1  
2  
3 
 
Column  totals:  
+  
+  
+ 
= Total Score 
If you checked off any problems, how difficult have these problems made it for you to do your work, 
take care of things at home, or get along with other people? 
Not difficult at all 
Somewhat difficult 
Very 
Difficult 
Extremely 
Difficult 
Table 12. 
PHQ-9 depression scale 
Mood questionnaires will be scored according to Table 13 below. 


 
 
54 
 Table 13. 
Toxicity grading based on mood questionnaire scores 
 
PHQ-9 
 
GAD-7 
Score 
Severity 
CTCAE 
grading 
Score 
Severity 
CTCAE 
grading 
0-4 
None 
Normal 
0-4 
None 
Normal 
5-9 
Mild 
Grade 1 
5-9 
Mild 
Grade 1 
10-19 
Moderate 
Grade 2 
10-14 
Moderate 
Grade 2 
20-27 
Severe 
Grade 3 
≥ 15 
Severe 
Grade 3 
 
4.1.2.2 
Hyperglycemia 
 
In preclinical studies, insulin/glucose homeostasis was impacted in various species (mice, 
rats, dogs), as expected from the mode of action of buparlisib.  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 1a study of buparlisib in 
patients with solid tumors (CBKM120X2101).  Therefore, no patients with uncontrolled 
diabetes mellitus will be enrolled in this study.  In all patients, fasting plasma glucose will 
obtained at screening and will be monitored throughout the trial.  For the treatment of glucose 
disturbances occurring under buparlisib treatment investigators are advised to adhere to the 
protocol guidelines outlined in Table 10 and as follows. 
4.1.2.2.1 Management of Hyperglycemia 
In addition to the dose modification and hyperglycemia treatment guidelines in Tables 9 and 
10: 
Under the supervision of an endocrinologist, an insulin regimen should be initiated 
according to institutional standard of care or the Treat-To-Target algorithm for 
Lantus® (Riddle, Rosenstock, and Gerich 2003). 
For any hyperglycemia ≥ Grade 1, the patient should continue to follow dietary 
guidelines provided by the American Diabetes Association (American Diabetes 
Association 2004). 
For each patient, a maximum of 2 dose reductions will be allowed after which the 
patient should be discontinued from the study.     In addition, a patient must 
discontinue treatment with buparlisib, if after treatment is resumed at a lower dose, 
hyperglycemia recurs at a worse severity. 


 
 
55 
For each patient, once a dose level reduction has occurred, the dose level may not be 
re-escalated in that patient during future treatment cycles with buparlisib. 
Based upon the results of preliminary clinical data and actual laboratory values (eg, 
glucose, insulin) generated, the treatment recommendations for study drug-induced 
hyperglycemia may be modified as needed. 
4.1.2.3 
Cardiac events 
 
Cardiac safety studies, conducted in vitro and in vivo, did not indicate a prominent 
electrophysiological risk.   The only effect considered relevant was a trend towards an increase 
in systolic and diastolic blood pressure, observed in two dog telemetry studies.  As a 
precaution in the first-in man study with buparlisib no patients with a severe or unstable 
cardiac disease or cardiac disease requiring continuous treatment, and no patients with 
uncontrolled hypertension will be enrolled in early clinical studies.  In addition, all patients 
will be assessed for cardiac diseases before start of treatment, while all patients enrolled in the 
trial will undergo regular cardiac monitoring throughout the conduct of the trial.  For the 
treatment of acute cardiac events occurring under buparlisib treatment investigators are 
advised to adhere to the protocol guidelines.  Vital signs, including pulse rate and blood 
pressure, will closely be followed during the early clinical studies. 
 
4.1.2.3.1 Management of Cardiac events 
At  the  screening  visit  a  12-lead  electrocardiogram  (ECG), will be performed to assess 
eligibility.  
4.1.2.3.2 Guidelines for the treatment of study drug induced stomatitis/ oral 
mucositis 
General guidance and management include patient awareness and early 
intervention. Evaluation for herpes virus or fungal infection should be considered. 
Patients should be informed about the possibility of developing mouth ulcers/ oral 
mucositis and instructed to report promptly any signs or symptoms to their physician, 
Patients should be  educated  about  good  oral  hygiene,  instructed  to  avoid  spicy/ 
acidic/salty foods,  and should follow the following guidelines: 
For mild toxicity (Grade 1), use conservative measures such as non-alcoholic 
mouth wash or salt water (0.9%) mouth wash several times a day until resolution. 
For more severe toxicity (Grade 2 in which case patients have pain but are able to 
maintain  adequate  oral  alimentation,  or  Grade 3  in  which  case  patients cannot 
maintain adequate oral alimentation), the suggested treatments are topical analgesic 
mouth treatments ( ie, local anesthetics such as benzocaine, butyl aminobenzoate, 
tetracaine hydrochloride, menthol, or phenol) with or without topical 
corticosteroids, such  as  triamcinolone  oral  paste  0.1%  (Kenalog  in Orabase®),  
or  as  per  local practice. 
Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may 
tend to worsen mouth ulcers.  It is preferable to avoid these agents. 
Antifungal agents should be avoided unless a fungal infection is diagnosed as they may 
interfere with buparlisib metabolism. Oral or systemic liver enzyme inhibitors such as 
topical antifungal creams are allowed. 


 
 
56 
4.1.2.3.3 Guidelines for the Treatment of Buparlisib-induced Psychiatric 
Disorders 
 
Psychiatric adverse events will be closely monitored and evaluated at each planned visit 
until recovery to Grade ≤ 1 or baseline status.    The grading of psychiatric adverse 
events/mood alterations must be based on the clinical interpretation of severity according 
to the NCI-CTCAE (v 4.03) guidelines. 
For patients who experience new or worsening of existing psychiatric AEs of Grade  
≥1, psychiatric consultation should be considered as described in 
Table 10. 
Patient self-reported mood questionnaires (GAD-7 and PHQ-9) will be used for screening 
and during the study treatment phase to aid the investigator in identifying new or 
worsening of events.    For additional  information  regarding  safety  assessments based  
on  patient self-reported mood questionnaires, please refer to Section Patient self rating 
mood questionnaires. 
If question 9 in the PHQ-9 has a positive response (as indicated by selecting "1", "2", or 
"3"), omit treatment with buparlisib and refer the patient for psychiatric consultation for 
optimal management regardless of the total questionnaire score or CTCAE grading to 
confirm if study drug should be interrupted or permanently discontinued.  In this specific 
case, the psychiatric advice can overrule the patient’s PHQ-9 self-assessment. During the 
study, subjects will be monitored at regular scheduled visits (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.  Additional assessments may be done according to the clinical judgment of 
the investigator if desired. 
 
4.1.2.3.4 Guidelines for the Treatment of Study Drug-induced Skin Toxicity 
Skin toxicity is a class-effect observed with PI3Ki/mTORi agents.  Close monitoring of 
potential skin reactions will be performed at each planned visit and will be reported as 
adverse event.   The most frequent skin adverse events reported are: maculopapular rash 
(only  a  minority  present  acneiform  rash)  (refer  to  Table 10  for  clinical management); 
pruritus and dry skin.  The onset is typically within the first 2 months of treatment start and 
is reversible with adequate comedication and treatment interruption if needed.  
Photographs of a skin rash event as well as skin biopsy are recommended, if possible.  
According to the investigators discretion, a paired    biopsy could be obtained (from both 
an affected and an unaffected skin area for local histopathology assessment) to further 
assess rash if clinical appropriate. 
Recommended therapies for skin toxicity events (refer to Table 10 for specific guidance 
according to the type of skin toxicity): 
Topical  steroids  of  moderate  potency  (face  and  folds): triamcinolone  0.025%; 
aclometasone 0.05% (< 8 weeks continuously), for mild and moderate rashes. 
Topical steroids of high potency (trunk/extremities):  fluocinonide 0.05%; clobetasol 
0.05% cream or spray (< 8 weeks continuously), for mild and moderate rashes. 
Oral antihistamines (sedating, evening): diphenhydramine 25 to 50mg TID; 
hydroxizine 25mg TID or QID; 
Oral antihistamines (non-sedating, day time): fexofenadine 180mg QD or 60mg TID 
(monitor the use of this class of drugs since skin toxicity has also been reported) 


 
 
57 
Oral corticosteroids:  prednisone 0.5mg/kg or equivalent up to 5 days of treatment 
In case of mild acneiform rashes topical antibiotics:    clindamycin 1% to 2%; 
erythromycin 1% to 2% (gel or solution formulation can be used, ointments cannot 
be used); metronidazole 1%; silver sulphadiazine. 
For  more  severe  acneiform  rashes  oral  antibiotics:    doxycycline  100mg BID; 
minocycline  100 mg  BID;  oxytetracycline  500mg  BID  for  6  weeks can  be 
considered.   If infection suspected (yellow crusts, purulent discharge, painful 
skin/nares), then switch to broad spectrum/gram negative antibiotics; consider skin 
swab for bacterial culture. 
Topical antipruritics (pramoxine 1%, doxepin 5% cream) applied twice daily 
For severe pruritus GABA Agonists:     Gabapentin 300mg every 8 hours, or 
pregabalin 50 to 75 mg every 8 hours (to adjust of renal impairment) can be 
considered.  Dose should be adjusted depending on patient’s clinical condition be 
of potential and common side effects observed with GABA agonists such as: 
somnolence,  dizziness  (both  drugs)  and  peripheral  edema  (Gabapentin)  among 
others AEs. 
Dry skin has been reported, it is recommended that patients with dry skin use mild and 
fragrance free soaps and detergents.  According to the severity and BSA extension patients 
may apply mild moisturizers, ammonium lactate cream 12% or salicylic acid cream 6% 
BID. 
Photosensitivity has been described in patients although preclinical experiments 
demonstrated that buparlisib has no potential phototoxic effect.  Patients should be advised 
to take measures to protect themselves from direct exposure to sunlight, including regular 
use of sunscreen (factor 20 at least), wearing of sunglasses, using of hats, and protective 
clothes when outdoors. 
4.1.2.3.5 Guidelines for the management of Posterior Reversible 
Encephalopathy Syndrome (PRES) 
 
There have been rare reports of PRES occurring under treatment with buparlisib.  Signs 
and symptoms may include severe headache, confusion or seizures, altered consciousness, 
visual disturbances, with or without associated high blood pressure.  Patients are instructed 
in the written patient information to inform their treating physician if they suspect such an 
event. Take appropriate measures in such cases to assess the signs and symptoms.  If PRES 
is suspected based on the signs and symptoms, buparlisib should be interrupted and a brain 
MRI should be performed to confirm the diagnosis. 
4.1.2.3.6 Management of Pneumonitis 
 
Pneumonitis is a known side effect of rapamycin analogues.   Based on the literature, the 
class of PI3K inhibitors has not previously been associated with the development of 
pneumonitis.   Clinically significant pneumonitis typically accompanied by non-specific 
symptoms including dyspnea, nonproductive cough, fatigue, and fever.   Diagnosis is 
generally suspected in individuals who develop these symptoms or in asymptomatic 
individuals  in  whom  a  routine  chest  CT  scan  reveals  a  new  ground  glass  or 
alveolar infiltrate. 
In ongoing clinical trials with buparlisib in the single agent setting two cases of 
Pneumonitis occurred.  In the study BKM120X2101 one patient experienced pneumonitis 


 
 
58 
Grade 2 eight weeks after the first dose of buparlisib at 100mg which resolved in 7 days 
after antibiotic therapy and discontinuation of the study treatment due to fatigue.   In the 
Japanese study BKM120X1101 one case of Pneumonitis occurred in a patient given 100 
mg one month after the start of study medication with buparlisib.   The patient experienced 
Pneumonitis with fatal outcome which was concomitant to progression of underlying 
malignancy including the progression of existing and the appearance of new lesions in 
combination with increasing pleural effusion (see Buparlisib Investigator Brochure). 
All patients participating in clinical trials administering buparlisib will be routinely asked 
about the occurrence of adverse events which could include new or changed pulmonary 
symptoms (consistent with lung abnormalities).  CT scans and pulmonary function test 
should be done, as clinically indicated, or if there are symptoms that indicate that the 
patient has developed Pneumonitis.  In case of a documented pneumonitis, the guidelines 
(including dose modifications) in Table 14 should be followed.  Consultation with a 
pulmonologist is highly recommended for any pneumonitis case identified during the 
study. 
 
Table 14.        Management of Pneumonitis 
Worst  
Grade  
Pneumonitis 
Required 
Investigations 
Management  
of  
Pneumonitis 
Buparlisib 
Dose Adjustment 
Grade 1 
CT scans with lung 
windows.  Repeat at least 
every 8 weeks until return 
to within normal limits. 
No specific 
therapy 
is 
required 
Administer 100% of 
buparlisib dose. 
Grade 2 
CT scan with lung 
windows. Consider 
pulmonary function 
testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat at least every 
8 weeks until return to 
within normal limits. 
Consider a bronchoscopy 
with biopsy and / or BAL. 
Symptomatic 
only.  Consider 
corticosteroids 
if symptoms are 
troublesome. 
Reduce buparlisib dose 
50% (see Table 10) 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 
1within 
3 weeks. 


 
 
59 
Grade 3 
CT scan with lung 
windows and pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest.  Repeat at least every 
6 weeks until return to 
within normal limits.  
Bronchoscopy with biopsy  
and / or BAL is 
recommended. 
Consider 
corticosteroids 
if 
infective 
origin is ruled 
out.  Taper as 
medically 
indicated. 
Hold treatment with 
buparlisib until recovery 
to 
≤ Grade 1.  May restart 
study treatment within 
3 weeks at a 
50% dose reduction if 
evidence of clinical 
benefit. 
Grade 4 
CT scan with lung 
windows and required 
pulmonary function 
testing, if possible, 
includes: spirometry,  
DLCO, and room air O2 
saturation at rest. Repeat 
at least every 6 weeks 
until return to within 
normal limits. 
Bronchoscopy with 
biopsy and / or BAL is 
recommended if 
possible. 
Consider 
corticosteroids 
if 
infective 
origin is ruled 
out.  Taper as 
medically 
indicated. 
Discontinue treatment 
with buparlisib. 
 
4.1.2.3.7 Management of Liver Toxicities 
 
Monitoring Cycle 1 and 2: every other week (if visit schedule allows a more frequent 
monitoring this should be considered) or more frequently if clinically indicated especially 
for patients with borderline acceptable AST/ ALT/ bilirubin* values. 
Monitoring Cycle 3 and more: monthly or more frequently if clinically indicated.  In case 
of any occurrence of ALT/ AST/ bilirubin* increase ≥ Grade 2 the liver function tests 
must be monitored weekly or more frequently if clinically indicated until resolved to ≤ 
Grade 1. 
In case of any occurrence of ALT/ AST/ bilirubin* increase ≥ Grade 3 the liver function 
tests must be monitored weekly or more frequently if clinically indicated until resolved to 
≤ Grade 1;  hereafter  the  monitoring  should  be  continued  every  other  week  or more 
frequently if clinically indicated until the end of treatment with study medication. 
Patients who discontinued study treatment should be monitored weekly, including LFTs* 
or more frequently if clinically indicated until resolved to ≤ Grade 1 or stabilization (no 
CTCAE grade change over 4 weeks). 
4.1.2.4 
Study discontinuation 


 
 
60 
 
All interruptions or changes to study drug administration must be recorded. 
It will be documented whether or not each patient completed the clinical study.  If for any 
patient either study treatment or observations were discontinued the reason will be 
recorded. Reasons that a patient may discontinue participation in a clinical study are 
considered to constitute one of the following: 
1. adverse event(s) 
2. abnormal laboratory value(s) 
3. abnormal test procedure result(s) 
4. disease progression 
5. protocol violation 
6. subject withdrew consent 
7. lost to follow-up 
8. administrative problems 
9. death 
4.2 Treatment Administration 
4.2.1 
Buparlisib Administration 
 
The study drug buparlisib will be self-administered (by the patients themselves).   The 
investigator will instruct the patient to take the study drug exactly as specified in the 
protocol.  Buparlisib will be administered on a continuous once daily dosing schedule at a 
dose of 80mg daily.   Patients should be instructed to take the dose of buparlisib with 
Sonidegib (see below) daily in the morning, two hours after a light breakfast (morning 
meal) at approximately the same time each day.  Buparlisib 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 buparlisib dose. 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose.  The occurrence and frequency of any vomiting during a 
treatment cycle must be noted as an adverse event.   If the patient forgets to take her/his 
dose before 6:00 PM, then the dose should be withheld that day and buparlisib 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 buparlisib dose delay of > 21 days from the 
previous dose, the patient must be discontinued from treatment completely and will only 
require a 28-day follow up visit for study completion. 
Medication labels will comply with US legal requirements and be printed in English. They 
will supply no information about the patient.  The storage conditions for study drug will be 
described on the medication label. 
 
4.2.2 Sonidegib Administration 


 
 
61 
 
The investigator needs to instruct the patient to take the study drug as per protocol. All 
dosages prescribed and dispensed to the patient and any dose change or interruption must 
be recorded in the dosage administration record CRF, as appropriately.  
 
Sonidegib Treatment and Treatment Schedule 
Study 
treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
regimen 
Sonidegib 
Capsule or tablet for oral use 
200 QD 
daily 
Sonidegib will be administered orally with buparlisib, on a continuous once daily dosing 
schedule at a dose of 200 mg.  Participating patients will receive flat doses on mg/ day 
basis and not according to their body weight or body surface area.   Sonidegib is supplied 
as 200-mg hard gelatin capsules or tablets.   Patients will receive 2 capsules or tablets. The 
shelf-life and storage conditions will be continually assessed based on accelerated and long 
term stability data Sonidegib.  Medication labels will be in the local language (English) 
and comply with the legal requirements of USA. 
Sonidegib should be taken as follows: 
Patients should be instructed to take their once-a day dose at approximately the 
same time each day 
Each daily dose of Sonidegib should be taken with a glass of water and consumed 
over as short a time as possible (eg, 1 capsule every 2 minutes) 
Patients should be instructed to swallow capsules whole and to not chew or open 
them 
Each daily dose of Sonidegib should be taken 2 hours after a light breakfast (eg, 
consisting of juice, toast and jam).   If breakfast was completed at 08:00 a.m., then 
study drug administration should occur at 10:00 a.m.  Food intake should be 
avoided for at least 1 hour after study drug administration 
Patients must avoid grapefruit, pomegranate, star fruit and Seville (sour) oranges 
during the entire study.  The juices and products containing these fruits may also be 
avoided. 
If vomiting occurs during the course of the treatment, then no re-dosing of the 
patient is allowed before the next scheduled dose 
If the patient forgets to take his/her daily morning dose, then he/she should take 
Sonidegib within 6 hours after the missed dose.  If more than 6 hours have passed, 
then that day’s dose should be omitted and the patient should continue treatment 
with the next scheduled dose.  Patients should inform the investigational site staff 
of any missed or delayed dose.  Clinical drug supply must be accounted for and 
patients will be asked to return all unused study drug and packaging on a regular 
basis, at the end of the study or at the time of study drug discontinuation. 
At the conclusion of the study, and, as appropriate during the course of the study, the 
Investigator will return all used and unused study drug, packaging, drug labels, and a copy 
of the completed drug accountability ledger to Novartis. 


 
 
62 
4.2.3       Concomitant therapy 
All medications (excluding prior chemotherapy and biologic, immunologic or radiation 
therapy) taken within 4 weeks prior to the administration of buparlisib/sonidegib and all 
concomitant therapy administration during the study with reasons for therapy should be 
recorded.  All prior chemotherapy; biologic, immunologic or radiation therapy; and 
surgery within 4 weeks prior to the administration of study drug, will be recorded. 
Patients on chronic medications that can be given concomitantly with buparlisib/ sonidegib 
should be maintained on the same dose and dose schedule throughout the study period, as 
medically feasible.  The investigator should instruct the patient to notify the study site 
about any new medications he/she takes after the start of the study drug.  All medications 
(other than study drug) and significant non-drug therapies (including herbal medicines, 
physical therapy and blood transfusions) administered after the patient starts treatment with 
study drug, and any changes in dosing should be recorded. 
In general, the use of any concomitant medication/therapies deemed necessary for the care 
of the patient is permitted with the following exceptions described below in Section  
 
4.2.3.1 
Drugs that are prohibited 
 
Other investigational therapies must not be used while the patient is on the study. 
Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) 
other than the study treatments must not be given to patients while the patient is on 
the study.  If such agents are required for a patient then the patient must be 
discontinued from the study. 
In vitro metabolism studies suggest that oxidative metabolism of buparlisib is 
predominantly mediated by CYP3A4 (fm>0.9), with only minor contributions of 
CYP1A1.  As buparlisib is a sensitive CYP3A4 substrate, co-administration of 
buparlisib with strong and moderate CYP3A4 inhibitors and CYP3A4 inducers is 
prohibited.  Refer to Table 15 for a list of prohibited drugs.  Please note this list 
may not be comprehensive. 
Based on in vitro studies, co-administration of buparlisib with CYP3A4 inducers 
is predicted to decrease the systemic exposure to buparlisib, thereby increasing the 
risk of exposing the patient to subtherapeutic drug levels.  Refer to Table 15 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 16 
entitled “List of Prohibited QT prolonging drugs” (ie, 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, ginsing.  Patients should stop using these herbal medications 7 
days prior to first dose of study drug. 


 
 
63 
Hormonal contraceptives may be affected by cytochrome P450 interactions, and 
are therefore not considered effective in this study. 
 
 
 
 
 
 
 
 
 
 
Table 15. 
List of prohibited CYP3A Inhibitors and Inducers 
CYP3A Inhibitors 
CYP3A Inducers 
Strong 
Moderate 
Strong 
Moderate 
clarithromycin 
conivaptan  
grapefruit juice 
Indinavir itraconazole 
ketoconazole  
Lopinavir Mibefradil 
nefazodone Nelfinavir 
posaconazole 
Ritonavir Saquinavir 
telithromycin 
troleandomycin 
voriconazole 
aprepitant atazanavir 
cimetidine 
ciprofloxacin 
darunavir diltiazem 
erythromycin 
fluconazole 
tofisopam verapamil 
amprenavir 
fosamprenavir 
elvitegravir 
tipranavir 
avasimibe 
carbamazepine  
Phenobarbital 
(barbiturate) 
phenytoin rifabutin  
rifampin St 
John's Wort 
bosentan efavirenz 
etravirine 
modafenil nafcillin 
ritonavir talviraline  
tipranavir 
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 
buparlisib AUC > 5-fold, and moderate inhibitors are predicted to increase buparlisib AUC ≥ 
2-fold but < 5-fold. 
This database of CYP inducers was compiled from the FDA’s “Guidance for Industry, 
Drug Interaction Studies;” from the Indiana University School of Medicine’s “Clinically 
Relevant” Table; and from (Pursche et al.  2008). 
All QT-prolonging drugs listed in Table 4-8 are prohibited for all patients from 
screening through permanent discontinuation of study treatment.   Table 16 below 
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. 
 


 
 
64 
 
Table 16. 
List of prohibited QT-prolonging drugs 
Drug 
QT risk(*) 
Comment 
Amiodarone 
Known risk for TdP 
Females > Males, TdP risk regarded as low 
Arsenic trioxide 
Known risk for TdP 
 
Astemizole 
Known risk for TdP 
No Longer available in U.S. 
Bepridil 
Known risk for TdP 
Females>Males 
Chloroquine 
Known risk for TdP 
 
Chlorpromazine 
Known risk for TdP 
 
Cisapride 
Known risk for TdP 
Restricted availability; Females > Males. 
Disopyramide 
Known risk for TdP 
Females > Males 
Dofetilide 
Known risk for TdP 
 
Domperidone 
Known risk for TdP 
Not available in the U.S. 
Droperidol 
Known risk for TdP 
 
Halofantrine 
Known risk for TdP 
Females>Males 
Haloperidol 
Known risk for TdP 
When given intravenously or at higher-than-
recommended doses, risk of sudden death, 
QT prolongation and torsades increases. 
Ibutilide 
Known risk for TdP 
Females>Males 
Levomethadyl 
Known risk for TdP 
 
Mesoridazine 
Known risk for TdP 
 
Methadone 
Known risk for TdP 
Females > Males 
Pentamidine 
Known risk for TdP 
Females > Males 
Pimozide 
Known risk for TdP 
Females > Males 
Probucol 
Known risk for TdP 
No longer available in U.S. 
Procainamide 
Known risk for TdP 
 
Quetiapine 
Possible risk for 
TdP 
Prohibited as this drug is a sensitive 3A4 
substrate 
Quinidine 
Known risk for TdP 
Females > Males 
Sotalol 
Known risk for TdP 
Females > Males 
Sparfloxacin 
Known risk for TdP 
 
Tacrolimus 
Possible risk for 
TdP 
Prohibited as this drug is a sensitive 3A4 
sibstrate with narrow TI 


 
 
65 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
 
Drug 
QT risk(*) 
Comment 
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 5fold 
or higher when co-administered with a potent inhibitor of the respective enzyme. 
4.2.3.2 
Drugs to be used with caution 
 
Preliminary  in  vitro  metabolism  studies  suggest  that  buparlisib  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 17 for a list of CYP450 substrates and carefully 
consider their co-administration with buparlisib. 
Particularly, caution is advised when buparlisib is coadministered 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 16 for a list of QT-prolonging medications to be used with caution. 
Note:  please refer also to Table 16 for a list of prohibited QT prolonging medication. 
Please refer to Table 17 for a list of CYP450 substrates and carefully consider 
their co-administration with buparlisib. 
Concomitant treatment with corticosteroids and buparlisib should be avoided, 
whenever possible, during this study.  A short duration (< 2 weeks) of systemic 
corticosteroids is allowed (eg, for chronic obstructive pulmonary disease, or as an 
anti-emetic).     Chronic  dosing  of corticosteriods  is  known  to  induce  CYP3A 
enzymes,  thereby increasing the risk  or  reducing  buparlisib  overall  exposure to 
sub-therapeutic levels. 
 
 


 
 
66 
 
Table 17.        List of CYP450 Substrates to be used with caution 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A** 
CYP2C8 
CYP2C9 
CYP2C19 
 
 
CYP3A** 
amodiaquine 
cerivastatin 
pioglitazone 
repaglinide 
rosiglitazone 
torasemide 
troglitazone 
celecoxib 
diclofenac 
flurbiprofen 
fluvastatin 
Glibenclamide 
(glyburide) 
gliclazide 
glimepiride 
glipizide 
indomethacin 
irbesartan 
ketobemidone 
lornoxicam 
losartan 
meloxicam 
naproxen 
nateglinide 
piroxicam 
rosiglitazone S-
ibuprofen 
sulfamethoxazo le 
tenoxicam 
tolbutamide 
torasemide 
valdecoxib 
amitriptyline 
citalopram 
clobazam 
clomipramine 
clopidogrel 
diazepam 
fluoxetine 
imipramine 
lansoprazole 
mephobarbital 
moclobemide 
omeprazole 
pantoprazole 
progesterone 
quazepam 
rabeprazole  
sertraline 
S-mephenytoin 
Adinazolam  
alfentanil 1,2 Alpha-  
dihydroergocryptine  
1 
Alprazolam 
Amlodipine 
Aripiprazole  
Atorvastatin 
Brecanavir brotizolam 
1 budesonide 1 
buspirone 1 
Capravirine  
Cerivastatin  
Chlorpheniramine 
cyclosporine 2 
darifenacin 1 
Diazepam 
diergotamine 2 
ebastine 1 eletriptan 1 
eplerenone 1 
ergotamine 2 
Estazolam everolimus 
1 
felodipine 1 
fentanyl 2 
flunitrazepam 
fluticasone 1 
lovastatin 1 
maraviroc 1 
midazolam 1 
nifedipine 
nisoldipine 
nitrendipine 
perospirone 1 
quinine 
sildenafil 1 
simvastatin 1 
sirolimus 1,2 
tolvaptan 
trazodone 
triazolam 1 
 
 
 Table 17. 
List of CYP450 Substrates to be used with caution (continued) 
* 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. 


 
 
67 
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 (eg, Torsades de Pointes). 


 
 
68 
 
 
Table 18. 
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 
 


 
 
69 
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 
 
Drug 
QT risk 
Comment 
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 
 
Drug 
QT risk 
Comment 
 
Octreotide 
Possible risk for Torsades de Pointes 
 
Ofloxacin 
Possible risk for Torsades de Pointes 
 


 
 
70 
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 
 
 
 
 
 
 
 
 
 
 
 


 
 
71 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
72 
4.3 
Visit schedule and assessments  
4.3.1 Evaluation and Visit Schedule (Table 19) 
 
Examination 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 to Cycle n 
Day of Cycle 
-21 
1 
 (Baseline) 
15 
1 
15 
3 
4 
5 
6 
7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(with 72 hours of 1st 
treatment  for WOCBP) 
                                                                
                                                                               As clinically indicated.  
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(including skin rash 
assessment) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Performance Status 
ECOG 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Neuro-psychiatric 
assessment (self-rating 
mood questionnaire GAD 
and PHQ) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Examination 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 to Cycle n 
Day of Cycle 
-21 
1 
 (Baseline) 
15 
1 
15 
3 
4 
5 
6 
7 
12-lead ECG* 
X 
 
As clinically indicated.  
Chest X-Ray  (if locally 
advanced disease only) 
X 
 
Every 8 weeks from start of treatment until progression as per RECI


 
 
73 
Radiological tumor 
assessment/response 
assessment (CT or MERI 
Scans if no clinically 
visible)** 
X 
 
 
 
 
X 
 
X 
 
X 
Hematology* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Profile* 
X 
 
 
X 
 
 
X 
 
X 
 
Fasting plasma glucose* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HgA1C* 
X 
 
 
 
 
X 
 
 
X 
 
Tumor biopsy for 
biomarkers3 
X 
 
 
 
 
X 
 
 
X 
 
* Can use screening if w/in 72 hours of baseline.  
 **Screening radiological assessments should be performed within 4 weeks of the 
first dose.   Radiological tumor assessment should be performed at baseline within 
28 days before start of treatment and subsequently every 8 weeks, until progression 
of disease or end of treatment. If stable after cycle 4, then CT scan to be performed 
every 12 weeks instead.  All assessments should be performed within ±7 days of the 
scheduled day of assessment.   The assessment at the EOT visit is only to be 
performed if the prior assessment occurred ≥ 21 days before. 
3 Tissue samples at baseline, week 12 and 24 (or EOT, whichever occurs first) 
will be taken and sent for whole exome sequencing, gene expression profiling 
and immunohistochemistry if accessible to tumor biopsy. 
  
4.3.2       Efficacy assessments 
Efficacy will be assessed on the basis of clinical examination using calipers if the target 
tumor is visible on the skin. If it is not visible on the skin tumor imaging will be used to 
assess   the   single   longest   diameter   for   the   basis   of   efficacy   assessment.   (see 
4.3.1 Evaluation and Visit Schedule (Table 19).  Tumor response by RECIST 1.1 criteria 
will be used for evaluation. 
4.3.3       Safety assessments 
Patients enrolled in this clinical trial will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this study (see 
Study Calendar).  Safety evaluations will consist of tumor assessments performed every 4 
weeks, routine hematology, comprehensive metabolic profiles, EKGs and urinalysis. 


 
 
74 
To date, Sonidegib has been shown to be well-tolerated in early phase clinical studies with 
the most common side effects consisting of fatigue, nausea, vomiting, anorexia, muscle 
cramps, and dysgeusia (5).  To date, the most common adverse events of patients on 
buparlisib ( ≥ 15%), regardless of grade and causality, reported in any treatment cycle were 
decreased appetite (45.5%), nausea (39.4%), constipation, diarrhea, fatigue (each 31.8%),  
rash  (30.3%),  hyperglycemia  (27.3%),  asthenia  (25.8%),  abdominal  pain, vomiting 
(each 22.7%), anxiety (21.2%), depression (19.7%), mucosal inflammation, pruritus 
(each18.2%), dyspnea (16.7%), AST increase, dry skin, dyspepsia, pyrexia, and 
somnolence (each 15.2%), data provided by Novartis. 
It is possible that the combination of the two medications, Sonidegib and buparlisib may 
lead to additive or synergistic side effects.  Independently, both medications are known to 
cause frequent gastrointestinal side effects such as nausea and vomiting and the 
concomitant administration of both may compound these side effects. 
All adverse events will be attributed to LB therapy unless they can be clearly attributed to 
progression or to another clearly identified etiology by the investigator.  Adverse events 
will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events Version 3.0. 
Intolerable toxicities are defined as new (not present at baseline) Grade 3 or 4 adverse 
events deemed to be related to LB therapy that are life threatening or irreversible, and 
when (in the opinion of the investigator) the risks outweighs the benefit of continued 
treatment. 
Women of childbearing potential will be required to have a negative serum pregnancy test 
at screening, urine pregnancy test on Day 1 and every 4 weeks while on study.  Women of 
childbearing potential or male patients with female partners of childbearing potential are 
required to use a highly reliable method of contraception, and for 12 weeks after 
discontinuation of LB therapy.  Patients must agree not to donate bodily fluids for 12 
months after discontinuation of LB therapy. 
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/ctc.htm#ctc_40). 
 
4.3.4       Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will 
be recorded during the study.  Drug accountability will be noted and patients will be asked 
to return all unused study medication. 
4.3.4.1 
Adverse events 
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical  condition  occurring  after  starting  the  study  drug  even  if  the  event  is  not 
considered to be related to study drug.  Medical conditions/diseases present before starting 


 
 
75 
study drug are only considered adverse events if they worsen after starting study drug. 
Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, are considered clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit during the study.  Adverse events also may be detected when they are 
volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments.   As far as possible, each adverse event should be 
evaluated to determine: 
1. the severity grade (mild, moderate, severe) or (Grade 1-4) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication 
taken; 
non-drug 
therapy 
given; 
hospitalization/prolonged 
hospitalization) 
5. whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately.  Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, 
or any other medically required intervention.   Once an adverse event is detected, it should 
be followed until its resolution, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the study 
drug, the interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can 
be found in the Investigators’ Brochure.   This information should be included in the 
patient informed consent and should be discussed with the patient during the study as 
needed. 
 
4.3.4.2 
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, ie, 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 


 
 
76 
after the patient has provided informed consent and until 4 weeks after the patient 
has stopped study treatment/participation 
after the patient begins taking study drug and until 4 weeks after the patient has 
stopped study treatment 
after protocol-specified procedures begin (eg, 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 (eg, 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 
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. 
4.3.5 
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  


 
 
77 
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 (eg, treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only 
be reported if a relationship to the Novartis study drug (or therapy) is suspected. 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
4.3.5.1 
Pregnancies 
 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported 
to Novartis within 24 hours of learning of its occurrence.  The pregnancy should be 
followed up for 3 months after the termination of the pregnancy to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the Novartis study treatment of any pregnancy 
outcome.  Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 
Pregnancy outcomes must be collected for the female partners of any males who took 
study treatment in this study.   Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother. 
The team needs to prepare information for the female partner of the male patient on 
required contraception.  This information needs to be given to the male patient at the ICF 
signing for him to share it with his female partner. Information for female partners of male 
study participants 
Your male partner is offered to participate in a clinical research study.  As a prerequisite to 
participate in this study your partner must agree to use a condom during intercourse.  This 
is important because test results of the study treatment in pregnant animals indicated that 
the medicine can harm an unborn baby through the sperm.   At the same time it is also 
important that you do not become pregnant while your partner is taking the medication. 
Therefore, you should use a highly effective method of birth control (contraception) during 
the time your male partner receives the study treatment and thereafter for another 3 months.  
Highly effective methods of contraception are those methods of birth control that have less 
than 1% of unwanted pregnancy during one year, if used appropriately according to the 
instructions of the manufacturer. Those methods are the following (a+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 


 
 
78 
Oral contraception, injected or implanted hormonal methods are not allowed as 
buparlisib potentially decreases the effectiveness of hormonal contraceptives. 
Fertile males, defined as all males physiologically capable of conceiving offspring 
must use condom during treatment, for 4 weeks (5 T1/2) after stopping treatment 
and for additional 12 weeks (16 weeks in total after study drug discontinuation) and 
should not father a child in this period. 
Female partner of male study subject should use highly effective contraception 
during dosing of any study agent and for 16 weeks after final dose of study therapy. 
For details on the most appropriate contraception you may talk to your regular doctor or if 
your male partner agrees with the study doctor. 
If you get pregnant despite taking the birth control precautions, please ask your partner to 
inform the study doctor as soon as possible.  The study doctor will ask your permission to 
collect information about you, your pregnancy and your child. 
4.3.5.2 
Laboratory evaluations 
 
Pregnancy Test 
A serum pregnancy test (β-HCG) is required for all women of child-bearing potential at 
screening, within 72 hours prior to the first dose of buparlisib.  Note: Postmenopausal 
women must have been amenorrheic for ≥ 12 months in order to be considered “of non-
childbearing potential”.  This should be documented appropriately in the patient’s medical 
history.  Additional pregnancy tests should be performed as clinically indicated. Will 
continue to check pregnancy tests once a month while in study. 
 
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. 
 
Coagulation Profile 
The coagulation profile includes prothrombin time or INR, and activated partial 
thromboplastin time.  
 
Serum chemistry 
 
Biochemistry includes the following parameters: K+, Na+, Ca++, Mg++, LDH, ALT,  
AST, total bilirubin (direct and indirect), creatinine, creatinine kinase, 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 every visit including baseline and 
end of treatment.   Subsequent assessments always include K+, Na+, Ca++, ALT, AST, 
total bilirubin (direct and indirect), creatinine, creatinine kinase, 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 


 
 
79 
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. 
 
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. 
 
4.3.5.3 
Vital signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight.  Blood pressure, pulse and respiration rate should be measured on 
patients after at least 3 minutes in the sitting position as per the visit schedule. 
4.3.5.4 
Physical examination 
Physical examination will be performed which must comprise a  total body examination 
(general appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities and basic nervous system).  Significant findings 
made after the start of study drug which meet the definition of an Adverse Event must be 
recorded.  Tumor exam will be done at each visit and will include measurements of single 
largest diameter of visible tumor or radiographic imaging for tumors that are not clinically 
visible. 
4.3.5.5 
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 
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). 
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.  This will be done as 
an online HIPPA compliant survey tool through Stanford. 
4.3.5.6 
ECG/ECHO 
A standard 12 lead ECG is to be performed at screening and as clinically indicated. 
An echocardiogram (ECHO) or MUGA will   be performed to assess eligibility. 
ECHO/MUGA will be repeated at Cycle 4 and then every 4th cycle thereafter. 
4.3.5.7 
Performance status 


 
 
80 
Performance status will be assessed at screening and per the visit schedule.  ECOG will be 
used for assessment (See Appendix A). 
4.3.5.8 
Special tests 
 
Chest X-ray 
Will be performed at baseline and every 8 weeks for monitoring per standard protocol. 
 
CT scan 
Will  be  performed  at  baseline,  at  4  weeks  and  every  8  weeks  thereafter  for  tumor 
assessment of non-visible tumors per RECIST 1.1 protocol. If CT scans show stability 
after cycle 4, then CT scan to be performed every 12 weeks instead. 
Biomarkers 
Tissue samples at baseline, week 12 and 24 (or EOT, whichever occurs first) will 
be taken and sent for whole exome sequencing, gene expression profiling and 
immunohistochemistry.    Whole exome sequence will include interrogation for 
DNA mutations in the tumor and peripheral blood.  Gene expression analysis will 
identify increases or decreases in pathways including Hedgehog and PI3K. 
Immunohistochemistry to quantify protein levels of Gli 1,2, Ptch 1,2, PI3K in semi-
quantitative fashion will be performed to confirm expression analysis results. 
Whole exome sequencing and gene expression analysis may identify novel 
resistance mechanisms in these BCCs that would be useful to inform future clinical 
trials 
5 
Investigational agent sampling and shipping information 
Martha Hamilton, PharmD, or her designated associate will receive study medications at 
the Stanford Investigational Pharmacy, Redwood City, CA. 
5.1        Investigational treatment 
For this study, the terms “investigational drug”, “study drug” or “study treatment” refers to 
the combination of Sonidegib and buparlisib.  If an individual drug is to be referenced the 
individual name will be present.  
 
5.2        How supplied 
buparlisib and Sonidegib will be dispensed at the start of every cycle, as needed. 
5.2.1       Buparlisib 
Novartis supplies buparlisib as 10-mg and 50-mg hard gelatin capsules.  buparlisib will be 
administered orally once a day, as part of each 28-day cycle.  Medication labels comply 
with the legal requirements of each country and will be printed in the local language.  The 
storage conditions for study drug will be described on the medication label. 


 
 
81 
5.2.2       Sonidegib 
Sonidegib will be supplied to the study investigators by Novartis.  Sonidegib is formulated 
in capsules and tablets of 200-mg, strengths.  The capsules are packaged in HDPE bottles 
with a child resistant closure.  Sonidegib will be administered orally once a day, as part of 
each 28-day cycle. 
Medication labels will conform to local legal requirements.  Patient number will be added 
by the site pharmacist.   The storage conditions for study drug will be described on the 
medication label.  Sonidegib will be dispensed at the start of every cycle, as needed. 
Sonidegib will be administered orally once a day, as part of each 28-day cycle.  The 
investigational site staff will inform each patient of their actual daily dose, and this will be 
recorded on the appropriate CRF. 
When possible, individual doses will consist of the minimum number of capsules equaling 
the total dose given the available capsule sizes. 
Doses for more than 7 days will be placed at 40 and patients will be informed of this at drug 
dispensing. 
 
5.3        Storage and Preparation 
The study drugs must be received at the study site by a designated person, handled and 
stored safely and properly, and kept in a secured location to which only the pharmacist and 
designated assistants have access.  Upon receipt, the investigational drugs should be stored 
according to the instructions specified on the drug labels.  Clinical supplies are to be 
dispensed only in accordance with the protocol. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability ledger.   Drug accountability will be noted by the field monitor 
during site visits and/or at the completion of the study.  All drug supplies are to be used 
only for this protocol and not for any other purpose.  Unless specifically instructed by 
Novartis, the investigator must not destroy any drug labels, or any partly used or unused 
drug supply.   Only after receiving written authorization by Novartis, the investigator  will  
be instructed to  either send  all  of the unused  and  partly used drug supplies  as  well  as  
the  empty  containers  to  the  address  provided  at  the  time  of authorization for 
destruction or to dispose of unused drug according to local regulations. 
5.4        Disposal and destruction 
The drug supply will be destroyed at a Novartis facility, Drug Supply group or third party, 
as appropriate.  Study drug destruction at the investigational site will only be permitted if 
authorized by Novartis in a prior agreement and if permitted by local regulations. 
6 
Data management 
6.1          Data collection 
Investigators must record the information required by the protocol. The following analysis 
sets will be used for statistical analysis and data reporting. 
The Full Analysis Set (FAS) consists of all patients who receive at least one (full or 
partial) dose of buparlisib and/or Sonidegib.  Patients will be classified according to the 
assigned treatment. 
Patients who are screened but never start treatment will be listed and will not be included 
in any of the summary tables. 


 
 
82 
The Safety Set consists of all patients who receive at least one (full or partial) dose of 
buparlisib and/or Sonidegib and have at least one valid post-baseline safety assessment. 
The statement that a patient has no adverse events (on the Adverse Event CRF) constitutes 
a valid safety assessment. 
Patients will be classified according to treatment received, where treatment received for 
each drug is defined as (i) the treatment assigned if it was received at least once, or (ii) the 
first treatment received when starting study medication if assigned treatment is never 
received.  Each patient will be classified into and analyzed consistently within one (and 
only one) treatment group. 
The Dose-determining Set consists of all patients from the safety set who either meet the 
minimum exposure criterion and have sufficient safety evaluations (as determined by the 
investigators and Novartis), or have experienced a DLT during the first two cycles.  This 
constitutes an evaluable patient for the determination of MTD. 
A patient is considered to have met the minimum exposure criterion at a treatment group if 
a patient has been treated with at least 75% (ie, 42 days) of the planned 8 weeks (56 days) 
doses of buparlisib and Sonidegib and the patient has been observed for at least 8 weeks 
following the first dose, and has completed sufficient safety evaluations, as agreed by the 
investigators and the Sponsor, to determine whether a DLT has occurred or not. 
The Biomarker Analysis Set (BAS) consists of all patients who receive at least one (full 
or partial) dose of buparlisib and LDE255 and provided at least one evaluable biomarker 
data. 
 
6.1.1       Variables 
• overall response rate (ORR) of LB therapy for patients with locally advanced or 
metastatic  BCC  in  Smoothened  inhibitor  naive  patients  (Cohort  1)  and  those  
whose disease is refractory or relapsed on Smoothened inhibitor monotherapy (Cohort 2). 
• median duration of response, on or after LB therapy 
• frequency and severity of adverse events, including serious adverse events of LB therapy 
• semi-quantitative  evaluation  of  immunostaining  for  biomarkers  including  Gli  1,  2, 
PTCH, Sufu, Smoothened, PI3K markers and gene expression profiles at baseline and 
following 12 weeks of treatment 
6.2        Analysis of the primary and key secondary variable(s) 
Primary variables 
Overall Response Rate by RECIST criteria will be assessed for cohorts 1 and 2. 
Secondary variables 
Median duration of response will be assessed for cohorts 1 and 2. 
Frequency of adverse events on LB therapy 
Changes in gene expression profiles of BCCs including Hedgehog pathway and PI3K 
pathways 
Correlation of particular gene expression profiles and response to LB therapy 


 
 
83 
7 
Statistical methods 
7.1        Statistical Methods 
7.1.1      Statistical model, hypothesis, and method of analysis 
This is an exploratory study to assess the Overall Response Rate (ORR) and median 
duration of response (DOR) for LB therapy after 12 weeks of treatment.  Cohort 1 and 2 
will not be compared directly but will be described separately, due to sample size 
limitations. 
Effect on Progression Free Survival and Overall Survival is beyond the scope of this 
proposal due to sample size necessary for sufficient power would require multi-center 
studies. 
7.1.2    Handling of missing values/censoring/discontinuations 
Patients will not be replaced in this protocol.    However, additional patients may be 
enrolled to ensure an adequate number of evaluable patients. 
As of the date of data-cutoff for the purposes of reporting: 
Patients continuing to receive study drug will have time-to-event data (eg, progression 
free survival, duration of response, etc.) censored at the date of last radiological disease 
assessment prior to the cut-off date. 
Continuing events (eg, adverse events, concomitant medication, etc.)  will  be 
summarized  using  the  data  cut-off  date  as  the  date  of  completion,  with  an 
indication within listings that the event is continuing. 
For patients who discontinue the study with ongoing events, the discontinuation date will be 
used as the completion date of the event with the appropriate censoring as described in the 
above paragraph. 
The reason for discontinuation from study will be summarized and listed, along with dates 
of first and last study drug, duration of exposure to study drug and date of discontinuation 
for each patient, by dose cohort in the core safety report and by dose-expansion part in the 
extension report 
8 
References 
Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J, Bernier G (2009) BMI1 
sustains human glioblastoma multiforme stem cell renewal.   J Neurosci Jul 15; 29(28): 
8884-96. 
Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, 
DiMeco F, Olivi A, Eberhart CG (2007) Cyclopamine-mediated hedgehog pathway 
inhibition depletes stem-like cancer cells in glioblastoma.    Stem Cells; Oct 25(10): 2524-
33. 
Berman  DM,  Karhadkar  SS,  Hallahan  AR,  et al  (2002)  Medulloblastoma  growth 
inhibition by hedgehog pathway blockade.  Science; 297: 1559-1561. 
Berman DM, Karhadkar SS, Maitra A, et al (2003) Widespread requirement for Hedgehog 
ligand stimulation in growth of digestive tract tumours.  Nature; 425: 846-51. 
Briggs KJ, Corcoran-Schwartz IM, Zhang W, et al (2008) Cooperation between the Hic1 
and Ptch1 tumor suppressors in medulloblastoma.  Genes & Development; 22: 770-785. 


 
 
84 
Chang AS, Atwood SX, Tartar D and Oro AE (2013) Surgical excision after neoadjuvant 
therapy  with  vismodegib  for  a  locally  advanced  and  resistant  basal  carcinomas  in  a 
Gorlin’s patient.  JAMA Dermatology, 140 (5): 639-40. 
Clement V, Sanchez P, de Tribolet N, et al (2007)] Hedgehog-Gli1 signaling regulates 
human glioma growth, cancer stem cell self-renewal, and tumorigenicity.    Current 
Biology; 17: 165-172. 
Einolf HJ (2007) Comparison of different approaches to predict metabolic drug-drug 
interactions. Xenobiotica 2007 Oct-Nov; 37 (10-11): 1257-94. 
Feldmann G, Dhara S, Fendrich V, et al (2007) Blockade of hedgehog signaling inhibits 
pancreatic cancer invasion and metastases: A new paradigm for combination therapy in 
solid cancers.  Cancer Research; 67: 2187-2196. 
Feldmann   G,   Fendrich   V,   McGovern   K,   et al   (2008)   An   orally   bioavailable 
small-moleculr inhibitor of hedgehog signaling inhibits tumor initiation and metastasis in 
pancreatic cancer.  Mol.  Cancer Ther.; 7: 2725-2735. 
Ferretti  E,  DeSmaele  E,  DiMarcotullio  L,  et al  (2007)  Hedgehog  checkpoints  in 
medulloblastoma:  the  chromosome  17p  deletion  paradigm.     Trends  in  Molecular 
Medicine; 11: 537-545. 
Gailani MR, StahleBackdahl M, Leffell DJ, et al (1996) The role of the human homologue 
of Drosophila patched in sporadic basal cell carcinomas.  Nature Genetics; 14: 78-81. 
Hann  CL,  Daniel  VC,  Sugar  EA,  et al  (2008)  Therapeutic  efficacy  of  ABT-737,  a 
selective inhibitor of BCL-2, in small-cell lung cancer.  Cancer Research; 68: 2321-2328. 
Ji Z, Mei FC, Xie J, et al (2007) Oncogenic KRAS suppresses Gli1 degradation and 
activates Hedgehog signaling pathway in pancreatic cancer cells.   J Biol Chem; 282: 
14048-14055. 
Jimeno A, Feldmann G, Suárez-Gauthier A, et al.   (2009) A direct pancreatic cancer 
xenograft model as a platform for cancer stem cell therapeutic development.  Mol Cancer 
Ther; 8: 310-314. 
Karhadkar  SS,  Bova  GS,  Abdallah  N,  et al  (2004)  Hedgehog  signalling  in  prostate 
regeneration, neoplasia and metastasis.  Nature; 431: 707-712. 
Lee Y, Miller HL, Jensen P, et al (2003) A molecular fingerprint for medulloblastoma. 
Cancer Research; 63: 5428-5437. 
McMahon  AP,   Ingham   PW,  Tabin  CJ   (2003)  Developmental  roles  and  clinical 
significance of hedgehog signaling.  Current Topics in Developmental Biology; 53:1-114. 
Nakada M, Kita D, Watanabe T, Hayashi Y, Teng L, Pyko I, Hamada J (2011) Aberrant 
Signaling Pathways in Glioma.  Cancers; 3, 3242-3278. 
Nakashima  H,  Nakamura  M,  Yamaguchi  H,  et al  (2006)  Nuclear  factor-kappa  B 
contributes to hedgehog signaling pathway activation through sonic hedgehog induction in 
pancreatic cancer.  Cancer Research; 66: 7041-7049. 
Nolan-Stevaux   O,   Lau   J,   Truitt   ML,   et al   (2009)   GLI1   is   regulated   through 
Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC 
cell survival and transformation.  Genes Dev; 23: 24-36. 
Olive K, Jacobetz MA, Davidson CJ et al.   (2009) Inhibition of Hedgehog Signaling 
Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer.  Science; 
324: 1457-1461. 
Romer JT, Kimura H, Magdaleno S, et al (2004) Suppression of the Shh pathway using a 
small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice.  Cancer 
Cell; 6: 229-240. 
Rudin CM, et al (2009) Brief Report: Treatment of Medulloblastoma with Hedgehog 
pathway inhibitor GDC-0449.  New England Journal of Medicine; 361: 1173-1178. 


 
 
85 
Rubin LL, de Sauvage FJ (2006) Targeting the Hedgehog pathway in cancer.   Nature 
Reviews Drug Discovery; 5: 1026-1033. 
Sasai K, Romer JT, Kimura H, et al (2006) Medulloblastomas derived from Cxcr6 mutant 
mice respond to treatment with a smoothened inhibitor.  Cancer Research; 67 (8):3871-7. 
St-Jacques  B,  Dassule  HR,  Karavanova  I  et al,  (1998)  Sonic  hedgehog  signaling  is 
essential for hair development.  Current Biology; 8 (19):1058-68. 
Thayer SP, di Magliano MP, Heiser PW, et al (2003) Hedgehog is an early and late 
mediator of pancreatic cancer tumorigenesis.  Nature; 425: 851-856. 
Thompson MC, Fuller C, Hogg TL, et al (2006) Genornics identifies medulloblastoma 
subgroups that are enriched for specific genetic alterations.  Journal of Clinical Oncology; 
24: 1924-1931. 
Tian H, Callahan CA, DuPree KJ, et al.  (2009) Hedgehog signaling is restricted to the 
stromal compartment during pancreatic carcinogenesis.  Proc Natl Acad Sci USA.  106: 
4254-4259. 
Uchida H, Arita K, Yunoue S, Yonezawa H, Shinsato Y, Kawano H, Hirano H, Hanaya R, 
Tokimura  H.    (2011)  Role  of  sonic  hedgehog  signaling  in  migration  of  cell  lines 
established  from  CD133-positive  malignant  glioma  cells.    J  Neurooncol  2011  Sep: 
104(3):697-704 
Von Hoff, D, Rudin C, LoRusso, P, Borad, M et al.  (2008).  Efficacy data of GDC-0449, a 
systemic Hedgehog pathway antagonist, in a first-in-human, first-in-class phase 1 study 
with locally advanced, multifocal or metastatic basal cell carcinoma patients (abstract). In: 
Proceedings of the 99th Annual Meeting of the American Association for Cancer 
Research; 2008 Apr 12-16; San Diego, CA.  Philadelphia (PA): AACR; 2008.  Abstract nr 
LB-138 
Watkins DN, Berman DM, Burkholder SG, et al (2003) Hedgehog signaling within airway 
epithelial progenitors and in small-cell lung cancer.  Nature; 422: 313-317. 
Wetmore C, Eberhart DE, Curran T (2001) Loss of p53 but not ARF accelerates 
medulloblastoma in mice heterozygous for patched.  Cancer Res; 61: 513-516. 
Xie JW, Murone M, Luoh SM, et al (1998) Activating Smoothened mutations in sporadic 
basal-cell carcinoma.  Nature; 391: 90-92. 
Yauch RL, Gould SE, Scales SJ, et al.   (2008) A paracrine requirement for hedgehog 
signalling in cancer.  Nature; 455: 406-410. 
Yauch  RL,  et al.    (2009)  Smoothened Mutation  Confers  Resistance  to  a  Hedgehog 
Pathway Inhibitor in Medulloblastoma.  Science; 326: 572-574. 
9 
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. 


 
 
86 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, 
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. 
APPENDIX B: Participant Eligibility Checklist 
Protocol Title: 
An open-label pilot study to evaluate the efficacy and safety 
of a combination treatment of Sonidegib and buparlisib for the 
treatment of advanced basal cell carcinomas 
Protocol Number: 
IRB-29839 
Principal 
Investigator: 
Anne Lynn S Chang, MD 
 
 
 
 
 
 
II. Subject Information: 
Subject Name/ID: 
Gender: 
Male 
Female 
III. Inclusion/Exclusion Criteria 
Inclusion Criteria 
Yes 
No 
Supporting 
Documentation* 


 
 
87 
1.  Age 18 years or older. 
 
 
 
2. Able to provide written informed consent obtained 
prior to any screening procedures 
 
 
 
3.  Histologically documented diagnosis of basal cell 
carcinoma deemed to be locally advanced or 
metastatic 
 
 
 
4.  ECOG performance status ≤ 2 
 
 
 
5.  At least one measurable site of disease (as defined by 
Response Evaluation Criteria in Solid Tumors), or 
other disease specific response assessment criteria, 
as appropriate. 
State age restriction and/or gender/race-ethnic 
restrictions. 
 
 
 
6. Patients with adequate bone marrow, liver and renal 
function, as specified below: 
 
 
 
• Absolute Neutrophil Count 
(ANC) ≥ 1.5 x 109/L 
• Hemoglobin (Hgb) ≥ 9 g/dL 
• Platelets ≥ 80 x 109/L 
• Serum total bilirubin ≤ 1.5 x ULN (upper limit of 
normal) 
• AST and ALT ≤ 2.5 x ULN or ≤ 5 x ULN if liver 
metastases are present 
• Plasma creatinine phosphokinase (CK) < 1.5 x  
ULN 
• Serum creatinine ≤ 1.5 x ULN or 24-hour clearance 
≥ 50 mL/min 
CK > ULN 
 
 
 
 
Exclusion Criteria  
Yes 
No 
Supporting 
Documentation* 


 
 
88 
1.  Cohort 1 only: prior therapy with non- 
Sonidegib 
Smo Inhibitor 
 
 
 
2.   Patients who have received prior treatment 
with a P13K inhibitor 
 
 
 
3.   Patients  with  a  known  hypersensitivity  to 
buparlisib or to its excipients 
 
 
 
4.   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  not  receiving corticosteroid therapy 
 
 
 
5.   Patients who have had major surgery within 4 
weeks of initiation of study medication. 
 
 
 
6.  Patients with concurrent uncontrolled medical 
conditions that may interfere with their 
participation in the study or potentially affect 
the interpretation of the study data. 
 
 
 
 
7.  Patients unable to take oral drugs or with lack 
of physical integrity of the upper  
gastrointestinal tract or known malabsorption 
syndromes.  State exclusion requirements due 
to co-morbid disease or incurrent illness, as 
needed. 
 
 
 


 
 
89 
8.  Patients who have neuromuscular disorders 
(eg, inflammatory myopathies, muscular 
dystrophy, amyotrophic lateral sclerosis and 
spinal muscular atrophy) or are on 
concomitant treatment with that are 
recognized to cause rhabdomyolysis, such as 
HMG CoA inhibitors (statins), clofibrate and 
gemfibrozil, and that cannot be discontinued 
at least 2 weeks prior to starting Sonidegib 
treatment. If it is essential that the patient 
stays on a statin to control hyperlididemia, 
only pravastatin may be used with extra 
caution. 
 
 
 
9. Patients who are planning on embarking on a 
new strenuous exercise regimen after initiation 
of study treatment.  NB: Muscular activities, 
such as strenuous exercise, that can result in 
significant increases in plasma CK levels 
should be avoided whilst on sonidegib 
treatment 
 
 
 
10. Patients who have taken part in an 
experimental drug study within 4 weeks of 
initiating treatment with Sonidegib. 
 
 
 
11. Patients who are receiving other antineoplastic 
therapy (eg, chemotherapy, targeted therapy or 
radiotherapy) concurrently or within 2 weeks 
of starting treatment with sonidegib. 
 
 
 
 


 
 
90 
12. Patients who are receiving treatment with 
medications known to be moderate and strong 
inhibitors or inducers of CYP3A4/5 or drugs 
metabolized by CYP2B6 or CYP2C9 that 
have narrow therapeutic index, and that cannot 
be discontinued before starting treatment with 
Sonidegib.  Medications that are strong 
CYP3A4/5 inhibitors should be discontinued 
at least 7 days and strong CYP3A/5 inducers 
for at least 2 weeks prior to starting treatment 
with Sonidegib. 
 
 
 
13. Pregnant or nursing (lactating women, 
where pregnancy is defined as the state of a 
female after conception and until the 
termination of gestation, confirmed by a 
positive hCG laboratory test 
(> 5 mIU/mL). 
 
 
 
14. Women of child-bearing potential, defined as 
all women physiologically capable of  
becoming pregnant, including women whose 
career, lifestyle, or sexual orientation 
precludes intercourse with a male partner and 
women whose partners have been sterilized by 
vasectomy or other means, UNLESS they are 
using two birth control methods.  The two 
methods can be a double barrier method or a 
barrier method plus a hormonal method.  
Adequate barrier methods of contraception 
include: 
• 
Diaphragm, condom (by the partner), 
intrauterine device (copper or hormonal), 
sponge or spermicide.  Hormonal 
contraceptives include any marketed 
contraceptive agent that includes an estrogen 
and/or a progestational agent. 
• 
Reliable contraception should be maintained 
throughout the study and for 3 months after 
study drug discontinuation. 
 
 
 
 


 
 
91 
15. Uncontrolled medical medical problems 
including acute or chronic liver disease, renal 
disease or pancreatitis, diarrhea >CTCAE grade 
2, active cardiac disease, uncontrolled diabetes, 
chronic steroids or other immunosuppressive 
agents 
 
 
 
16. 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), dehydroepiandrosterone 
(DHEA), gingko biloba,  yohimbe, saw 
palmetto, and ginseng. Fruits include the 
CYP3A inhibitors Seville oranges, grapefruit, 
pummelos, or exotic citrus fruits. 
 
 
 
17. 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 15 for a list of 
prohibited inhibitors and inducers of CYP3A  
(Please note that co-treatment with weak 
inhibitors of CYP3A is allowed). 
 
 
 
18. 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 
 
 
 
19. Use of statin drugs or other medications known 
to associate with rhabdomyolysis. These drugs 
must be discontinued at enrollment 
 
 
 


 
 
92 
20. 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 
 
 
 
21. Patients who have undergone major surgery ≤ 2 
weeks prior to starting study drug or who have 
not recovered from side effects of such therapy. 
 
 
 
22. Patients who are currently taking therapeutic 
doses of warfarin sodium or any other 
coumadin-derivative anticoagulant.  Low 
molecular weight heparin is allowed. 
 
 
 
23. Known diagnosis of human immunodeficiency 
virus (HIV) infection, Hepatitis B or Hepatitis  
C 
 
 
 
24. History of another malignancy within 3 years, 
except cured basal cell carcinoma of the skin, 
cured squamous cell carcinoma of the skin or  
excised carcinoma in situ of the cervix 
 
 
 
25. 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) 
≥ 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) 
 
 
 


 
 
93 
26.  Patients unwilling or unable to comply with 
the protocol. 
 
 
 
*All subject files must include supporting documentation to confirm subject eligibility. 
The method of confirmation can include, but is not limited to, laboratory test results, 
radiology test results, subject self-report, and medical record review. 
 IV.   Statement of Eligibility 
This subject is eligible  / ineligible for participation in the study. 
Signature :  
Date: 
Printed Name: