Clinical trial NCT01563354
Conditions: Neuroendocrine Carcinoma of the Lung and Thymus
Keywords: neuroendocrine carcinoma; lung; thymus; pasireotide LAR; everolimus,adult,SOM230,carcinoma,lung cancer,
Sponsor: Novartis Pharmaceuticals
Start date: 2013-08-16; Completion date: 2020-02-10
Enrollment: 124 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This was a multicenter, randomized, phase II study evaluating Everolimus or Pasireotide LAR alone or in combination in adult patients with advanced (unresectable or metastatic) neuroendocrine carcinoma of the lung and thymus

Detailed description:
This was a prospective, multicenter, randomized, open-label, 3-arm, phase II study with a single-stage design in each arm. The purpose of this study was to test the effectiveness and safety of Everolimus or Pasireotide LAR alone or in combination in adult patients with advanced (unresectable or metastatic) neuroendocrine carcinoma (typical and atypical) of the lung and thymus. It was expected that a total of 120 patients with 40 patients in each arm were to be enrolled into this study. Patients were seen weekly for one month and monthly thereafter. Radiological and biochemical response assessments were performed every 3 months.

Patients with disease control (stable disease or better) in the combination arm or monotherapy with pasireotide LAR and everolimus who had not experienced unacceptable toxicity were permitted to continue treatment in the extension phase of the study and were seen every 3 months. Patients could remain in the extension phase as long as they continued to have clinical benefit and had not fulfilled any of the study discontinuation criteria. All patients had a safety follow-up visit 56 days after last treatment dose.

Arms: arm 1: Pasireotide long acting release (LAR) 60 mg will be administered as an intra muscular (i.m.) depot injection once every 28 days starting on Day 1 arm 2: Everolimus 10 mg taken orally (p.o) once daily starting on Day 1 arm 3: Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily starting on Day 1
Interventions: intervention 1: Pasireotide LAR intervention 2: Everolimus intervention 3: Pasireotide LAR and Everolimus Combination
Intervention descriptions: intervention 1: 60 mg was administered as an intra muscular depot injection once every 28 days starting at Day 1 intervention 2: 10 mg tables administered orally once a day intervention 3: Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily

Protocol documents:
Prot_000.pdf: 
Clinical Development & Medical Affairs
SOM230 (Pasireotide) LAR and RAD001 (Everolimus)
Protocol CSOM230DIC03 / NCT01563354  
Multicenter 3-arm trial to evaluate the efficacy and safety of 
Pasireotide LAR or Everolimus alone or in combination in 
patients with well differentiated neuroendocrine carcinoma 
of the lung and thymus - LUNA Trial
Authors
 
 
Document type
Amended Protocol Version
EUDRACT number
2011-002872-17
Version number
05 (Clean)
Development phase
II
Document status
Final
Release date
07-Nov-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Protocol Summary
Study title:
Multicenter 3-arm trial to evaluate the efficacy and safety of Pasireotide LAR or Everolimus alone or in 
combination in patients with well differentiated neuroendocrine carcinoma of the lung and thymus -
LUNA Trial
Study phase:
II
Study objectives:
Primary objective

To evaluate the efficacy of pasireotide LAR and everolimus alone or in combination in 
progressive patients with a well differentiated neuroendocrine tumor of the lung or thymus. 
The primary endpoint is defined as the proportion of patients who are progression free (i.e. 
disease control rate) at 9 months, according to RECIST V. 1.1. Disease control rate is 
defined as the proportion of patients showing a best overall response of complete (CR) or
partial (PR) response or stable disease (SD), according to RECIST V. 1.1.
Secondary objectives

To assess the overall progression-free survival (PFS) throughout the study in patients with a 
well 
differentiated 
neuroendocrine 
tumor 
of 
the 
lung 
or
thymus.
The endpoint progression-free survival (PFS) is defined as the time from first study drug 
administration to objective tumor progression or death from any cause, according to RECIST 
V. 1.1.

To assess the disease control rate of pasireotide LAR and everolimus alone or in combination 
in patients with a well differentiated neuroendocrine tumor of the lung or thymus at 12 months.

To assess the time to response, duration of response, objective response rate and best 
overall response of pasireotide LAR and everolimus alone or in combination during 12 
months of treatment in patients with a well differentiated neuroendocrine tumor of the lung or
thymus.
The endpoint of “time to response” is defined as the time from start of treatment to the first 
objective tumor response (PR or CR) observed,
according to RECIST V.
1.1. 
The endpoint of “duration of response” is defined as the time from onset of the first 
objective tumor response (CR/PR) to objective tumor progression or death from any cause.
The endpoint of “objective response rate” is defined as the proportion of patients showing a
best overall response of CR or a PR at 9 and 12 months, according to RECIST V. 1.1. criteria.
The endpoint of “best overall response” is defined as the best response recorded from the 
start of the treatment until disease progression/recurrence, taking as reference for PD the 
smallest measurements recorded since the treatment started.

To assess the biochemical response rate (BRR), duration of biochemical response (DBR) and 
biochemical progression-free survival (BPFS) of pasireotide LAR and everolimus alone or in 
combination in patients with a well differentiated neuroendocrine tumor of the lung or thymus.
The endpoint of “biochemical response rate (BRR)” is the percentage of patients showing 
normalization or a decrease of ≥30% of serum chromogranin A (CgA), compared to baseline.
The endpoint of “duration of biochemical response (DBR)” is defined as the time from the 
first documentation of biochemical response to the first documentation of biochemical 
progression* or to death due to any cause, whichever occurs first.
*Biochemical progression is defined as the increase of serum CgA levels ≥25% versus
baseline.


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The endpoint of “biochemical progression-free survival (BPFS)” is the time from the first 
study drug administration to the first documentation of biochemical progression or to death 
due to any cause, whichever occurs first.
Additionally, the biochemical response on the basis of urine 5-hydroxyindole acetic acid 
(5HIAA) will be assessed

To assess the safety and tolerability of pasireotide LAR and everolimus alone or in 
combination as measured by rate and severity of adverse events in patients with a well 
differentiated neuroendocrine tumor of the lung or thymus
Safety will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.0. Incidence of adverse events (AEs), serious adverse events (SAEs), changes 
from baseline in vital signs, ECG tracings and laboratory results (hematology, blood chemistry) 
will be reported.
Study population:
The target population is comprised of adult patients with an advanced (unresectable or metastatic) well 
differentiated neuroendocrine carcinoma (typical and atypical according to the 2004 WHO criteria) of 
the lung or thymus. Patients must be >18 years old with WHO Performance status <2 and have 
adequate hematologic, renal and hepatic function.
Number of patients:
It is expected that a total of 120 patients with 40 patients in each arm will be enrolled into this study.
Overview of study design:
This is a prospective, multicenter, randomized, open-label, 3-arm, phase II study with a single-stage 
design in each arm to evaluate the efficacy and safety of pasireotide LAR (SOM230) and everolimus 
(RAD001) alone or in combination in the treatment of patients with a well differentiated neuroendocrine 
carcinoma of lung or thymus.
The number of patients enrolled is targeted to be approximately 120 with 40 patients randomized to 
each arm as follows:
Arm 1: treatment with pasireotide (SOM230) LAR (60 mg/month i.m.),
Arm 2: treatment with everolimus (RAD001) (10 mg/day p.o.),
Arm 3: treatment with pasireotide LAR (60 mg/month i.m.) and everolimus (10 mg/day p.o.).
Patients with disease control (SD or better) in the combination arm or monotherapy with pasireotide 
LAR and everolimus and who are not experiencing unacceptable toxicity are permitted to continue 
treatment after the 12-month treatment period, in the extension phase of the study.
Statistical considerations:
The primary objective of each single-stage trial arm is to evaluate the efficacy of pasireotide LAR and 
everolimus alone or in combination in patients with a well differentiated neuroendocrine tumor of the 
lung or thymus.
The primary variable is defined as the proportion of patients who are progression free at Month 9
based on RECIST V. 1.1.
A Fleming single stage design will be employed for each arm. Let p0 be the highest proportion of 
patients progression-free at Month 9 which would indicate that the treatment is clearly ineffective, and 
p1 be the minimum required proportion of patients progression-free. The trial tests the null hypothesis 
H0 that the observed proportion of patients progression-free, p, is less than or equal to p0 against the 
alternative hypothesis H1 that p is greater than or equal to p1. It consists of entering a predetermined 
number of subjects and deciding in favor of p0 or p1 based on the success rate observed by using an 


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appropriate cut-off between p0 and p1. If the number of responses is greater than or equal to R+1, p0 
is rejected. If the number of responses is less than or equal to R, p1 is rejected.
In this trial, p0 and p1 have been set equal to 0.20 and 0.45 respectively. Forty (40) patients are 
planned to be randomized in each treatment group. If the number of responses is 13 or more, the 
hypothesis that p ≤ p0 = 20% is rejected with a target alpha error rate of 5% and an actual alpha error 
rate of 4.3%; if the number of responses is 12 or less, the hypothesis that p ≥ p1 = 45% is rejected 
with an actual beta error rate of 4%.
The secondary objective of “Progression-free survival (PFS)” is defined as the time from first study 
drug administration to objective tumor progression or death from any cause. If a patient has not had an 
event, PFS is censored at the date of the last adequate tumor assessment. PFS will be explored by 
presenting the Kaplan-Meier curve and estimator.
Operating characteristics (One-arm, single-stage, Fleming design)
p0
p1
Target
Cut-Off
R + 1
N
Actual
Alpha
Beta
alpha
Beta
20%
45%
5%
10%
13
40
4.3%
4%


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Table of contents
Protocol Summary...............................................................................................................2
Table of contents .................................................................................................................5
List of figures ......................................................................................................................9
List of tables ........................................................................................................................9
List of abbreviations..........................................................................................................11
Glossary of terms...............................................................................................................15
Amendment 5 ....................................................................................................................16
1
Background........................................................................................................................43
1.1
Overview of neuroendocrine tumors of the lung and thymus ...............................43
1.1.1
Lung neuroendocrine carcinoma...........................................................43
1.1.2
Thymus Neuroendocrine Carcinoma ....................................................44
1.2
Introduction to investigational treatment(s) and other study treatment(s).............45
1.2.1
Overview of Pasireotide (SOM230) LAR.............................................45
1.2.2
Overview of Everolimus (RAD001).....................................................49
54
2
Rationale............................................................................................................................55
2.1
Study rationale and purpose...................................................................................55
2.2
Rationale for the study design ...............................................................................57
2.3
Rationale for dose and regimen selection..............................................................57
2.4
Rationale for choice of combination drugs............................................................58
2.5
Rationale for choice of comparators drugs............................................................58
3
Objectives and endpoints...................................................................................................58
3.1
Primary objective...................................................................................................61
3.2
Secondary objectives.............................................................................................61
62
4
Study design ......................................................................................................................62
4.1
Description of study design ...................................................................................62
4.1.1
Screening/Baseline phase......................................................................62
4.1.2
Treatment phase ....................................................................................63
4.1.3
Extension phase.....................................................................................63
4.2
Timing of interim analyses and design adaptations...............................................65
4.3
Definition of end of the study................................................................................65
4.4
Early study termination..........................................................................................65
5
Population..........................................................................................................................65
5.1
Patient population..................................................................................................65


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5.2
Inclusion criteria ....................................................................................................65
5.3
Exclusion criteria...................................................................................................66
6
Treatment...........................................................................................................................69
6.1
Investigational treatment, other study treatment, supportive treatment ................69
6.1.1
Dosing regimen.....................................................................................69
6.1.2
Ancillary treatments..............................................................................70
6.1.3
Rescue medication ................................................................................70
6.1.4
Handling of Specific Toxicities ............................................................70
6.1.5
Guidelines for continuation of treatment ..............................................83
6.1.6
Treatment duration................................................................................83
6.2
Dose escalation guidelines (Phase 1 studies only) ................................................84
6.3
Dose modifications................................................................................................84
6.3.1
Dose modification and dose delay ........................................................84
6.3.2
Treatment interruption and treatment discontinuation..........................86
6.4
Concomitant medications/therapies.......................................................................88
6.4.1
Permitted concomitant therapy .............................................................89
6.4.2
Permitted concomitant therapy requiring caution and/or action...........90
6.4.3
Prohibited concomitant therapy ............................................................90
6.5
Patient numbering, treatment assignment and randomization...............................91
6.5.1
Patient numbering .................................................................................91
6.5.2
Treatment assignment and randomization ............................................92
6.5.3
Treatment blinding................................................................................92
6.6
Study drug supply..................................................................................................92
6.6.1
Study drug preparation and dispensation ..............................................92
6.6.2
Study drug packaging and labeling.......................................................96
6.6.3
Drug supply and storage........................................................................96
6.6.4
Study drug compliance and accountability ...........................................97
6.6.5
Disposal and destruction .......................................................................98
7
Visit schedule and assessments .........................................................................................98
7.1
Study flow and visit schedule................................................................................98
7.1.1
Pre-screening assessments ..................................................................106
7.1.2
Screening.............................................................................................106
7.1.3
Treatment period.................................................................................106
7.1.4
End of core study visit, including premature withdrawal and study 
discontinuation visit ............................................................................106
7.1.5
Extension period..................................................................................108


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7.2
Assessment types.................................................................................................109
7.2.1
Efficacy assessments...........................................................................109
7.2.2
Safety and tolerability assessments.....................................................112
7.2.3
Pharmacokinetics ................................................................................118
118
7.2.5
Other assessments ...............................................................................120
8
Safety monitoring and reporting......................................................................................120
8.1
Adverse events.....................................................................................................120
8.1.1
Definitions and reporting ....................................................................120
8.1.2
Laboratory test abnormalities..............................................................121
8.1.3
Adverse events of special interest.......................................................121
8.2
Serious adverse events.........................................................................................122
8.2.1
Definitions...........................................................................................122
8.2.2
Reporting.............................................................................................122
8.3
Emergency unblinding of treatment assignment .................................................123
8.4
Pregnancies..........................................................................................................123
8.5
Warnings and precautions....................................................................................124
8.6
Data Monitoring Committee................................................................................124
8.7
Steering Committee .............................................................................................124
9
Data collection and management.....................................................................................125
9.1
Data confidentiality .............................................................................................125
9.2
Site monitoring ....................................................................................................125
9.3
Data collection.....................................................................................................126
126
9.4
Database management and quality control..........................................................126
10 Statistical methods and data analysis ..............................................................................126
10.1
Analysis sets ........................................................................................................127
10.1.1
Full Analysis Set .................................................................................127
10.1.2
Safety Set ............................................................................................127
10.1.3
Per-Protocol Set ..................................................................................128
10.1.4
Dose-determining analysis set.............................................................128
10.1.5
Pharmacokinetic analysis set...............................................................128
10.1.6
Other analysis sets...............................................................................128
10.2
Patient demographics/other baseline characteristics ...........................................128
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................128
10.4
Primary objective.................................................................................................129


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10.4.1
Variable...............................................................................................129
10.4.2
Statistical hypothesis, model, and method of analysis........................129
10.4.3
Handling of missing values/censoring/discontinuations.....................129
10.4.4
Supportive analyses.............................................................................130
10.5
Secondary objectives ...........................................................................................130
10.5.1
Key secondary objective(s).................................................................130
10.5.2
Other secondary efficacy objectives ...................................................130
10.5.3
Safety objectives .................................................................................131
10.5.4
Pharmacokinetics ................................................................................133
133
135
10.7
Interim analysis....................................................................................................136
10.8
Sample size calculation........................................................................................136
10.9
Power for anal ysis of key secondary variables...................................................136
11 Ethical considerations and administrative procedures ....................................................136
11.1
Regulatory and ethical compliance......................................................................136
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................136
11.3
Informed consent procedures...............................................................................137
11.4
Discontinuation of the study................................................................................137
11.5
Publication of study protocol and results.............................................................137
11.6
Study documentation, record keeping and retention of documents.....................138
11.7
Confidentiality of study documents and patient records .....................................138
11.8
Audits and inspections.........................................................................................139
11.9
Financial disclosures............................................................................................139
12 Protocol adherence ..........................................................................................................139
12.1
Amendments to the protocol................................................................................139
13 References (available upon request)................................................................................140
14 Appendices......................................................................................................................145
14.1
Appendix 1...........................................................................................................145
14.1.1
Introduction.........................................................................................146
14.1.2
Efficacy assessments...........................................................................146
14.1.3
Efficacy definitions .............................................................................154
14.1.4
Data handling and programming rules................................................163
14.1.5
References (available upon request) ...................................................167


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List of figures
Figure 4-1
Study design..........................................................................................64
Figure 6-1
Procedure for QTcF prolongations........................................................81
Figure 6-2
LFT Management Algorithm................................................................83
List of tables
Table 1-1
Differential pathological findings in NE lung tumors (2004 WHO 
classification) (Travis et al. 2004; *Chong et al. 2006)........................43
Table 1-2
Binding profile for octreotide and pasireotide at SSTR 1-5 (IC50, 
M)..........................................................................................................46
Table 1-3
Most frequent AEs associated with Pasireotide LAR treatment...........47
Table 3-1
Objectives and related endpoints ..........................................................59
Table 6-1
Dosing modification for hyperglycemia ...............................................76
Table 6-2
Guidelines for management of non-infectious pneumonitis.................77
Table 6-3
Monitoring for positive baseline hepatitis B results .............................78
Table 6-4
Guidelines for management of hepatitis B............................................78
Table 6-5
Guidelines for management of hepatitis C............................................79
Table 6-6
Dosing modification criteria for suspected pasireotide LAR-related 
toxicities................................................................................................84
Table 6-7
Everolimus dose level modification guidelines ....................................85
Table 6-8
Dosing modification criteria for suspected everolimus-related 
toxicity...................................................................................................85
Table 6-9
Recommendations for patient discontinuation following study drug 
adjustment .............................................................................................87
Table 6-10
Clinically relevant drug interaction: inducers & inhibitors of 
isoenzyme CYP3A4..............................................................................88
Table 6-11
Clinically relevant drug interactions: substrates, inducers, and 
inhibitors of PgP and PgP/CYP3A dual inhibitors ...............................89
Table 6-12
Preparation and dispensing ...................................................................93
Table 6-13
Handling and preparation of pasireotide LAR dose..............................93
Table 6-14
Supply and storage of study treatments ................................................97
Table 7-1
CORE STUDY – Visit evaluation schedule (12 months).....................99
Table 7-2
EXTENSION PHASE - Visit evaluation schedule.............................104
119
Table 10-1
Overall lesion response at each assessment ........................................129
Table 10-2
Design features for single-arm trials...................................................136
Table 14-1
Response criteria for target lesions .....................................................151


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Table 14-2
Response criteria for non-target lesions..............................................153
Table 14-3
Overall lesion response at each assessment ........................................154
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................161
Table 14-5
Options for event dates used in PFS, TTP, duration of response........162


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List of abbreviations
5-FU
5-Fluorouracil
5-HIAA
5-hydroxyindole acetic acid 
AC
Atypical carcinoid tumor 
ACE
Angiotensin-converting enzyme
ACTH
Adrenocorticotropic hormone 
ADA
American Diabetes Association 
ADR
Adverse drug reaction
AE
Adverse event
AKT/PKB 
Protein kinase B
ALT (GPT)
Alanine aminotransferase (glutamic pyruvic transaminase)
ASCO
American Society of Clinical Oncology
AST (GOT)
Aspartate aminotransferase (glutamic oxaloacetic transaminase) 
ATC
Anatomical Therapeutic Chemical
AUC 
Area under the curve 
b.i.d.
Bis in die/twice a day
BAL 
Bronchoalveolar lavage
beta-HCG 
Beta-human chorionic gonadotropin 
BPFS 
Biochemical progression-free survival
BRR
Biochemical response rate
BSC 
Best supportive care
BUN 
Blood urea nitrogen
cAMP
Cyclic adenosine monophosphate
CDS
Core data sheet 
CgA
Chromogranin A
CI
Confidence interval 
Cl
Clearance
CPK 
Creatine phosphokinase
CR 
Complete response
CRF 
Case Report/Record Form
CRO 
Contract Research Organization 
CS&E
Clinical Safety and Epidemiology 
CSR
Clinical Study Report
CT
Computed Tomography
CTC/CTCAE 
Common Toxic Criteria/Common Toxic Criteria for Adverse Events
CYP3A4 
Cytochrom P450 3A4
DBL
Database lock
DBR
Duration of biochemical response
DKA
Diabetic ketoacidosis
DLCO
Diffusing capacity of the lung for carbon monoxide
DLT
Dose limiting toxicity 
DM 
Diabetes mellitus
DMC 
Data Monitoring Committee
EASD
European Association for the Study of Diabetes
EBUS 
Endobronchial ultrasound-guided fine needle aspiration
EC
Ethics Committee


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ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOS
End of study
FAS
Full Analysis Set
FSH 
Follicle-stimulating hormone
GCP 
Good Clinical Practice 
GEP
Gastroenteropancreatic 
GERD
Gastroesophageal reflux disease 
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
GIP
Glucose-dependent insulinotropic polypeptide
GLP-1
Glucagon-like peptide-1 
HbA1c 
Hemoglobin A1c subtype (glycated hemoglobin) 
HBcAb
Hepatitis B core antibody 
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV DNA
Hepatitis B Virus – Deoxyribonucleic acid
HCV-RNA PCR
HCV Ribonucleic acid – Polimerase Chain Reaction
HDL
High-density lipoprotein
HIF 
Hypoxia-inducible factor
HMG-CoA 
3-hydroxy-3-methyl-glutaryl-CoA
HPF
High-power fields
HR
Hazard ratio
i.m.
Intramuscular(ly)
i.v.
Intravenous(ly)
IB 
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICF
Informed consent form
ICH 
International Conference on Harmonization
IEC
Independent Ethics Committee
IGF
Insulin-like growth factor 
IHC 
Immunohistochemistry
ILD 
Interstitial lung disease
IN 
Investigator Notification
INR 
Internation Normalized Ratio 
IRB
Institutional Review Board 
ITT
Intent-To-Treat population
IVRS 
Interactive Voice Response System
IWRS
Interactive Web Response System
LAR 
Long-acting release 
LCC
Large cell carcinoma 
LDH
Lactate dehydrogenase 
LFT
Liver function test
LH
Luteinizing hormone
MedDRA
Medical Dictionary for Regulatory Activities
MEN-1 
Multiple endocrine neoplasia type 1
MRI 
Magnetic Resonance Imaging 


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MTD
Maximum tolerated dose 
mTOR
Mammalian target of rapamycin 
MUGA
Multiple-Gated Acquisition
NE 
Neuroendocrine
NET
Neuroendocrine Tumor 
NSCLC
Non small cell lung cancer 
o.d.
Omni die/once a day 
p.o.
Per os/by mouth/orally
ORR
Objective response rate
OS
Overall survival
PCR 
Polymerase Chain Reaction
PD 
Progressive disease
PFS 
Progression-free survival
PFT
Pulmonary function tests
PGP
P-glycoprotein
PI3K
Phosphoinositide 3-kinase
PJP 
Pneumocystis jirovecii pneumonia
PK 
Pharmacokinetics
pNET
Pancreatic NET
PR 
Partial response
PRRT
Peptide receptor radionuclide therapy 
PT 
Prothrombin time
PTEN 
Phosphatase and tensin homolog
PTS 
Post-text supplements 
PTT
Partial prothrombin time
QD
Quaque die/every day 
RAD001
Everolimus
RAP
Reporting Analysis Plan
RCC
Renal cell carcinoma
REB
Research Ethics Board
RECIST 
Response Evaluation Criteria In Solid Tumors 
s.c.
Subcutaneous
SAE 
Serious adverse event
SCLC
Small cell lung cancer 
SD
Stable disease
SDev 
Standard deviation
SEER
Surveillance, Epidemiology and End Results
SEGA
Subependymal giant cell astrocytoma
SGOT 
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase 
SOM230
Pasireotide
SSA
Somatostatin analogue
SSC
Small cell carcinoma
SC
Steering Committee
SSRs
Somatostatin receptors
SSTR
Somatostatin receptor subtype


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t.i.d.
Ter in die/three times a day
TdP
Torsades de Pointes
TC 
Typical carcinoid tumor
Tmax
Time of occurrence for maximum (peak) drug concentration
TSC 
Tuberous sclerosis complex
TSH 
Thyroid stimulating hormone
TTP
Time to tumor progression
ULN 
Upper limit normal
VEGF
Vascular endothelial growth factor
VP-16
Etoposide phosphate
WBC 
White blood cell
WHO 
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (eg: q28 days)
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being testing in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not 
include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage
Other study treatment
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment
Subject Number (Subject No.)
A unique identifying number assigned to each patient/healthy volunteer who 
enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned completion 
of all study treatment administration and/or assessments; at this time all study 
treatment administration is discontinued and no further assessments are 
planned, unless the patient will be followed for progression
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints


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Amendment 5
Amendment rationale
In total, 124 patients have been randomized in the trial. 43 patient completed the core phase of 
the study and 41 entered in the extension phase.So far, 30 patients have discontinued the study 
treatment and 11 patients are still ongoing in the Extension phase. 
The primary analysis of the study data was performed on 26th February 2016. For the core 
phase analysis, the data cutoff that was applied for a patient was either 12 months of study 
treatment or “End of Core Phase Evaluation” phase.
The primary efficacy endpoint was defined as the proportion of patients who were progression 
free at Month 9, based on RECIST V1.1. The primary analysis was to check if a sufficient 
number of patients were progression free at month 9 and the null hypothesis would be either 
accepted or rejected on the basis of the total number of responders. Accordingly, it would be 
concluded that the primary objective has been met/not met. 
While performing the primary analysis for PFR at month 9, it was observed that enough 
number of responses was observed in all the treatment arms. In case of Pasireotide-LAR and 
combination arm, 13 patients had responses out of 41 patients and for Everolimus, 14 patients 
had responses out of 42 patients. The observed number of responses was enough to claim that 
the null hypothesis can be rejected. Hence it can be said that the primary objective was met.
The Study Steering Committee assessed the results of the primary endpoint during the 
Steering Committee Meeting held in May 2016. As patients were receiving a benefit from 
participation in the study, the study protocol is being amended. This amendment includes 
details to extend the duration of the study [from 104 weeks (2 years) to as long as all patients 
continue to demonstrate benefit and do not fulfill any of the study discontinuation criteria]. 
Only tumor evaluation and safety data will be collected after the 4th Visit in the Extension 
Phase. In addition to that, some sections of the protocol have been clarified and some 
inconsistencies corrected.”Other major changes implemented with the current protocol 
are:
to delete 
, 
and 
as protocol author 
and to add 
as 
 and 
 as 
.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, red font for insertions.
Table of contents and list of tables have been updated according to modifications 
implemented throughout the protocol. Main changes were made to the following protocol 
sections:
Protocol summary
Summary modified to be in line with changes included in the protocol, and with study
Endpoints.


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Section 1

Updates to include new information on pasireotide/everolimus marketing approvals,
clinical experience, and safety data
Section 4
Section 4 and Figure 4-1

Modification of the duration of extension phase from “until disease progression” to “until 
they no longer demonstrate benefit or fulfill any of the study discontinuation criteria”.

Modification of end of study definition from “the last visit two years after the start of 
treatment of the last randomized patient or when all patients have progressed whichever 
comes first  to when all patients  have discontinued the study.
Section 7
Section 7 and Table 7-1
Specification Patients who discontinue study treatment after 12 months of treatment, without 
evidence of progression or for reasons other than disease progression will continue to have 
tumor evaluation assessments “until disease progression or LPLV whichever occurs first”.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Amendment 4
Amendment rationale
The amended version 03 (finalized on July 2013) of the study protocol is being amended after 
the submission to Competent Authorities/Ethics Committee mainly to remove the replacement 
policy (to avoid the introduction of biases in the study), to change the timepoint at which the 
primary endpoint will be evaluated (from month 12 to month 9) and to update information on 
everolimus and pasireotide LAR based on the new versions of the respective Investigator 
Brochures (ed. 13 dated 12 May 2014 for everolimus; ed. 14 dated 02 June 2014 for 
pasireotide LAR). In addition to that, some information already present in the protocol have 
been clarified and some inconsistencies corrected.
In order to avoid biased results, it has been decided to remove the replacement policy for 
patients discontinuing the trial for reasons other than disease progression and for patients with 
missing tumor assessment or unknown overall lesion response for the evaluation of the 
primary endpoint. These cases will be considered as “non-progression free” for the primary 
endpoint (i.e. rate of progression free, defined also as disease control rate) and will be 
censored at the time of the last adequate tumor assessment for the time-to-event endpoints (e.g. 
progression-free survival analysis).
As a consequence of the above decision (i.e. removal of the replacement policy), it has been 
decided to change the timing of the primary endpoint from Month 12 to Month 9 and to 
modify the assumptions for sample size estimation and the decision rule based on the primary 
endpoint, according to the Fleming single-stage design (see Section 10.8).
The reason for this change in the timing of the analysis is to limit the impact of the 
discontinuations for reasons other than disease progression on the decision rule. The 
assessment at 9 months is also supported by the disease severity in the study population 
recruited.
Of all neuroendocrine tumors (NETs), almost 25% are located in the respiratory tract. Typical 
carcinoids comprise between 1 to 2% and atypical carcinoids 0.1 to 0.2% of all pulmonary 
neoplasms (Öberg et al. 2012). However, data currently available on the recruitment of LUNA 
trial diverges from this prevalence, showing a higher proportion of patients with atypical 
histological classification.
Compared to the subgroup analysis performed in the lung-NET patients from RADIANT-2 
(44 patients), patients recruited in the LUNA study present with a higher aggressive tumor 
biology (Fazio et al. 2013). In the RADIANT-2 subgroup of lung-NET, 75% of patients were 
classified as well-differentiated (low-grade, mitotic count <2 x 10 HPF) versus the LUNA 
study where a higher proportion of patients are well differentiated, atypical (intermediate 
grade, mitotic count of 2-10 x 10 HPF).
According to the evaluation and advice received by the Steering Committee (SC) members, 
the timepoint of 9 months for the analysis of the primary endpoint is reasonable and 
meaningful, based on current clinical experience and known biological behavior of lung-NET 
tumors.


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No change in the treatment duration (i.e. 12 months in the core study) has been implemented.
The 12-month assessments will remain to provide sufficient data for an accurate overall 
efficacy assessment of the treatments and to follow the standard evaluation of endpoints such 
as 12-month progression-free survival (PFS) in similar patient populations.
New information extrapolated from the recent [pasireotide Investigator Brochure] (IB, ed. 14
dated 02 June 2014) which has been reported in the protocol is:

update on marketing approvals, and new applications for marketing authorization;

update on safety data, with a special focus on hyperglycemia and QT-prolongation effects, 
and management recommendations for drug-related adverse events;

description of the results of clinical studies in patients with NETs;

update in terms of concomitant medications being allowed or prohibited;

effects on fertility.
Data being included in the protocol based on the new [everolimus Investigator Brochure] (ed. 
13 dated 12-May-2014) are related to:

update on marketing approvals and new applications for marketing authorization;

update on the number of patients being exposed to this agent during clinical trials and on 
cumulative post-marketing exposure in the oncology setting;

update on safety data, and management recommendations for drug-related adverse events;

update on the results of the main clinical studies in NET patients;

update in terms of concomitant medications being allowed or prohibited;

effects on fertility.
Other major changes implemented with the current protocol are:

to delete 
as protocol author and to add
 as expert statistician

to remove the distinction between the key secondary endpoint and the other secondary 
endpoints;

to evaluate secondary endpoints both at 9 and 12 months;

to delete “time to progression (TTP)” from the list of secondary endpoints. In this setting,
results on TTP are expected to be equivalent to PFS;
 
 
 
 
 
 
 
 
 
 


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
to reword the sentence related to the exclusion criterion #16. The positivity to hepatitis C 
antibody test (anti-HCV) indicates that a patient has a history of HCV infection (despite a 
negative viral load at baseline) but it will not exclude the subject from the enrollment into 
the LUNA study. Patients known to have a history of HCV infection, despite a negative 
viral load test at baseline (including those that were treated and are considered “cured”)
should be monitored every 4 weeks (± 1 week) for the risk of hepatitis C reactivation. The 
monitoring interval for the risk of hepatitis C reactivation has been changed from 4-8 
weeks to 4 weeks (± 1 week);

to specifiy that the monitoring for hepatitis B/C reactivation has to be performed in all 
patients, irrespective of the treatment arm they have been assigned to, taking into account 
the results arising from the four hepatitis B tests and the positivity for anti-HCV, 
respectively. However, in light of evidence that the risk for hepatitis B/C reactivation is 
related to everolimus, the drug interruption/discontinuation recommendations will apply to 
everolimus only;

to specify that, in case of non-infectious pneumonitis, the drug 
interruption/discontinuation recommendations will apply to everolimus only, in light of 
evidence that the risk for this event is related to this agent;

to specify that the monitoring of ECG changes has to be performed in all patients, 
irrespective of the treatment arm they have been assigned to, taking into account the 
observed QTcF value. However, in light of evidence that the risk for ECG changes is 
related to somatostatin analogue (SSA) treatment, the drug interruption/discontinuation 
strategy will apply to pasireotide LAR only;

to specify that, for the duration of the trial, pasireotide LAR and everolimus will be 
supplied by Novartis or by local commercial stock, if available. Therefore, if at any time 
during the study life pasireotide LAR or everolimus become available in the Countries 
participating to the study, the local commercial stock should be used;

to specify that patients could take their daily dose of everolimus as a single 10-mg tablet 
or as two 5-mg tablets taken together (QD), depending on the tablet strength available in 
the Country;

to add a sentence in which it is specified what can occur in case a patient misses the daily 
dose of everolimus at the scheduled time point. The patient will be given two options: to 
take the study drug within 8 hours after the normal time of administration, or to skip it 
until the next day;

to specify that, after the occurrence of an AE and the consequent reduction of pasireotide 
LAR dose, the re-escalation from 20 to 40 mg has to be performed within 56 days;

to include the possibility to use the 2.5 ml syringe, if the 3-ml is not available, to 
reconstitute pasireotide LAR suspension;

to clarify that all images for tumor assessment will be saved on a CD-rom and will be 
locally stored at the site in order to allow any future double check of the tumor assessment, 
if needed;

to include a sentence referring to the identification of pathological lymph nodes as target 
lesions, when measurable (i.e. short axis ≥ 15mm by CT scan), as per RECIST V. 1.1;


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
to include the definition of short axis for lymph nodes as the axis perpendicular to longest 
diameter, which will contribute to the baseline sum, as per RECIST V. 1.1;

to include the definition of biochemical response for chromogranin A (CgA), the main 
biochemical marker (Kouvaraki et al. 2004; Yao et al. 2010), and for 5-hydroxyindole 
acetic acid (5HIAA) [in accordance to the criteria of the Italian Trials in Medical 
Oncology Group (Bajetta et al. 1993; Bajetta et al. 2006)];

to specify that the biochemical response rate (BRR) and biochemical progression will be 
evaluated on the basis of serum CgA levels. Additionally, the biochemical response on the 
basis of urine 5HIAA will be assessed;

to include a sentence referring to diet restrictions to apply when patients are asked to 
collect urine samples for 5HIAA evaluation in view of the fact that some foods contain 
significant amounts of hydroxyindoles that may influence 5HIAA measurements. Thus, 
patients will be asked to amend their diet for three days before starting urine collection 
and during the collection to avoid interference with the test;

to update and reword sections on prohibited medications and medications that require 
caution and/or action, in order to be better understandable;

to correct protocol inconsistencies and typos.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, red font for insertions.
Table of contents and list of tables have been updated according to modifications
implemented throughout the protocol. Main changes were made to the following protocol 
sections:
Protocol summary

Summary modified to be in line with changes included in the protocol, and with study 
endpoints listed in Table 3-1 and in Section 3.2.
Section 1

Removal of cell size (large) from Table 1-1 when referring to typical and atypical 
carcinoids because, in the 2004 WHO classification criteria, there is no reference to cell 
size for typical and atypical carcinoids.

Harmonization of the 5-year overall survival rates reported in this section, by using the 
paper from Chong et al. (2006) as a reference. The rates included in Table 1-1 were 
slightly different from those reported in the text of the section. 

Updates to include new information on pasireotide/everolimus marketing approvals, 
clinical experience, and safety data, as in the new IBs. 
Section 3

Section 3 and Table 3-1 modified to:

change the timepoint for the primary endpoint (from 12 to 9 months), as by 
amendment rationale;


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
remove the distinction between the key secondary endpoint and the other secondary 
endpoints;

remove the secondary endpoint “time to progression (TTP)”, as by amendment 
rationale;

include the definitions of “objective response rate”, “best overall response”, “duration 
of biochemical response” and “biochemical progression-free-survival”.
Section 4

Clarification that tumor measurements will be based on triphasic CT/MRI, as as already 
reported in Section 7.2.1.1.

Correction of a mistake in the sentence “Disease control rate is defined as progression-free 
survival (PFS) according to RECIST V. 1.1” to “Disease control rate and progression-free 
survival will be evaluated during the extension phase”.
Section 5

Specification that patients with a well differentiated tumor will be enrolled in the study, as 
by study title and study objectives.

Clarification being added to the inclusion criterion #1 stating that patients with a well 
differentiated tumor will be enrolled in the study, as by study title and study objectives.

Clarification being added to the inclusion criterion #3 stating that baseline tumor 
assessment will be performed by triphasic CT/MRI, as already reported in Section 7.2.1.1.

Removal of the Hepatitis C antibody test (anti HCV) from the exclusion criterion #16. The 
positivity to this test does not exclude patients from enrollment into the LUNA study.
Section 6.1

Sections
“Management 
of 
Infections” 
and 
“Management 
of 
stomatitis/oral 
mucositis/mouth ulcers” updated according to the new everolimus IB (ed. 13).

Section “Management of hyperglycemia” updated according to the new pasireotide IB (ed. 
14), with subsection “Monitoring of glucose levels” updated to specify some information 
that were already included in the patient diary, and subsection “Dose adjustments”
reworded to specify that the interruption of treatment due to grade 3 hyperglycemia should 
not last ≥56 days from last dose, for pasireotide, and should not last ≥28 days from last 
dose, for everolimus (as already reported in Section 6.3.1.1 and Section 6.3.1.2).

Section “Management of non-infectious pneumonitis” updated according to information 
included in the new everolimus IB (ed. 13), with specification that, in case of non-
infectious pneumonitis, the dose reduction strategy applies only to everolimus since this 
AE can be related to the treatment with this agent.

Section “Monitoring for hepatitis B reactivation” updated, as by amendment rationale, to:

correct a mistake in Table 6-3 (distinction of patients with prior or no prior HBV 
vaccination);

specify that patients at risk of hepatitis B reactivation should have HBV DNA 
monitored every 4 weeks (± 1 week);


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
specify that the monitoring for hepatitis B reactivation has to be performed in all 
patients, irrespective of the treatment arm they have been assigned to, taking into 
account the results arising from the four hepatitis B tests.

Section “Monitoring for hepatitis C” updated, as by amendment rationale, to:

clarify that a patient who tests positive for the presence of HCV-RNA PCR will be 
ineligible for the LUNA study whereas a patient known to have a history of HCV 
infection (despite a negative viral load at screening) should be monitored every 4 
weeks (± 1 week);

specify that the monitoring for hepatitis C reactivation has to be performed in all 
patients with a known history of HCV infection, irrespective of the treatment arm 
they have been assigned to.

Section “Management of ECG changes” updated to include new information on the 
cardiac safety profile of pasireotide, as in the new pasireotide IB (ed. 14), with 
specification that the monitoring of ECG changes has to be performed in all patients, 
irrespective of the treatment arm they have been assigned to, taking into account the 
observed QTcF value.

Section “Hepatic safety management” reworded to make it clearer, easier to understand, 
and aligned with that described in Table 6-4.
Section 6.3

Inclusion of a sentence in Table 6-6 to specify that re-escalation of pasireotide LAR from 
20 to 40 mg has to be performed within 56 days.

Inclusion of a sentence to specify that the initial once-daily oral dose of everolimus (10 
mg) can be administered either as two 5 mg tablets taken together (QD) or as a single 10 
mg tablet, and in case a dose reduction is required due to toxicity, patients initially 
receiving the 10 mg strength will be provided with the 5 mg strength.

Table 6-8 updated according to what reported in the new everolimus IB (ed. 13).
Section 6.4

Section modified to include also concomitant therapies, not only concomitant medications
(with the possibility of performing palliative radiotherapy or surgery during the study, 
after discussion with Novartis Clinical Trial Team).

Overall section reworded to make it clearer and easier to understand, and being aligned 
with updated information from the new IBs (ed. 13 for everolimus; ed. 14 for pasireotide).

Introduction of a new sentence stating that the use of the anticoagulant medication 
warfarin should be avoided. Warfarin should be replaced by selective Factor Xa inhibitors 
(rivaroxaban, apixaban, dabigatran) which are acceptable from a safety point of view since 
there have no effect on prothrombin time (PT), and partial thromboplastin time (PTT).

Inclusion of a sentence stating that “prolonged (>2 weeks in duration) treatment with 
systemic corticosteroid treatment is not allowed during the study”.

Inclusion of the link to the website listing the drugs prolonging the QT interval. The 
previous link did not run any more.


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Section 7.1

Section updated to change the order of the following criteria for premature withdrawal: 
“Pregnancy, patient withdrawing informed consent, new cancer therapy, patient lost to 
follow-up and death”, because they are not “study specific criteria” but common criteria 
for discontinuation.

Specification of information regarding QTcF value, according to what reported in Section 
6.1.4.9.

Removal of the replacement policy, as by amendment rationale.
Section 7.2

Change in the timepoint for the primary endpoint (from 12 to 9 months), as by amendment 
rationale.

Inclusion of a sentence clarifying that all images will be saved on a CD-rom and will be 
locally stored at the site in order to allow any future double check of the tumor assessment, 
if needed.

Inclusion of new paragraphs referring to the calculation of the baseline sum of the longest 
diameters for all target lesions; the identification of pathological lymph nodes as target 
lesions, when measurable; and the definition of short axis for lymph nodes, as per 
RECIST V. 1.1.

Inclusion of the subsection “Response assessment” for the primary endpoint which was 
previously reported for secondary efficacy assessment only. This part was modified by 
separating response assessment for target lesions from that of non-target lesions, 
according to RECIST V. 1.1 criteria.

Inclusion of the definition of biochemical response for CgA, the main biochemical marker 
(Kouvaraki et al. 2004; Yao et al. 2010), and for 5HIAA [in accordance to the criteria of 
the Italian Trials in Medical Oncology Group (Bajetta et al. 1993; Bajetta et al. 2006).

Specification that the biochemical response rate (BRR) and biochemical progression will 
be evaluated on the basis of serum CgA levels. Additionally, the biochemical response on 
the basis of urine 5HIAA will be assessed.

Inclusion of a sentence referring to diet restrictions to apply when patients are asked to 
collect urine samples for 5HIAA evaluation.

Inclusion of a sentence stating that total white blood cells (WBC) count will be evaluated 
as absolute and, only if available, as differential.

Inclusion of the chance to evaluate urea, instead of BUN, if BUN cannot be directly 
evaluated.

Change in the second time point at which female patients of childbearing potential should 
have a negative serum pregnancy test (not 48 hours prior to treatment start but at visit 2).

Section “Hepatitis screening” revised to:

remove a contradictory statement in terms of screening for hepatitis B. Prior to 
randomization, all patients (not a selected group of patients at risk) must be tested for 
Hepatitis B viral load and serologic markers, that is: Hepatitis B 
VirusDeoxyribonucleic acid (HBV-DNA), Hepatitis B surface antigen (HBsAg), 
Hepatitis B surface Antibody (HBsAb), and Hepatitis B core Antibody (HBcAb), as 


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by exclusion criterion #16. If a patient tests positive for the presence of HbsAg and/or 
HBV-DNA, he/she will be considered ineligible for the study according to Exclusion 
Criterion #16. In case of eligibility, the results from the other two tests (HBsAb and 
HBcAb) will detect which patients have to be monitored for the risk of hepatitis B 
reactivation every 4 weeks during the study, as reported in Section 6.1.4.8;

remove a contradictory statement in terms of screening for hepatitis C. All patients 
will be tested for HCV-RNA PCR. If positive, the patient will be considered ineligible 
for the LUNA study, according to the Exclusion criterion #16. Patients known to have 
a history of HCV infection (positivity to anti HCV), despite a negative viral load at 
baseline, will be monitored for the risk of hepatitis reactivation. The monitoring will 
take place every 4 weeks (± 1 week) (not every 4-8 weeks as previously stated). 
Section 8

Correction of the name of the form in which information about deaths will be collected. 

Section being updated according to information on fertility included in the new IBs (ed. 13
for everolimus; ed. 14 for pasireotide). 
Section 10:

Change of some part of this section referring to the statistical methods and data analysis, 
as by amendment rationale.

Change in the list of major protocol violations, to be in line with changes introduced in the 
VAP3 (Novartis Validation and Planning 3) module that classify protocol deviations.

Change in the timepoint at which the primary endpoint will be evaluated (from 12 to 9 
months), as by amendment rationale.

Updated sample size section with new null and alternative hypotheses, as per amendment 
rationale.

Removal of the secondary endpoint “TTP”, as by amendment rationale.

Change in the analysis of infections which will be no more analysed separately from AEs. 

Clarification of the way ECG data will be analysed, from a statistical point of view.

Change in the way vital signs will be analysed.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Amendment 3
Amendment rationale
The amended version 02 (finalized on December 2012) of the study protocol is being 
amended after the submission to Competent Authorities/Ethics Committee mainly to 
implement several requests of modification from Competent Authorities/Ethics Committee, to 
update information of pasireotide LAR based on the new version of the Investigator Brochure 
ed. 13 dated 24-May-2013, to correct information based on the RAD001 IB ed 11 erratum 
document dated 24-May-2013, and to better clarify some information already present in the 
protocol.
Competent Authorities requests are focused especially on:

Clarify the target population described in Inclusion criterion #1

Implement an exclusion criterion for female patients pregnant and breast-feeding

Implement a more frequent monitoring of the Thyroid Function Tests

Implement a more detailed guidance for physicians in the response to a QTc prolongation 
on ECG.
The new information extrapolated from the Pasireotide LAR IB ed. 13 dated 24-May-2013 
which will be implemented in the protocol is:

The description of the results of a phase III study with NET patients treated with 
Pasireotide LAR.
The data to be modified in the protocol based on the RAD001 IB ed. 11 Erratum dated 
24-May-2013 are related to:

Afinitor dose adjustment and management recommendation for Non-Infectious 
Pneumonitis

Effects of everolimus on fertility.
Other changes implemented with the current protocol are:

To include 
 and 
and to delete 
 as protocol authors

To delete the specification in the Amendment 2 Rationale section that there is the 
possibility to increase the Everolimus dose in case of tolerability issues for patients with 
non-infectious pneumonitis

To delete the specification in the Changes to the Protocol section of Amendment 2 that 
there is the possibility to increase the Everolimus dose in case of tolerability issues for 
patients with non-infectious pneumonitis 

To update comment in the Changes to the Protocol section of Amendment 2, related to 
Section 6.1.4.7

To correct some typos in Amendments 1 and 2 Rationales

Clarify in the Inclusion Criterion #2 that the administration of the study drugs can be also 
the first line of treatment

To enhance clarity of the end of the treatment definition and align sections


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
To correct a wrong information in Table 6-9 about the possibility to keep the patient in 
study even if the re-escalation of the dose of Pasireotide LAR from 20mg to 40mg is not 
possible

To reword and reorganize paragraphs of sections of prohibited medications and the 
medications that require caution and/or action, in order to be better understandable 

To include the possibility to use the Pasireotide LAR 40mg to obtain the dose of 20mg if 
20mg strength is not available at the site 

To clarify the IVRS randomization process

To update Table 7-1 with the new assessments required by the Competent Authorities. (i.e. 
ECG and Thyroid Function Tests)

To correct the Table 7-2 to clarify that Pasireotide LAR and/or Everolimus will be 
provided also at visit 18 for patients that continue treatment at the end of the Core Phase

To align the description of the assessments in the body of the protocol with Tables 7-1 and 
7-2

To correct some protocol inconsistencies and typing errors.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, red font for insertions.
Table of contents and list of tables have been updated according to modification implemented 
throughout the protocol. Changes were made to the following protocol sections:
Section 2.1:

Section updated for Pasireotide LAR clinical efficacy in NET.
Section 4.1.3:

Section updated to enhance clarity of the end of the treatment definition.
Section 4.4:

Section updated to clarify which are the Novartis reasons for an Early study 
discontinuation.
Section 5.2:

Revision of Inclusion Criterion # 1 to add a clear explanation of which patients’ 
population will be included in the study.

Revision of Inclusion Criterion #2 to add the clarification that there is no limit to the 
number of previous treatment lines and also naïve patients can be enrolled.
Section 5.3:

Introduction of a new exclusion criterion for female patients pregnant and breast-feeding.

Revision of the Exclusion criterion # 21 to better clarify the risk factors for Torsades de
Pointes.


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Section 6.1.4.7:

Table 6-2 was corrected to insert:

the right grade of improvement of Non-Infectious Pneumonitis from which the 
treatment could re-start.

the right time within which the treatment should be re-started to avoid patient 
withdrawal from the study in presence of Non-Infectious Pneumonitis grade 2.

the right time within which the treatment should be re-started to avoid patient
withdrawal from the study in presence of Non-Infectious Pneumonitis grade 3.
Section 6.1.4.9:

Revision of the section to update the indications for the management of the ECG changes.
Figure 6-3:

Figure updated based on the new indications implemented in the section 6.1.4.9.
Section 6.1.7:

Section updated to align sections related to the end of study definition.
Section 6.3.2:

Table 6-9 has been modified in order to correct a typo; to specify that if the dose re-
escalation of Pasireotide LAR to 40mg is not possible the patient cannot be maintained in 
the study.
Section 6.4.2:

Revision of the section to reword and reorganize the paragraphs of the section of the 
medications that require caution and/or action, in order to be better understandable.
Section 6.4.3:

Revision of the section to reword and reorganize paragraphs of section of prohibited 
medications, in order to be better understandable.
Section 6.5.1:

Revision of the section to better clarify the IVRS randomization process.
Section 6.5.2:

Revision of the section to better clarify the IVRS randomization process.
Section 6.6.1.1:

The Table 6-13 has been modified in order to indicate that the 20mg dose could be 
obtained using also a portion of the volume of the 40mg strength. 

Section updated to add the indication that if the 20mg strength is not available at the site 
the dose could be obtained from the 40mg strength.
Section 7.1:

The Table 7-1 has been modified in order to:

Specify that the assessment performed at the End of Core study also apply for the 
Early withdrawal.


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
Specify that the visit 18 has to be performed at week 52 and not at week 53.

Specify that the Thyroid function tests will be performed at week 12 (visit 8) and at 
week 24 (visit 11).

Specify that ECG will be performed at week 8 (visit 7).

Specify that Pasireotide LAR injection will be done also at visit 18 for patients that 
will continue treatment at the end of the Core Phase.

Specify that Everolimus administration will be done also at visit 18 for patients that 
will continue treatment at the end of the Core Phase.

The Table 7-2 has been modified in order to:

Specify that Pasireotide LAR injection will be done monthly at visit 18 for patients 
that will continue treatment at the end of the Core Phase.

Specify that Everolimus administration will be done also at visit 18 for patients that 
will continue treatment at the end of the Core Phase.

Specify that patients who discontinue study treatment after 12 months of treatment 
without evidence of progression or for reasons other than disease progression will 
continue to have tumor evaluation assessments.
Section 7.2.2.5.2:

Sections changed to add the timelines for the International Normalized Ratio (INR) during 
the Extension phase.
Section 7.2.2.5.6:

Sections changed to add the timelines for the Lipid profile during the Extension phase.
Section 7.2.2.5.7:

Section changed to specify that the thyroid function tests will be assessed at week 12 (visit 
8) and at week 24 (visit 11).
Sections 7.2.2, 7.2.2.2, 7.2.2.5, 7.2.2.5.1, 7.2.2.5.3, 7.2.2.5.4, 7.2.2.5.4, 7.2.2.5.5, 7.2.2.5.8, 
7.2.2.6.4, 7.2.2.7.1:

Sections updated with the indication that the timeline of these assessments for the 
Extension phase are indicated in the Table 7-2.
Section 8.4:

Section changed to update the information about the fertility present in the RAD001 IB ed.
11 Erratum dated 24-May-2013.
Section 10:

Section changed to delete the last paragraph because the assumption described in it is not 
applicable for the study.


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IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Amendment 2
Amendment rationale
The amended version 01 (finalized on November 29th, 2011) of the study protocol is being 
amended before submission to Competent Authorities/Ethics Committee mainly to clarify the 
importance of routine patient glucose self-monitoring, to detect and treat hyperglycemia as 
early as possible, and to give specific guidance on dose adjustment in the different treatment 
arms.
The combination of pasireotide LAR, which alters insulin and incretin secretion, and 
everolimus, which may affect insulin sensitivity, could result in a higher risk for 
hyperglycemia than each agent alone. Based on the currently available preliminary data, it is 
hypothesized that one possible reason for the high rate of grade 3 hyperglycemia could be the
suboptimal monitoring of blood glucose.
In study CSOM230F2102 (pasireotide LAR 60 mg q28d in combination with everolimus 10 
mg qd) three hyperglycemia grade 3 Adverse Events (AEs) were observed, two of them were 
reported as serious adverse events (SAEs). One patient had a medical history of diabetes 
mellitus. Concomitant medications included metformin. The patient accidentally received 
pasireotide at a single dose of 80 mg. The patient had not received everolimus. Fifteen days 
after commencing pasireotide the patient developed signs of hyperglycemia with symptoms of 
fatigue and polydipsia. Five days later, the patient was admitted to the hospital for 
hyperglycemia (self-measured at 
 mg/dl and measured in hospital at 
 mg/dl). The 
subject was treated with insulin adjusted to blood glucose levels. Pasireotide dosage was 
reduced to 40mg. The investigator reported that the study medication along with the 
insufficient antidiabetic medication had contributed to the hyperglycemia. Due to the tight 
monitoring in this study, and early intervention for treating hyperglycemia, this patient was 
well managed and did not develop more severe complications of hyperglycemia. The second 
patient´s medical history included diabetes mellitus type II. The patient received the first dose 
of the study medication (everolimus) at a dose of 10 mg. Twelve days after start of study drug 
the patient was hospitalized to initiate insulin therapy (Insulin Lispro injection) for treatment 
of diabetes mellitus.
As of July 3, 2012, in study CSOM230I2201 (oral everolimus alone or in combination with 
pasireotide LAR i.m.) the majority of patients included to date developed various degrees of 
hyperglycemia irrespective of glucose values at baseline. Pooled analysis of blinded safety 
data identified eighteen patients with grade ≥3 hyperglycemia so far. Five cases were reported 
as SAE, two of these comprised a grade 4 hyperglycemia (ketoacidosis). One of theses cases 
developed metabolic acidosis with fatal outcome. This patient’s medical history included left 
colectomy, intestinal occlusion, hypertension, chronic obstructive bronchopneumonia and 
dyslipidemia. Concomitant medication included candesartan cilexetil, ezetimibe, omeprazole, 
and tiotropium bromide. The patient started medication with everolimus and pasireotide LAR 
and received one dose of pasireotide LAR and the last dose everolimus on study day 27. On 
day 24, the patient started developing asthenia, deterioration of general condition, vomiting, 
and diarrhea. Three days later the patient was hospitalized and showed signs of confusion, 
dehydration, marbled skin under the lower limb: blood culture was positive for E. Coli, and


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ketoacidosis was diagnosed. On day 29, the patient died with an acute, severe metabolic 
acidosis that may have resulted from ketoacidosis, although sepsis was also considered as a 
contributory factor. In addition to ketoacidosis, inhalation pneumonia, sepsis and acute 
respiratory distress were also considered as having contributed to the patient’s death.
The other patient who had Grade 4 hyperglycemia had a medical history that included 
hypertension, diabetes mellitus type II, insomnia, and hypercholesterolemia. Concomitant 
medications included repaglinide, metformin, omeprazole, lisinopril with hydrochlorothiazide, 
zolpidem, emuliquen and paracetamol. The patient started the study medication everolimus 
and pasireotide LAR and received one dose of pasireotide, and 20 days of everolimus. On day 
21 of cycle 1, the patient presented with a deterioration of 
 health status, and suffered from 
fainting and was hospitalized and diagnosed with diabetic ketoacidosis on the same day. Lab 
results showed a glucosuria of 
 mg/dL, glucose (serum) of 
 mg/dL, troponin I 
 
mg/L, CK (creatinine kinase) 
 U/ and hemoculture showed Klebsiella oxycota. 
Hyperglycemia was controlled with insulin, and the patient was treated with antibiotics. Study 
treatment was interrupted as a result of the event. The patient was discharged from the 
hospital 12 days later after hyperglycemia was controlled and treatment with intravenous 
antibiotics was completed.
In order to prevent and appropriately treat hyperglycemia, specific guidance on dose 
adjustment in the different treatment arms is provided. Management of hyperglycemia in the 
combination and pasireotide LAR monotherapy arms was updated and monitoring of glucose 
levels for patients with normal glucose at baseline in combination and pasireotide LAR 
monotherapy arms by fingerstick testing was added. The glucose assessments by fingerstick
testing for patients with normal glucose metabolism at baseline and allocated in the 
everolimus monotherapy arm were removed, as the assessments are not considered required 
for these patients, based on the currently known safety profile. Furthermore, all patients will 
be required to have local laboratory assessments of glucose level during all study visits. The 
glucose level will be assessed at day 49 visit in patients of everolimus monotherapy arm only 
if medically indicated. Other changes implemented with the current amendment are:

To include
 and to delete 
 and 
 as protocol authors

To include updated information on antitumor activities of somatostatin analogues and 
clinical experience on pasireotide LAR

To update information on approval status of everolimus worldwide and on clinical 
experience with everolimus

To remove the background information on mutational status of genes encoding for drug 
targets and for proteins involved in drug target pathway

To include pre-clinical data in study rational and purpose 

To update rational for dose and regimen selection section

To include the possibility to reduce everolimus by two dose levels to 5 mg every other day 
in case of tolerability issues

To include the 20 mg strength of pasireotide LAR that should be used to re-start study 
drug treatment in case of tolerability issues

To classify as extension phase (instead of follow-up phase) the treatment period following 
the core study


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
To specify also in the inclusion criteria #3 and #5 that MRI can be used to assess lesions at 
baseline to maintain consistency throughout the protocol

To clarify that the use of subcutaneous (s.c.) somatostatin analogs is allowed up to 48 
hours prior to starting study treatment (exclusion criterion #3)

To clarify that the 6 months wash-out period from previous therapy with radioligand 
therapy is considered prior to starting study treatment. The recovery from the adverse
effects of such therapy is requested

To reduce the wash-out period (from 3 months to 4 weeks or 5 half lives, whichever is 
longer) from prior chemotherapy and immunotherapy prior to starting study treatment 
considering appropriate a 4 weeks- or 5 half-lives wash out period (exclusion criterion #7).
The recovery from the adverse effects of such therapy is requested

To exclude
from study participation
patients with hepatic artery embolization, 
cryoablation or radiofrequency ablation of hepatic metastasis within the last 3 months 
prior to starting study treatment. The recovery from the adverse effects of such therapy is 
requested

To reduce the wash-out period (from 3 months to 4 weeks or 5 half lives, whichever is 
longer) from a previous treatment with an investigational drug within a clinical trial prior 
to starting study treatment , considering appropriate a 4 weeks- or 5 half-lives wash out 
period (exclusion criterion #8). The recovery from the adverse effects of such therapy is 
requested

To reduce the wash-out period (from 3 months to 4 weeks) from previous radiotherapy 
prior to starting study treatment (exclusion criterion # 14). The recovery from the adverse 
effects of such therapy is requested

To exclude from study participation patients with detectable HBV-DNA to be consistent 
with the exclusion of patients with chronic active hepatitis B at baseline (exclusion 
criterion #15)

To exclude from study participation patients with detectable HCV-RNA-PCR test at 
baseline to be consistent with the exclusion of patients with chronic active hepatitis C
(exclusion criterion #15)

To specify that a wash-out period of 5 half lives from previous treatment with drugs 
known to prolong QT is needed for inclusion in the clinical trial (exclusion criterion #20)

To specify that highly effective contraception measures should be followed during clinical 
trial participation (exclusion criterion #23)

To change the allowed dose delay from 21 to 28 days to recover from on treatment 
toxicities considering the 28-day cycle duration

To specify that the combination treatment of pasireotide LAR and everolimus will be 
discontinued in case one drug of the combination is discontinued due to an adverse event.

To specify that, in case of tolerability issues, no dose re-escalation for everolimus will be 
performed

To provide recommendation about treatment management in case of tolerability issues


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
To clarify that everolimus dose can be reduced up to 5 mg every other day in case the 
patient requires co-administration of a CYP3A4 and PgP inhibitors to adjust the AUC to 
the range observed without inhibitors

To delete the PK samples management for patients receiving an inducer of CYP3A4 in 
addition to everolimus, since no PK analysis is planned during study conduction

To specify that strong CYP3A4 and PgP inhibitors are not allowed during study 
participation

To update the list of allowed concomitant medications during study participation
according to new information available

To specify that azithromycin co-administration is not allowed while on study treatment
being a drug that induces QT prolongation

To delete the specifications about the needle to be used to withdraw the suspension of 
pasireotide LAR as needles will be used according to local practice

To update baseline requirements, target lesion definition and response assessment
according to RECIST 1.1

To define response of CgA or 5HIAA as normalization or a ≥50% reduction of CgA
or 5HIAA levels compared to baseline

To specify that free thyroid T3 and T4 hormone levels will be collected at 
screening/baseline and EOS

To introduce the possibility to perform serum pregnancy test instead of urine pregnancy
test at baseline, every months during core phase and every 3 months during extension 
phase, according to local practice
 

To include some details about the Data Monitoring Committee and the Steering 
Committee

To correct some protocol inconsistencies and typing errors.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, red font for insertions.
Table of contents and list of tables have been updated according to modification implemented 
throughout the protocol.
Changes were made to the following protocol sections:
Section 1.2.3

Section updated for pasireotide LAR pre-clinical and clinical experience.
Section 1.2.2

Section updated for everolimus approvals from FDA and EMA.
Section 1.2.2.3

Section updated for everolimus clinical experience.


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Section 1.2.3

Section modified to remove information on mutational status of genes encoding for drug 
targets and for proteins involved in drug target pathway.
Section 2.1

Section modified to include pre-clinical data supporting the use of the combination of 
pasireotide LAR and everolimus.
Section 2.3

Section updated for previous clinical data details.
Section 4.1.2

Section revised to better clarify that everolimus and pasireotide LAR dose can be adjusted 
in case of toxicity issues.
Section 4.1.3

Section title changed according to re-classification of follow-up phase to extension phase.
Figure 4.1 

Follow up phase changed to extension phase.
Section 5.2

Revision of inclusion criteria #3 and #5 to add the possibility to assess lesions using MRI 
at baseline.
Section 5.3

Revision of the following exclusion criteria:

Exclusion criterion #3: to specify that s.c. somatostatin analogs are allowed up to 48 h 
prior to start of study treatment.

Exclusion criterion #6: to specify that patients who received radioligand therapy 
within 6 months prior to starting study treatment are excuded. The recovery from the 
adverse effects of such therapy is requested for study participation.

Exclusion criterion #7: to reduce wash-out period from previous chemotherapy or 
immunotherapy prior to starting study treatment. The recovery from the adverse 
effects of such therapy is requested.

Introduction of a new exclusion criterion for patients who received cryoablation or 
radiofrequency ablation with hepatic artery embolization, of hepatic metastasis within 
the last 3 months prior to starting study treatment. The recovery from the adverse 
effects of such therapy is requested.

Exclusion criterion #8: to reduce the wash-out period from previous treatment with an 
investigational drug within a clinical trial prior to starting study treatment. The 
recovery from the adverse effects of such therapy is requested.

Exclusion criterion #13: to reduce the interval between previous radiotherapy and the 
start of study treatment administration. The recovery from the adverse effects of such 
therapy is requested.


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
Exclusion criterion #14: to correct the value for O2 saturation at rest on room air from 
80 to 88%.

Exclusion criterion #15: to specify that patients with detectable HBV-DNA and HCV-
RNA-PCR at baseline are not eligible.

Exclusion criterion #21: to specify that drugs known to prolong QT are allowed as far 
as not administered within 5 half lives prior to start of study treatment.

Exclusion criterion #23 and addition of a new exclusion criterion: to update the 
definition of highly effective contraception.
Section 6.1.4.5

Modification of the section
to implement appropriate hyperglycemia screening, 
monitoring and management. Table 6-1 added to summarize hyperglycemia management.
Section 6.1.4.7

Table 6-2 was modified to specify everolimus dose adjustment in case of grade 2 non-
infectious pneumonitis.
Section 6.1.4.8

Revision of the section to remove references to prophylactic treatment for patients with 
detectable HBV-DNA at baseline and patients with detectable HCV RNA at baseline. 
Section 6.1.4.9 

Figure 6-3 modified to remove text boxes referring to PK samples.
Section 6.1.5 

Figure 6-4 modified to specify that no PK sample will be collected.
Section 6.3.1.1

Revision of the section to specify that pasireotide LAR dose reduction up to 20 mg is 
allowed and change the allowed dose delay from 21 to 28 days to recover from toxicities.
Section 6.3.1.2 

Revision of the section to specify that everolimus dose reduction to 5 mg every other day 
is allowed, to clarify that after the recovery form tolerability issues no dose-re-escalation 
of everolimus will be performed and to change the allowed dose delay to recover from 
toxicities.
Section 6.3.2

Recommendations for treatment management in case of tolerability issues have been 
provided. Table 6-9 has been introduced.


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Section 6.4.1 

Tables updated with inducers, moderate and strong inhibitors. 
Section 6.4.2 

Revision of the section to:

Add an explanation about the use with caution of PgP and CYP3A4 inducers and 
inhibitors during the study

Change the everolimus dose to be used in case of concomitant use CYP3A4 or PgP 
inhibitors.

Update the list of PgP and CYP3A4 inducers and inhibitors. 
Section 6.4.3

Revision of the section to specify that strong CYP3A4 and PgP inhibitors are not allowed 
during study participation and that everolimus blood level will not be assessed for patients 
receiving CYP3A4 inducer. The co-administration with azithromycin was deleted as it 
induces QT prolongation.
Section 6.6.1

Pasireotide 20 mg strength introduced in Table 6-11.
Section 6.6.1.1

Revision of the section to delete the specifications of the needle to be used for pasireotide 
LAR preparation and administration. Furthermore, details of pasireotide LAR 20 mg 
strength are provided.
Section 6.6.3.1 

Pasireotide LAR 20 mg strength has been introduced.
Section 7.1

The Table 7-1 has been modified in order:

To specify that concomitant medication and adverse events will be evaluate also on 
day 49. To provide indications about the glucose level assessment in the different 
treatment arms.

To include a safety follow up visit to be performed 56 days after treatment 
discontinuation for patients with disease progression at week 53 or who prematurely 
discontinued study treatment.

To specify that PTT will be performed at screening/baseline

The Table 7-2 has been modified:

To change follow up phase into extension phase

To include a safety follow up visit to be performed 56 days after treatment 
discontinuation.

To provide indications about the glucose level assessment in the different treatment 
arms.


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Section 7.1.4.1

Section modified to specify that patients with blood glucose values consistently in excess 
of 250 mg/dL persisting after interruption of study drug in spite of continuous, appropriate 
therapeutic intervention(s) will be discontinued.
Section 7.1.5

Section title was modified from Follow up period to Extension period.
Section 7.2.1.1

Revision of the section to introduce the possibility to assess lesions using MRI at baseline, 
to re-classify follow up phase as extension phase and to better specify baseline 
requirements and target lesion definition according to RECIST v1.1.
Section 7.2.1.2

Revision of the section to re-classify follow up phase as extension phase and to better 
clarify the response assessment according to RECIST v 1.1 and to define response of
CgA or 5HIAA as normalization or a ≥50% reduction of CgA or 5HIAA levels
compared to baseline.
Section 7.2.2.5.3

Section modified according to modification of section 7.2.2.5.4.
Section 7.2.2.5.4

Section added to provide details about the assessment of glucose, insulin, and glycated 
hemoglobin during study participation.
Section 7.2.2.5.7

Section changed to specify that free T3 and T4 hormones are included in thyroid function 
assessments.
Section 7.2.2.5.9

Definition of effective contraception has been updated. Name of follow up phase has been 
changed to extension phase. The possibility to perform serum pregnancy test instead of
urine pregnancy test has been introduced.
Section 7.2.2.5.10

The referenced number of exclusion criterion for hepatitis C and B has been corrected 
from 21 to 16.
 
Section 7.2.4.2

In Table 7-5 the visit number was corrected from visit 6 and 7 to visit 7 and 8.
Section 8.4

Section revised to include highly effective contraception requirements.


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Section 8.6

Section modified to provide further details on Independent Data Monitoring Committee.
Section 8.7

Section modified to specify that a Steering Committee charter will be provided.
Section 10.4.1

Section modified to add MRI.
 
Section 13

Reference section has been updated.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Amendment 1
Amendment rationale
The original version (version 00, finalized on October 6th, 2011) of the study protocol is being 
amended before submission to Competent Authorities/Ethics Committee to increase the 
hepatic-related safety measures for patients treated with pasireotide LAR.
During an internal medical review of liver related laboratory values, 3 healthy volunteers 
treated with pasireotide (SOM230) were identified with elevations in liver function tests. Two 
subjects met the criteria for Hy’s Law (i.e. ALT > 3 x ULN with concurrent total bilirubin >2 
x ULN, without increases in alkaline phosphatase and no other cause(s) identified for the 
abnormal findings). One subject received pasireotide 600 g bid s.c. for 7 days, while the 
second subject received pasireotide 1950 g bid s.c. for 5 days. The third subject (pasireotide 
600 g bid s.c. for 7 days) had ALT and total bilirubin increases that met the criteria for Hy’s 
Law but the alkaline phosphatase was not assessed and the subject received a potentially 
confounding concomitant medication. ALT values for all 3 subjects were greater than 3 x 
ULN but < 4 x ULN and total bilirubin values were < 4 x ULN. All 3 cases were 
asymptomatic, presented within 10 days after initial pasireotide s.c. administration, and were 
reversible with discontinuation of pasireotide. None of the cases were reported as adverse 
events and the subjects completed the respective studies per protocol. 
An assessment of liver enzyme categorical outliers has been completed across the pasireotide 
s.c. development program (up to October 2011). The 3 healthy volunteers that met the 
biochemical criteria of Hy’s Law (including the subject without the ALP value) are included 
amongst the 654 healthy volunteers as presented below. None of the other patients (i.e. 
Cushing’s disease, carcinoid syndrome or acromegaly) in the development program met the 
criteria for Hy’s Law.

654 healthy volunteers have been exposed to pasireotide s.c.:

3 out of 654 (0.5%) met the biochemical criteria of Hy's Law 

16 out of 654 (2.4%) subjects had an ALT or AST > 3x ULN 

3 of the healthy volunteers had an ALT or AST > 5xULN

17 out of 654 (2.6%) subjects had a total bilirubin of 2xULN (including 7 patients 
with pre-existing liver disease and elevations of total bilirubin)

156 patients in phase 1 and phase 2 trials have been exposed to pasireotide s.c.: 

None of the patients met the biochemical criteria of Hy's Law 

6 out of 156 (3.8%) patients had an ALT or AST > 3xULN 

4 out of 156 (2.6%) patients had an ALT or AST > 5xULN

2 out of 156 (1.3%) patients had a total bilirubin of ≥2xULN; 

162 patients with Cushing’s disease in phase 3 trials have been exposed to pasireotide 
(s.c.): 

None of the patients met the biochemical criteria of Hy's Law 

8 out of 162 (4.9%) patients had an ALT or AST > 3x ULN 


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
1 out of 162 (0.6%) patients had an ALT or AST > 5x ULN

None of the patients out of 162 with Cushing’s disease had a total bilirubin of ≥
2xULN.
The pasireotide Compassionate Use Program (approximately 200 patients as of October 2011) 
was also reviewed. A single Cushing’s disease patient 
 who was 
previously presented in an Investigator Notification in September 2010 was the only patient 
identified meeting the biochemical criteria Hy’s Law.
A review of the unblinded data from the clinical program with the pasireotide long acting 
release (LAR) formulation did not reveal cases meeting the biochemical criteria Hy’s Law .
As a consequence of these observations, enhanced hepatic-related safety measures will be 
taken to ensure patient safety. 
Other minor changes implemented with the following amendment are:

To change the Statistician. The responsibility passed from 
 to 
 ad interim

To include
 as author of the clinical trial protocol.

To align inclusion and exclusion criteria

To specify that one single vial of 60 mg pasireotide LAR will be reconstituted with the 
vehicle instead of one 20 mg vial plus one 40 mg vial. The 40 mg vial will be supplied to 
sites to be used in case pasireotide LAR dose is reduced for suspected pasireotide LAR-
related toxicities.

To specify that gallbladder evaluation will be performed together with the radiological 
tumor evaluation as safety assessment at baseline for all patients, on treatment only for 
patients treated with pasireotide LAR.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, red font for insertions.
Changes were made to the following protocol sections:

Section 5.2 Inclusion criteria

Section 5.3 Exclusion criteria

Section 6.1.5 Hepatic Safety Management NEW

Section 6.3.2.1 Hepatic-related discontinuation criteria

Section 6.6.1.1 Preparation procedure for pasireotide LAR

Section 6.6.3.1 Pasireotide LAR

Section 7.1 Study flow and visit schedule

Section 7.1.4.1 Criteria for premature patient withdrawal

Section 7.2.1.1 Primary efficacy assessment

Section 7.2.2 Safety and tolerability assessments

Section 7.2.2.5.2 Coagulation

Section 7.2.2.5.3 Biochemistry


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
Section 7.2.2.5.4 Liver Function Tests

Section 7.2.2.5.9 Hepatitis screening

Section 7.2.2.6.4 Gallbladder Assessment
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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1
Background
1.1
Overview of neuroendocrine tumors of the lung and thymus
1.1.1
Lung neuroendocrine carcinoma
Lung cancer is the third most frequent cancer type of men and women worldwide. The main 
types of lung cancer are non small cell lung cancer (NSCLC; 70%-80%) and small cell lung 
cancer (SCLC, ~25%). Lung “carcinoid” tumors are well differentiated neuroendocrine 
carcinomas (lung-NETs) of the lung and account for 1%–2% of all pulmonary neoplasms and 
for ~25% of all carcinoid tumors. Approximately 10%–20% of pulmonary carcinoids are 
atypical carcinoids, and the remaining 80%–90% are typical carcinoids. Patients with 
carcinoid tumors are younger than those with common primary lung cancer. Unlike typical 
carcinoids, atypical carcinoids are associated with a history of cigarette smoking (83%–94% 
of cases) and occur more often in men (2:1) (Schreurs et al. 1992). Most typical carcinoids 
(80%–90%) are stage I, whereas approximately 50% of atypical carcinoids are stage I cancers. 
The standard treatment with curative intent for carcinoid tumors is surgery to completely 
remove the tumors. The 5-year overall survival rates for typical carcinoids and atypical 
carcinoids are 87% and 56%, respectively, and the survival rate for atypical carcinoid is 
significantly poorer than that for typical carcinoid (Chong et al. 2006).
Lung-NETs share most morphological and clinical features observed in gastrointestinal NETs. 
Similarly, pure NETs and mixed forms can be distinguished pathologically. Clinical 
presentation of NETs range from benign typical carcinoid tumors (TCs) to atypical carcinoid 
tumors (ACs) having a low-grade behavior, to the highly aggressive poorly differentiated 
carcinomas of the small and large cell neuroendocrine types, which share the same poor 
prognosis (Righi et al. 2007).
As per 2004 WHO classification of NETs of the lung, architectural and other parameters,
together with the mitotic index and the presence of necrosis as the two most relevant 
characteristics, lead to the current classification into the four different categories proposed in 
the spectrum of NETs of the lung (Travis et al. 2004).
Table 1-1
Differential pathological findings in NE lung tumors (2004 WHO 
classification) (Travis et al. 2004; *Chong et al. 2006)
Organoid pattern
Typical carcinoid 
(TC)
Atypical
carcinoid (AC)
Large cell NE 
carcinoma
Small
cellcarcinoma
Characteristic
Characteristic
Present, less extensive
Absent
Cells size
Large
Small
Cytoplasm
Abundant
Abundant
Abundant
Scanty
Nuclear 
pleomorphism
Usually absent
Occasionally
present
Present
Present
Prominent nucleoli
No
No
Yes
No
Mitoses (x10 HPF)
<2
2-10
>10 (mean 70)
mean 70
Necrosis
Absent
Usually focal
Extensive
Extensive
5-year overall 
survival*
87%*
56%*
21%*
<10%


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In lack of knowledge about precise functional classification of these tumors in terms of 
hormonal production, only common NE markers are of diagnostic significance in the 
definition of identification of pulmonary NETs. Among such markers, chromogranins/
secretogranins are of major interest; chromogranin A (CgA) is stored in high amounts in well 
differentiated NETs and to a variable extent in poorly differentiated NE carcinomas.
The current therapeutic approach and only curative treatment of pulmonary NETs is surgical 
resection based on the principle of complete resection with preservation of as much normal 
lung tissue as possible. Pulmonary NETs always require major surgical procedures with 
systematic nodal dissection, and a careful search for multifocal lesions should always be
performed (Ferolla et al. 2009).
Afinitor has been approved in 2016 by FDA and the European Commission as first systemic 
treatment for patients with advanced, progressive, non-functional lung NET, based on the 
results from RADIANT-4 trial. Before this approval certain treatment approaches by use of 
chemotherapy as single-agent treatment or in combination had shown anti-tumoral activity in 
neuroendocrine tumors. Under these, in the recent past, temozolomide showed good results in 
advanced NETs. In a retrospective analysis in which the efficacy of temozolomide was 
evaluated in 36 patients with advanced stages of neuroendocrine tumors (gastric, thymic, 
pulmonary, pancreatic origin), an overall objective radiologic response rate of 14%, and stable 
disease of 53% was observed. In particular, patients with bronchial and thymic carcinoids had 
disease control rate (response or stabilization) in 62% and 71% of cases, respectively 
(Ekeblad et al. 2007). Other chemotherapy regimens (e.g. streptozotocin + 5-FU, cisplatinum
+ etoposide) in the treatment of patients with metastatic pulmonary carcinoid tumors showed 
a low effect on tumor growth (Granberg et al. 2001).
Even though, up to now only Afinitor is approved to be used in the treatment of lung- NETs. 
Till today, the clinical management of bronchial neuroendocrine tumors is not standardized 
and clear therapeutic guidelines are still missing.
1.1.2
Thymus Neuroendocrine Carcinoma
The thymic neuroendocrine tumours are epithelial tumours of the thymus gland that are
predominantly or exclusively composed of neuroendocrine cells which can be demonstrated 
on immunohistochemistry.
The neuroendocrine tumours of the thymus comprise of typical carcinoid (TC) and atypical 
carcinoid (AC), as well as large cell carcinoma (LCC) and small cell carcinoma (SCC).
The prevalence of thymic carcinoid is approximately 0.3% of total carcinoids of all sites. 
These tumours are uncommon and occur in all age groups with male predominance.
In 1972, Rosai and Higa reported that thymic carcinoids may occur in association with 
multiple endocrine neoplasia type 1 (MEN-1), a genetic disorder that predisposes to the 
development of multiple endocrine and non-endocrine proliferations (Rosai et al. 1972).
A large number of cases of NETs arising in the thymus are associated with paraneoplastic 
syndromes. Among these, Cushing’s syndrome is the most frequent given that an increased 
secretion of ACTH has been reported in one-third of sporadic thymic NETs.


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An aggressive surgical approach in the management of thymic neuroendocrine tumour offers 
the best possible treatment. The role of chemotherapy and radiotherapy (RT) in the 
postoperative management of thymic neuroendocrine tumour continues to be debated.
Single agents or combination drug therapies with 5-fluorouracil, streptozotocin, carmustine, 
etoposide phosphate (VP-16), and cisplatin have been used previously without any significant 
impact on the recurrence rate or overall survival. Thymic carcinoid tumours express 
somatostatin receptors (SSRs) and there are successful interventions with long acting 
octreotide in primary and metastatic tumours (Dutta et al. 2010; Ferolla et al. 2007).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of Pasireotide (SOM230) LAR
Pasireotide is an injectable somatostatin analogue. The formulation of pasireotide used in this 
trial is the long-acting depot formulation (long-acting release, LAR).
It is a novel cyclohexapeptide with the following chemical name: (2-Aminoethyl)carbamic 
acid (2R,5S,8S,11S,14R,17S,19aS)-11- (4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-
(1H-indol-3-ylmethyl)-4,7,10,13,16,19-
hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-
hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt. Inactive 
ingredients 
of 
pasireotide 
LAR 
include: 
mannitol, 
carmellose 
sodium 
(carboxymethylcellulose sodium), poloxamer 188 and water for injection.
Pasireotide has been approved in Europe and in the US as a subcutaneous (s.c.) formulation 
under the trade name Signifor® for the treatment of patients with Cushing’s disease for whom 
medical therapy is appropriate. Pasireotide, as the long-acting depot formulation, is also being 
developed for the treatment of acromegaly. Data from two Phase III studies in acromegaly 
which both met their primary endpoint became available in 2012, and marketing authorization 
for pasireotide LAR in the treatment of acromegalyhas been granted both by FDA and the 
European Commission in 2015. Pasireotide LAR is also being studied for the treatment of 
Cushing’s disease, neuroendocrine tumors, and dumping syndrome.
1.2.1.1
Mechanism of Action
Like natural somatostatin and other somatostatin analogues, pasireotide exerts its 
pharmacological activity via binding to somatostatin receptors. There are five known 
somatostatin receptor subtypes (SSTR): SSTR 1, 2, 3, 4 and 5. Somatostatin receptors are 
expressed in different tissues under normal physiological conditions. Somatostatin analogues 
activate these receptors with different potencies (Schmid and Schoeffter 2004) and this 
activation results in a reduced cellular activity and inhibition of hormone secretion. 
Somatostatin receptors are strongly expressed in many solid tumors, especially in 
neuroendocrine tumors where hormones are excessively secreted e.g. acromegaly (Freda 
2002), gastroenteropancreatic (GEP)-NET (Oberg et al. 2004) and Cushing’s disease (Van der 
Hoek et al. 2005).
First-generation somatostatin analogues (octreotide and lanreotide) have a high affinity to 
SSTR subtype 2 (SSTR2), with moderate or no affinity to the remaining subtypes. Pasireotide 


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is a novel cyclohexapeptide somatostatin analogue that exhibits a unique binding profile, 
binding with high affinity to four of the five known human somatostatin receptors (Table 1-2).
Compared to Sandostatin® (octreotide acetate), pasireotide exhibits a binding affinity which is 
30-40 times higher for human SSTR1 and SSTR5, 5 times higher for human SSTR3, and 
similar to the affinity for SSTR2 receptors. A detailed summary of available preclinical data is 
provided in the [pasireotide LAR Investigator’s Brochure].
Table 1-2
Binding profile for octreotide and pasireotide at SSTR 1-5 (IC50, M)
Compound
SSTR1
SSTR2
SSTR3
SSTR4
SSTR5
Octreotide acetate (SMS)
2.8×10-7
3.8×10-10
7.1×10-9
>10-6
6.3×10-9
Pasireotide (SOM230)
9.3×10-9
1.0×10-9
1.5×10-9
>10-6
1.6×10-10
Ratio of IC50: octreotide/
Pasireotide
30
0.4
5
--
40
1.2.1.2
Antitumor actions of somatostatin analogs
Somatostatin analogs show antineoplastic activity in a variety of experimental models in vivo
and in vitro (Pollak and Schally 1998, Schally 1988, Weckbecker et al. 1993). They inhibit 
the growth of various cancer cell lines, such as those of gastric, lung, colorectal, prostatic, 
ovarian, kidney, brain, or thyroid origin (Froidevaux and Eberle 2002, Keri et al. 1996, 
Schally et al. 2004, Weckbecker et al. 1993). 
Pasireotide has shown anti-tumor effects in vitro and in vivo. Pasireotide LAR (8 and 80 
mg/kg s.c.) dose-dependently decreased tumor volume to 66% and 21% of control in a human 
prostate tumor model (DU-145) (Schmid et al. 2010). Furthermore, pasireotide inhibited 
proliferation in primary NET cell lines (KRJ-I and P-STS) ( Kidd et al. 2011). 
A recent analysis of the Surveillance, Epidemiology and End Results (SEER) database found 
a significant increase in survival from 1988 to 2004 compared with 1973 to 1987, coinciding 
with the introduction of octreotide in 1988 (Yao et al. 2008a). More recently, the PROMID 
study has shown that octreotide LAR was able to increase time to tumor progression (TTP) 
when compared to placebo from 6 months to 14.3 months in patients with advanced NET of 
the midgut or unknown primary tumor location (Rinke et al. 2009). The effect of higher doses 
of octreotide on tumor growth has also been evaluated using a non-marketed formulation of 
the compound. In one study, 12 patients with advanced, progressive midgut NETs received 
octreotide pamoate 160 mg every second week for 2 months followed by monthly injections 
for 12 months. Stable disease was achieved by 75% of patients for a median duration of 12 
months (range 6 to 24 months).
1.2.1.3
Clinical Experience
Overall, clinical experience with pasireotide in humans shows an adverse event (AE) profile 
similar to that of octreotide, with the exception of an increased frequency of hyperglycemia. 
Preliminary data from a healthy volunteer study [CSOM230C2101] which assessed single i.m. 
doses of pasireotide LAR up to 60 mg (N=5 per cohort) show that pasireotide LAR was well 
tolerated, and that the adverse events observed are comparable with those observed with 


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octreotide LAR. Diarrhea was the most common adverse event which was sometimes 
associated with abdominal pain and/or flatulence. The gastrointestinal events were mild or 
moderate in severity. About half of the subjects reported transient mild injection site pain.
Preliminary safety data are available from 20 carcinoid patients inadequately controlled by 
somatostatin analogues treated with pasireotide LAR study [CSOM230C2110] (Table 1-3). 
These patients were under treatment with pasireotide LAR i.m. depot injections at doses of 20 
mg, 40 mg or 60 mg for up to six weeks at the time of the safety summary. Pasireotide LAR 
was generally well tolerated. The mean change in average number of bowel movements from 
baseline (mean of the seven days prior to the first pasireotide LAR injection compared to the 
mean of the last 7 days of months 3) was +12.4 (SDev 47.2) in the 20 mg group, -7.2 (SDev 
32.0) in the 40 mg group and -11.3 (SDev 36.5) in the 60 mg group. The most commonly 
reported AEs were gastrointestinal; however, most of these events were considered unrelated 
to study drug. PK Interim analysis has shown that a steady state appeared to be achieved 
following three monthly i.m. injections of 20 mg (N=12), 40 mg (N=14) or 60 mg (N=16) 
pasireotide LAR in carcinoid patients. 
Table 1-3
Most frequent AEs associated with Pasireotide LAR treatment
Adverse Event
(Preferred term)
Pasireotide LAR
20 mg
(N=5)
n (CTC= grade 3)
Pasireotide LAR
40 mg
(N=7)
n (CTC= grade 3)
Pasireotide LAR
60 mg
(N=8)
n (CTC= grade 3)
Pasireotide LAR
Any dose
(N=20) n (%)
(n=CTC grade 3)
Diarrhea
1
2
2
5 (25.0%)
Fatigue
1
2 (1)
1
4(20.0%) (1)
Dyspnea
1
2 (1)
1
4 (20.0%) (1)
Flushing
1
1 (1)
1(1)
3 (15.0%) (2)
Back Pain
1
1
1
3 (15.0%)
Nausea
1
1
0
2 (10.0%)
Palpitations
0
2
0
2 (10.0%)
Abdominal Pain
1
1
0
2 (10.0%)
Steatorrhea
1
1
0
2 (10.0%)
Asthenia
1
1
0
2 (10.0%)
Headache
0
1
1
2 (10.0%)
Anorexia
0
1
1
2 (10.0%)
Hyperglycemia
0
1 (1)
1
2 (10.0%) (1)
Odema Peripheral
0
1
0
1 (5.0%)
Erythema
1
0
0
1 (5.0%)
Number (%) of patients with most frequent AEs (>5% for any dose group) regardless of relationship to study drug 
(preliminary data from study [CSOM230C2110])
Source: [CSOM230C2110]
Similar results were obtained in other Phase I, Phase II and III studies, with the most 
frequently reported AEs being of gastrointestinal origin, predominantly diarrhea, nausea, and 
abdominal pain. Generally, these events were mild, transient, and only occasionally caused 
patients to discontinue treatment.
Specifically, single doses of pasireotide s.c. up to 1500 μg QD and multiple s.c. doses up to 
1500 μg QD, 750 μg b.i.d., and 2100 μg b.i.d., and continuous (7-day) s.c. infusion by a pump, 
have been well tolerated by healthy volunteers and patients with acromegaly, metastatic 


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carcinoid tumor, or Cushing’s disease. The most common AEs of gastrointestinal origin were 
seen at all doses, but occurred more frequently at higher doses in all studies. The frequency of 
gastrointestinal events appeared to decrease with time in multiple-dose studies. A number of 
subjects also reported mild-to-moderate headaches. Generally, events were mild, transient, 
and only occasionally caused patients to discontinue treatment.
The overall conclusion arising from cumulative review of Signifor® post-marketing data 
(cumulative patient exposure since the first launch of pasireotide being estimated of
approximately 98 patient-years) is that the safety profile seen from the post-marketing 
experience so far is consistent with the known labeled core safety information in the Core 
Data Sheet (CDS).
Further details on the safety of pasireotide LAR can be found in [pasireotide LAR 
Investigator’s Brochure]. In addition, the Section 6.1.4 of the protocol (“Handling of specific 
toxicities”) describes in details some specific AEs associated with pasireotide treatment, with 
a special focus on hyperglycemia, and QT interval prolongation.
1.2.1.3.1 Pasireotide clinical studies in NETs
In a Phase I study of pasireotide LAR in patients with metastatic carcinoid 
tumors [CSOM230C2110], clinical response of symptom improvement over a 3-
month period was seen most often at the highest dose (60 mg every 28 days).
In a Phase II study of pasireotide s.c. in patients with metastatic carcinoid tumours 
[CSOM230B2202], clinical response of symptom improvement was observed at doses of 600 
μg s.c. b.i.d. and above. For those patients who achieved complete or partial treatment success,
the disease stabilized. Overall, tumor response assessment indicated there was no evidence of 
tumor shrinkage. Given the results of this study, doses above 600 μg s.c. b.i.d. were 
considered for future clinical trials to maximize the clinical benefit of pasireotide in patients 
with metastatic carcinoid tumors.
In another phase II, in patients with advanced NETs of the digestive system whose symptoms 
of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR, 
pasireotide 600–900 mg s.c. bid was effective and generally well tolerated in controlling the 
symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 
patients showed 13 patients with stable disease and ten with progressive disease at study end 
(Kvols et al. 2012).
A Phase III study ([CSOM230C2303]) comparing pasireotide LAR 60 mg versus octreotide 
LAR 40 mg in patients with metastatic carcinoid tumors (at the time of the snapshot on 17 
Nov-2011 when 88 patients have been treated) was terminated early as futility was 
demonstrated based on the proportion of patients achieving symptom response at Month 6. 
The overall proportion of patients who achieved symptom response at Month 6 was 9/43 
patients (20.9%) in the pasireotide group and 12/45 patients (26.7%) in the octreotide group.
The odds ratio of achieving symptom response at Month 6 among patients receiving 
pasireotide versus octreotide was 0.731 (95% confidence interval: 0.271, 1.974). The 
proportion of patients who achieved stable disease at Month 6 was higher in the pasireotide 
group (60.8% vs. 42.3%), while overall response rate (CR+PR) at Month 6 was comparable 
between the two treatment groups (2.0% in the pasireotide group vs. 3.8% in the octreotide 


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group). Disease control rate was 62.7% with pasireotide LAR and 46.2% with octreotide LAR 
(odds ratio: 1.96; 95%IC: 0.89-4.32, p=0.93). An unplanned, exploratory analysis based on 
investigator’s assessment presented at the 2013 ASCO annual meeting showed that 
pasireotide LAR significantly extended the median time without tumor growth by five months 
and reduced the risk of cancer progression by 54% compared to octreotide LAR. The median 
investigator-assessed PFS was 11.8 months in the pasireotide LAR arm and 6.8 months in the 
octreotide LAR arm, which was statistically significant (HR=0.46; P=0.045).
1.2.2
Overview of Everolimus (RAD001)
Everolimus is a derivative of rapamycin
with the following chemical name:
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-
{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-
dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4azatricyclo[30.3.1.04,9] hexatriaconta-
16,24, 26,28-tetraene-2,3,10,14,20-pentaone.
Inactive ingredients of immediate release tablets are: butylhyroxytoluene/butylated 
hydroxytoluene, magnesium stearate, lactose monohydrate, hypromellose/hydroxypropyl 
methylcellulose, crospovidone, lactose anhydrous.
Everolimus has been in clinical development since 1996 as an immunosuppressant in solid 
organ transplantation. Everolimus was approved in Europe (July 2013) and other global 
markets (trade name: Certican®) for renal and cardiac transplantation, and in the United States 
(trade name: Zortress®) for the prevention of organ rejection of kidney transplantation who 
are at low-to-moderate immunologic risk. It is also indicated for the prophylaxis of allograft 
rejection in adult patients receiving a liver transplant.
Everolimus has also undergone extensive development in oncology as Afinitor® since 2002
for patients with various hematologic and non-hematologic malignancies as a single agent or 
in combination with other antitumor agents. Afinitor® was approved for advanced renal cell 
carcinoma (RCC) in 2009 in various countries, including Europe and the US. In 2010, 
Afinitor® received accelerated USA approval for patients with subependymal giant cell 
astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require 
therapeutic intervention but are not candidates for curative surgical resection. Everolimus is 
also available as Votubia® in the EU (conditional approval in 2011) for patients aged ≥3 years 
with SEGA associated with TSC who require therapeutic intervention but are not amenable to 
surgery. In light of the results from the Core Phase of study [M2301] (EXIST-1), the 
approved indication was subsequentely updated on 29 August 2012 by FDA who granted 
accelerated approval for the following expanded indication “pediatric and adult patients with 
TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively 
resected”. The European Commission granted approval for the expanded indication on 15
November 2013. In addition, Afinitor® received accelerated approval from FDA in 2012 for 
the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate 
surgery. The effectiveness of Afinitor® in the treatment of renal angiomyolipoma is based on 
an analysis of durable objective responses in patients treated for a median of 48.1 weeks
(study [M2302], EXIST-2) (Bissler et al. 2013). Further follow-up of patients is required to 
determine long-term outcomes. On 31 October 2013, the EC granted Votubia® for the 
following indication: “treatment of adult patients with renal angiomyolipoma associated with 


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TSC who are at risk of complications (based on factors such as tumor size or presence of 
aneurysm, or presence of multiple or bilateral tumors) but who do not require immediate 
surgery”. 
Afinitor® was also approved for treating “progressive pancreatic NET (pNET) in patients with 
unresectable, locally advanced, or metastatic disease” in 2011 in various countries, including 
the USA and Europe. A broader regulatory approval of Afinitor® for the treatment of 
advanced NETs was granted in some countries based on the results of Phase III study [C2325] 
of everolimus in combination with octreotide LAR (Sandostatin LAR®) versus Sandostatin 
LAR® and placebo in patients with advanced NETs with a history of carcinoid syndrome.
As of 14 Sep 2016, Afinitor® has been approved in 113 countries worldwide for patients with 
pNET/neuroendocrine tumors.In 2012, Afinitor® received approval for the treatment of 
postmenopausal women with advanced hormone receptor-positive, HER2-negative breast 
cancer (advanced HR+/HER2- breast cancer) in combination with exemestane in a number of 
countries worldwide, including the US, where it is approved after failure of treatment with 
letrozole or anastrozole in the USA, and in the EU, following a non-steroidal aromatase 
inhibitor.
Most recently, approvals were granted to Afinitor by the European Commission, FDA and 
several other Health Authorities for the treatment of advanced progressive non-functional 
neuroendocrine tumors of gastrointestinal and lung origin based on the results of the 
RADIANT-4 study [T2302].
Everolimus is being investigated as an anticancer agent based on its potential to act:

directly on the tumour cells by inhibiting tumour cell growth and proliferation and/or

indirectly by inhibiting angiogenesis leading to reduced tumour vascularity, via potent 
inhibition of tumour cell vascular endothelial growth factor (VEGF) production and
VEGF-induced proliferation of endothelial cells.
1.2.2.1
mTOR pathway and cancer
At the cellular and molecular level, everolimus acts as a signal transduction inhibitor. It 
selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase which 
regulates cell growth, proliferation and survival. The mTOR kinase is mainly activated via the 
PI3 kinase pathway through AKT/PKB and the tuberous sclerosis complex (TSC1/2). 
Mutations in these components or in PTEN, a negative regulator of PI3 kinase, may result in 
their dysregulation. Abnormal functioning of various components of the signaling pathways 
contributes to the pathophysiology of numerous human cancers. Various preclinical models 
have confirmed the role of this pathway in tumour development (Cohen and McGovern 2005,
Bjornsti and Houghton 2004).
1.2.2.2
Preclinical studies
Everolimus inhibits the proliferation of a range of human tumour cell lines in vitro including 
lines originating from lung, breast, prostate, colon, melanoma and glioblastoma with 
particular potency against VEGF-induced proliferation suggesting that everolimus may also 
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In preclinical models, the administration of everolimus was associated with reduction of 
protein phosphorylation in target proteins downstream of mTOR, notably phosphorylated (p)-
S6 (p-S6) and p-4E-BP1, and occasionally with an increase in phosphorylated AKT, a protein 
upstream of mTOR signaling pathway.
1.2.2.3
Clinical experience
The pharmacokinetic characteristics of everolimus have been extensively investigated in the 
context of the drug’s development as an immunosuppressant in solid organ transplantation 
where everolimus was administered twice daily as a part of an immunosuppressant, multi-
drug regimen consistently including cyclosporin A and glucocorticoids. Recent Phase I 
studies provide steady-state pharmacokinetics for both the weekly and daily schedules at 
varying dose levels in patients with advanced cancers (O’Donnell et al. 2008; Tabernero et al.
2008).
Everolimus is rapidly absorbed after oral administration, with a median time to peak blood 
levels (tmax) of 1-2 hours post dose. Everolimus is mainly metabolized by CYP3A4 in the liver 
and to some extent in the intestinal wall. Everolimus is also a substrate of P-glycoprotein (P-
gp). Therefore, absorption and subsequent elimination of systematically absorbed everolimus
may be influenced by medicinal products that interact with CYP3A4 and/or P-glycoprotein. 
Caution should be exercised when co-administering everolimus with CYP3A4 inhibitors or 
inducers. A detailed summary of available PK data is provided in the [Investigator’s 
Brochure].

.
In addition, healthy volunteer subjects and non-oncology hepatically impaired subjects have 
participated in clinical pharmacology studies.
Overall, safety data available from completed, controlled and uncontrolled studies indicate 
that everolimus is generally well tolerated at weekly or daily dose schedules. Its safety profile 
is characterized by manageable AEs, mostly of grade 1 and 2 in severity. These AEs are 
generally reversible and non-cumulative. 
On the basis of a pooled safety data in oncology patients receiving everolimus (N=2,470) in
clinical studies (including randomized, double-blind, placebo- or active comparator-controlled 
phase-III trials and phase II studies related to the approved indications in oncology), the most 
common adverse drug reactions (ADRs) [incidence ≥1/10 and suspected to be related to 
treatment by the Investigator] were (in decreasing order): stomatitis, rash, fatigue, diarrhea, 
infections, nausea, decreased appetite, anemia, dysgeusia, pneumonitis, hyperglycemia, 
weight decreased, pruritus, asthenia, peripheral edema, hypercholesterolemia, epistaxis, and 
headache. The most common grade 3 or 4 ADRs (incidence ≥1/100 to <1/10 and suspected to 
be related to treatment by the investigator) were stomatitis, anemia, hyperglycemia, fatigue, 
infections, pneumonitis, diarrhea, asthenia, thrombocytopenia, neutropenia, dyspnea, 
lymphopenia, proteinuria, hemorrhage, hypophosphatemia, rash, hypertension, aspartate 
aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, and pneumonia.
In the pooled safety database, the following new or worsening clinically relevant laboratory 
abnormalities were reported with an incidence of ≥1/10 (very common, listed in decreasing 
frequency):


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
hematology: hemoglobin decreased, lymphocytes decreased, white blood cells decreased, 
platelets decreased, and neutrophils decreased (or collectively as pancytopenia);

clinical chemistry: glucose (fasting) increased, cholesterol increased, triglycerides 
increased, AST increased, phosphate decreased, ALT increased, creatinine increased, and 
potassium decreased.

Most of the observed abnormalities were mild (grade 1) or moderate (grade 2). Grade 3/4
hematology and chemistry abnormalities include:

hematology: lymphocytes decreased, hemoglobin decreased (very common), neutrophils 
decreased, platelet count decreased, white blood cells decreased (all common).

clinical chemistry: glucose (fasting) increased (very common), phosphate decreased, 
potassium decreased, AST increased, ALT increased, creatinine increased, cholesterol 
(total) increased, triglycerides increased, albumin decreased (all common)
Non-infectious pneumonitis, which is a known risk for all mTOR inhibitors, was identified 
early in the program and management guidelines were implemented. Infections (including 
fungal) were observed more commonly with everolimus.
Finally, in clinical trials and post-marketing spontaneous reports, everolimus has been 
associated with serious cases of: 

hepatitis B reactivation, including fatal outcome (with reactivation of infections being an 
expected event during periods of immunosuppression);

renal failure events (including acute renal failure), some with fatal outcome, and 
proteinuria (thus, renal function of patients should be monitored
particularly in situations where patients have additional risk factors 
that may further impair renal function);

amenorrhea (including secondary amenorrhea);

pneumocystis jirovecii pneumonia (PJP), some with fatal outcome;

angioedema (reported with and without concomitant use of everolimus and ACE 
inhibitors).
1.2.2.3.1 Everolimus Phase II/III studies in NETs
In pancreatic NET cells, mTOR is activated in response to signalling by insulin-like growth 
factor 1 (IGF-1) (Van Gompel 2004, von Wichert et al. 2000). Interruption of this signalling 
pathway through treatment with everolimus in combination with a somatostatin analogue was 
the goal of a recent phase 2 clinical trial conducted by J. Yao at the MD Anderson Cancer 
Center (Yao et al. 2010). The clinical data on efficacy and safety of everolimus plus depot
octreotide 30 mg IM every 28 days in patients with metastatic or unresectable, well-
differentiated, neuroendocrine carcinoma have recently been updated (Yao et al. 2007 and 
2008b). A total of 60 evaluable patients have been treated in two cohorts; the two cohorts of 
patients received everolimus at 5 mg/day and 10 mg/day. Out of the sixty treated diseases, 30 
were carcinoids, and 30 islet cell tumours. Sixty-five percent of the patients were in 
progression at the time of study entry. Overall, 13 (22%) patients were reported to have partial 


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response (5 carcinoids and 8 islet cell tumours, respectively), 42 (70%) with stable disease (24 
in carcinoids and 18 in islet cell, respectively) and 5 (8%) with progressive disease (1 in 
carcinoid and 4 in islet cell, respectively) per RECIST. Overall, median PFS was 60 weeks 
(63 in carcinoids and 50 in islet cell, respectively). Median overall survival (OS) has not been 
reached yet, with a 2-yr survival rate of 81%. The combination of everolimus and Sandostatin 
LAR 30 mg appears to have been well tolerated. The most common toxicity reported was 
mucositis. CTC grade 3/4 toxicities reported included: anemia, thrombocytopenia, aphthous 
ulcer, diarrhea, edema, fatigue, hyperglycemia, nausea, pain, and rash.
RADIANT-1 [CRAD001C2239] is a phase II open label, parallel group study in pNET in 
which patients were allowed to receive either everolimus 10 mg daily as monotherapy 
(stratum 1) or everolimus 10 mg daily in combination with Sandostatin LAR 30 mg (stratum 
2). A total of 160 evaluable patients have been assigned in the 2 strata: 115 patients in stratum 
1 and 45 in stratum 2. 11 out of the 115 patients (9.6%) who received everolimus alone had a 
partial response vs. 2 (4.4%) in the second stratum (octreotide combined with everolimus). A 
stable disease was achieved in 67.8% (78 patients) of the patients in the stratum 1, and 80% of 
the patients (36 patients) in the stratum 2. Median PFS was 9.7 months in the stratum 1 and 
16.7 months in the stratum 2. The median OS was 24.9 months in stratum 1 but it was not 
reached for stratum 2 at the time of data cut-off (Yao et al. 2010). New data arising from this 
study are consistent with previous observations, by showing a median OS of 28.8 months in 
stratum 1 vs 38.8 months in stratum 2 [RAD001 Investigator brochure].
RADIANT-3 [CRAD001C2324] is a phase III double-blind trial in which 410 patients with 
advanced pancreatic neuroendocrine tumours were randomised 1:1 to everolimus 10 mg/day + 
best supportive care (BSC) or placebo + BSC. Results from this study demonstrated a 
statistically significant clinical benefit of everolimus over placebo by a 2.4-fold prolongation 
of median PFS as per local investigator assessment (11.04 vs 4.6 months; hazard ratio [HR] = 
0.35; 95% confidence interval [CI] 0.27–0.45; p < 0.0001), resulting in a 65% reduction in the 
estimated risk of progression (HR 0.35; p<0.0001). Similar results were obtained by central 
review (Yao et al. 2011). The estimated rate of patients who were alive and progression-free 
at 18 months was 34.2% with everolimus as compared with 8.9% with placebo, indicating that 
a sizable proportion of patients achieved a prolonged benefit with everolimus. The overall 
survival results (cut-off date: 28 February 2010) are not yet mature and no statistically 
significant difference in OS was noted (HR=0.99; 95% CI: 0.68-1.43). Crossover of 72.9% of 
patients from placebo to open-label everolimus following disease progression likely 
confounded the detection of any treatment-related difference in OS.
Overall, safety findings from the longer-term follow-up of studies [C2324] (RADIANT-3) 
and [C2239] (RADIANT-1) did not alter the established safety profile of everolimus. The 
overall clinical benefits support the treatment of patients with advanced pNETs; the safety 
profile was manageable and consistent with previous experience in this setting. No new safety 
concerns emerged. Most adverse events (AEs) were of grade 1-2 intensity and were transient.
RADIANT-2 [CRAD001C2325] is a phase III double-blind trial in which 429 patients with 
advanced neuroendocrine tumours and a history of carcinoid syndrome symptoms were 
randomised 1:1 to everolimus + octreotide LAR or placebo + octreotide LAR. Median PFS by 
investigator review (284 events) was significantly better with everolimus and octreotide (12.0 
vs 8.6 months; HR = 0.78; 95% CI 0.62–0.98; p = 0.018), but by central review (223 events), 


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the difference was not significant (16.4 vs 11.3 months; HR = 0.77; 95% CI 0.59–1.00; p = 
0.026) (Pavel et al. 2010, Pavel et al. 2011).
An exploratory subanalysis from the RADIANT-2 study evaluated the efficacy and safety of 
everolimus + octreotide LAR in a cohort of patients with low-to-intermediate grade advanced 
lung NETs (n=44) (Fazio et al. 2013). 33 patients were on treatment with everolimus + 
octreotide LAR, and 11 patients were on placebo + octreotide LAR. Median PFS was 13.63 
months in the everolimus + octreotide LAR arm vs 5.59 months in the placebo + octreotide 
LAR arm (relative risk for progression: HR, 0.72; 95% CI, 0.31–1.68; P=0.228). More 
patients receiving everolimus + octreotide LAR experienced minor tumor shrinkage (not 
partial response as per RECIST) than those receiving placebo plus octreotide LAR (67% vs
27%). Overall, this exploratory subanalysis of the RADIANT-2 trial indicates that in patients 
with advanced lung NET, the addition of everolimus to octreotide LAR improves median PFS 
by 2.4-fold compared with placebo + octreotide LAR. These clinically significant 
observations support the continued evaluation of everolimus treatment regimens in this patient 
population.
All these results indicating that everolimus is effective in p-NETs (RADIANT-3) and in NETs
associated with carcinoid syndrome (RADIANT-2) are supported by recent evidence from 
RAMSETE, a phase II single-arm study in 73 patients with advanced, progressive,
nonsyndromic, nonpancreatic NETs who received everolimus (10 mg/day) monotherapy
(Pavel et al. 2012). In this study, everolimus was associated with a high proportion of stable 
disease (55%), the best response, along with a favorable PFS (median: 185 days; 95% CI: 
158-255). Efficacy analysis by tumor origin reveals stable disease in 63.2% of patients with 
primary tumor origin in the lung, thymus, bronchus, or mediastinum vs 42.9% of patients with 
primary tumor origin other than the lung, bronchus or mediastinum.
 
 
 
 
 
o  
 
 
 


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2
Rationale
2.1
Study rationale and purpose
Rapamycin analogs have significant antiproliferative action in a variety of tumors, including 
pNETs. Sensitivity to rapamycin is reduced by a negative feedback loop via Akt inhibition of 
mTOR that decrease S6K and abolish this inhibitory feedback loop to IRS-1, resulting in 
increased Akt phosphorylation (O'Reilly et al. 2006). SSAs can inhibit the PI3K pathway by 
inhibiting p85 tyrosine phosphorylation and decreasing Akt phosphorylation, sensitize cells to 
mTOR-inhibition and increase the antiproliferative effects of rapamycin (Cerovac et al. 2010, 
Grozinsky-Glasberg et al 2008). This hypothesis has been verified in a rat xenograft model 
using the human prostate tumor model (DU-145). Here, single injections of pasireotide LAR 
resulted in significant dose-dependent reduction of tumors (Schmid et al. 2010) ). Treatment 
with everolimus resulted in a dose-dependent increase of pAKT in tumor tissue. This increase 
in pAKT was strongly reduced when everolimus and pasireotide LAR were co-administered, 
both in vitro and in vivo (Schmid et al. 2010), (Javle, personal communication). In the rat, 
pasireotide inhibits IGF-1 plasma levels much more effectively than octreotide at comparable 
concentrations and has a longer-lasting inhibitory effect. In contrast to octreotide, pasireotide 
shows no signs of escape over time up to 126 days. The superior IGF-1 lowering property of 
pasireotide was also observed in Beagle dogs; pasireotide is at least 3 times more potent than 
octreotide in reducing IGF-1 levels in this species. In Rhesus monkeys, 3 consecutive 
injections of pasireotide markedly decreased IGF-1 plasma levels from 24 hours onwards 
while octreotide was only marginally active. In Cynomolgus monkeys, chronic infusion of 
pasireotide leads to a dose-dependent decrease in IGF-1 levels. [Pasireotide s.c. and 
Pasireotide LAR Investigator’s Brochure] As pasireotide inhibits IGF-1 release more potently 
than octreotide (Weckbecker et al. 2002), the above data suggest that everolimus and 
pasireotide have a role in inhibiting cell growth and tumor proliferation by interrupting the 
IGF-1/PI3K/mTOR signaling cascade, and that everolimus in combination with pasireotide 
may arrest growth and tumor proliferation to a greater extent than either agent alone and than 
the combination of everolimus and octreotide.
Somatostatin analogs are the current gold standard medical therapy for the treatment of the 
disease-related symptoms of functioning NETs (also known as carcinoid syndrome) and 
functioning pNETs (Oberg et al. 2009). These peptides are effective in reducing symptoms of 
carcinoid syndrome, specifically diarrhea and flushing, where SSAs provide symptomatic 
improvement in approximately 58% to 76% of patients with carcinoid syndrome (Oberg et al.
2004). Octreotide (Sandostatin®) and lanreotide (Somatuline®) are the only compounds 
approved for clinical use that exert their activity primarily via binding to receptor SSTR2 
(Schmid and Schoeffter 2004). Although many patients initially respond to treatment with 
these agents, adequate symptom control can no longer be achieved in approximately 50% of 
them as early as 12 to 18 months after initiation of therapy. There has been accumulating 
evidence that octreotide does not only control symptoms in patients with functioning NETs, 


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but also exerts antiproliferative effects (Appetecchia and Baldelli 2010). This antiproliferative 
effect of octreotide has been proven in the PROMID trial, a randomized, double-blind, 
placebo-controlled, multicenter trial in patients with well differentiated inoperable or 
metastatic midgut NETs. This study reported a significant delay in time to progression (TTP) 
in patients treated with Sandostatin® LAR 30 mg compared to placebo (Rinke et al. 2009). 
There is evidence that many tumor cells become resistant to these agents by either 
downregulation of SSTR2 or over expression of other SSTRs (Cescato et al. 2006, Tulipano et 
al. 2004). If this is true, then pasireotide may have a beneficial effect in patients who have 
become resistant to these agents via its enhanced binding to other receptor subtypes. 
RADIANT-1 study [CRAD001C2239] suggested that the combination of everolimus with 
octreotide could further improve PFS in patients with NETs (Yao et al. 2010). This has been
tested in a large multinational randomized, double-blind, placebo-controlled, phase III trial
comparing octreotide plus placebo with octreotide plus everolimus in patients with 
functioning NETs: the RADIANT-2 trial [CRAD001C2325]. Although the study narrowly 
failed to meet its primary PFS endpoint, results provide evidence for the clinical benefit of 
everolimus, in combination with octreotide LAR, in this patient population (as per the 
adjudicated central radiology review). A 23% reduction in the hazard rate of progression in 
favor of the combination arm was observed. 47.2% of patients receiving the combination 
treatment were estimated to be progression free at 18 months compared with 37.4% in the 
monotherapy group, indicating that a larger proportion of patients derived longer benefit in 
the combination with octreotide [CRAD001C2325 CSR], thus lending further evidence of the 
benefit of the combination of everolimus and a SSA. In addition, an exploratory subanalysis 
from the RADIANT-2 in a cohort of patients with low-to-intermediate grade advanced lung-
NETs (n=44) (Fazio et al. 2013), the addition of everolimus to octreotide LAR improved
median PFS by 2.4-fold compared with placebo + octreotide LAR (13.63 months vs 5.59 
months; relative risk for progression: HR, 0.72; 95% CI, 0.31–1.68; P=0.228). Such evidence 
supports the continued evaluation of everolimus treatment regimens in this patient population.
A Phase III study [CSOM230C2303] comparing 60 mg of pasireotide LAR vs. 40 mg of 
octreotide LAR in patients with metastatic carcinoid tumors was terminated early as futility 
was demonstrated based on the proportion of patients achieving symptom response at Month 
6. The overall proportion of patients who achieved symptom response at Month 6 was 9/43 
patients (20.9%) in the pasireotide group and 12/45 patients (26.7%) in the octreotide group. 
The odds ratio of achieving symptom response at Month 6 among patients receiving 
pasireotide vs. octreotide, was 0.731 with 95% confidence interval (0.271, 1.974).The 
proportion of patients who achieved stable disease at Month 6 was higher in the pasireotide 
group (60.8% vs. 42.3%) while overall response rate (CR+PR) at Month 6 was comparable 
between the treatment groups (2.0% in the pasireotide group vs. 3.8% in the octreotide group). 
Pasireotide LAR significantly extended the median time without tumor growth by five months 
and reduced the risk of cancer progression by 54% compared to octreotide LAR. The median 
investigator-assessed PFS was 11.8 months in the pasireotide LAR arm and 6.8 months in the 
octreotide 
LAR 
arm, 
which 
was 
statistically 
significant 
(HR=0.46; 
P=0.045)
[CSOM230C2303].
Thus, the rationale for this study is based on both preclinical and clinical considerations:


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
combined inhibition of IGF-1-, PI3K- and mTOR-pathways by pasireotide and everolimus 
may control tumor growth more effectively than either compound alone;

combination of everolimus with sandostatin LAR seems to improve progression-free 
survival in NET patients. Thus, the combination of everolimus with pasireotide LAR 
might result in even better tumor control.
The purpose of this study is to assess efficacy and safety of pasireotide LAR and everolimus
alone or in combination.
2.2
Rationale for the study design
This is a 3-arm, open-label trial evaluating the efficacy and safety of pasireotide LAR or 
everolimus alone or in combination in patients with a well differentiated neuroendocrine 
carcinoma of the lung or thymus.
2.3
Rationale for dose and regimen selection
The proposed dose of pasireotide LAR is 60 mg once every 28 days (q28d). As of 31 July
2012, following monthly (q28d) injections of 20 mg, 40 mg or 60 mg pasireotide LAR in 
carcinoid patients [CSOM230C2110], results showed approximately linear dose-exposure 
proportionality and a steady state achieved following three injections. The release patterns of 
pasireotide from the first injection of 40 and 60 mg LAR in acromegaly patients and carcinoid 
patients were similar to those from a single dose of 40 and 60 mg LAR in healthy volunteers. 
Thus, pasireotide LAR at 60 mg was chosen as standard dose for further development in 
patients with neuroendocrine tumors. In an ongoing study [CSOM230C2110], pasireotide 
LAR 60 mg q28d was shown to be safe in NET patients.
The proposed everolimus dosage regimen is 10 mg/day in both monotherapy and combination 
therapy settings. This is the registered dose for everolimus (Afinitor®) as antiproliferative 
agent. This regimen is based both on Novartis Phase I/II/III studies and on results from an 
investigator-sponsored study in NET. Pharmacodynamic modeling indicates that downstream 
effectors of mTOR are completely suppressed by everolimus at the 10 mg/day dose. In an 
investigator-sponsored study of everolimus in combination with octreotide in NETs, toxicity 
observed with everolimus 10 mg/day was similar to that observed for everolimus 5 mg/day 
(Yao et al. 2007, Yao et al. 2008b). Combination of everolimus 10 mg/day with octreotide 
LAR 30 mg q28d in another phase II study in patients with pNET [CRAD001C2239] was safe 
and effective (Yao et al. 2010). Therefore, a dose of everolimus 10 mg/day will be evaluated 
in this study.
In a phase I dose-escalation study to determine the safety of pasireotide LAR and everolimus
[CSOM230F2102], the dose level of 10 mg everolimus and 60 mg pasireotide LAR was 
declared to be safe (Chan et al. 2010). Preliminary data from this study were presented at 
ASCO GI 2010. Patients were treated with pasireotide at each dose level, beginning with 
pasireotide s.c. for 4 weeks in combination with daily everolimus, followed by monthly 
pasireotide LAR injections in combination with daily everolimus. To achieve steady state, 
pasireotide s.c. was continued for 2 weeks following the first injection of pasireotide LAR. 
The first dose level of pasireotide LAR 40 mg and everolimus 5 mg recruited 3 patients 
without reaching dose-limiting toxicity (DLT). One patient developed grade 3 hyperglycemia 


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and was started on insulin therapy. The second dose level of pasireotide LAR 40 mg and 
everolimus 10 mg recruited three patients. One patient developed grade 3 hyperglycemia and 
was started on insulin therapy. The third dose level of pasireotide LAR 60 mg and everolimus 
10 mg was expanded to recruit six patients. One patient developed grade 3 rash and grade 4 
hyperglycemia with need for insulin therapy. This was declared maximum tolerated dose 
(MTD), and it was planned to expand this cohort to 12 patients. All patients in this study 
showed disease stabilization (
 
, personal communication). Therefore, a dose of 
everolimus 10 mg/day in combination with pasireotide LAR 60 mg q28d will be used in this 
trial.
2.4
Rationale for choice of combination drugs
Inhibition of mTOR by everolimus induces growth inhibition, cell cycle arrest and decreased 
signaling by mTOR and ERK1/2 in the tested cell lines. Everolimus may have a role in
inhibiting cell growth, and tumor proliferation by interrupting the IGF-1/PI3K/mTOR 
signaling cascade. Moreover, everolimus inhibits angiogenesis also in an indirect way, via 
potent inhibition of tumor cell HIF-1 activity and VEGF production and VEGF-induced 
proliferation of endothelial cells, leading to reduced tumor vascularity. These observations 
suggest the hypothesis that everolimus may arrest growth and tumor proliferation activity 
through the dual inhibition of mTOR and an anti-angiogenic effect.
Pasireotide LAR inhibits IGF-1 and the GH/IGF-1 axis more efficiently than octreotide.
Everolimus is a strong inhibitor of mTOR. Therefore, it is reasonable to expect that 
pasireotide LAR in combination with everolimus will be more effective in inhibiting IGF-1 
and mTOR, thus having additional clinical benefits in NET patients than either agent alone.
2.5
Rationale for choice of comparators drugs
Not applicable.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate the efficacy of pasireotide LAR and everolimus alone or in 
combination in progressive patients with a well differentiated 
neuroendocrine tumor of the lung or thymus
Primary endpoint is defined as the proportion of patients who are 
progression free (i.e. “disease control rate”*) at 9 months, according 
to RECIST V. 1.1
*”Disease control rate” is defined as the proportion of patients 
showing a best overall response of complete (CR) or partial (PR) 
response or stable disease (SD), according to RECIST V. 1.1.
Secondary
Refer to Section 10.5.1
To assess overall progression-free survival (PFS) throughout the study 
in patients with a well differentiated neuroendocrine tumor of the lung 
or thymus.
“Progression-free survival (PFS)” is defined as the time from first 
study drug administration to objective tumor progression or death 
from any cause, according to RECIST V. 1.1
Refer to Section 10.5.2
and Section 10.5.3
To assess the disease control rate of pasireotide LAR and everolimus 
alone or in combination, at 12 months, in patients with a well 
differentiated neuroendocrine tumor of the lung or thymus.
“Disease control rate” at 12 months, according to RECIST V. 1.1.
To assess the time to response, duration of response , objective 
response rate and best overall response of pasireotide LAR and 
everolimus alone or in combination during 12 months of treatment in 
patients with a well differentiated neuroendocrine tumor of the lunf or 
thymus.
The endpoint “time to response” is defined as the time from start of 
treatment to the first objective tumor response (PR or CR) observed,
according to RECIST V. 1.1. 
The endpoint “duration of response” is defined as the time from onset 
of the first objective tumor response (CR/PR) to objective tumor 
progression or death from any cause.
The endpoint “objective response rate” is defined as the proportion of 
patients showing a best overall response of CR or PR at 9 and 12 
months, according to RECIST V. 1.1. criteria.
The endpoint “best overall response” is defined as the the best 
response recorded from the start of the treatment until disease 
progression/recurrence, taking as reference for PD the smallest 
measurements recorded since the treatment started.
To assess the biochemical response rate (BRR), duration of 
biochemical response (DBR) and biochemical progression-free 
survival (BPFS) of pasireotide LAR and everolimus alone or in 
combination in patients with a well differentiated neuroendocrine tumor 
of the lung or thymus
The endpoint “biochemical response rate (BRR)” is the percentage of 
patients showing normalization or a decrease of ≥ 30% of serum CgA
compared to baseline.
The endpoint “duration of biochemical response (DBR)” is defined as 


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Objective
Endpoint
Analysis
the time from the first documentation of biochemical response to the 
first documentation of biochemical progression or to death due to any 
cause, whichever occurs first. 
Biochemical progression is defined as an increase of serum CgA
levels ≥25% versus baseline.
The endpoint “biochemical progression-free survival (BPFS)” is 
defined as the time from the first study drug administration to the first 
documentation of biochemical progression or to death due to any 
cause, whichever occurs first.
Additionally, the biochemical response on the basis of urine 5-
hydroxyindole acetic acid (5HIAA) will be assessed.
To assess the safety and tolerability of pasireotide LAR and 
everolimus alone or in combination as measured by rate and severity 
of adverse events in patients with a well differentiated neuroendocrine 
tumor of the lung or thymus.
Safety will be assessed using the Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0. Incidence of adverse events 
(AEs), serious adverse events (SAEs), changes from baseline in vital 
signs, ECG tracings and laboratory results (hematology, blood 
chemistry) will be reported.


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3.1
Primary objective
To evaluate the efficacy of pasireotide LAR and everolimus alone or in combination in 
progressive patients with a well differentiated neuroendocrine tumor of the lung or thymus. 
The primary endpoint is defined as the proportion of patients who are progression free (i.e. 
disease control rate) at 9 months, according to RECIST V. 1.1.
Disease control rate is defined as the proportion of patients showing a best overall response of 
complete (CR) or partial (PR) response or stable disease (SD) according to RECIST V. 1.1
3.2
Secondary objectives

To assess overall progression-free survival (PFS) throughout the study in patients with a 
well 
differentiated 
neuroendocrine 
tumor 
of 
the 
lung 
or
thymus.
The endpoint “progression-free survival (PFS)” is defined as the time from first study 
drug administration to objective tumor progression or death from any cause, according to 
RECIST V. 1.1.

To assess the disease control rate of pasireotide LAR and everolimus alone or in 
combination, at 12 months, in patients with a well differentiated neuroendocrine tumor of 
the lung or thymus.

To assess the time to response, duration of response, objective response rate and best
overall response of pasireotide LAR and everolimus alone or in combination during 12 
months of treatment in patients with a well differentiated neuroendocrine tumor of the 
lung or thymus.
The endpoint “time to response” is defined as the time from start of treatment to the first 
objective tumor response (PR or CR) observed, according to RECIST V. 1.1. 
The endpoint “duration of response” is defined as the time from onset of the first 
objective tumor response (CR/PR) to objective tumor progression or death from any cause.
The endpoint “objective response rate” is defined as the proportion of patients showing a 
best overall response of CR or a PR at 9 and 12 months, according to RECIST V. 1.1. 
criteria.
The endpoint “best overall response” is defined as the best response the best response 
recorded from the start of the treatment until disease progression/recurrence, taking as 
reference for PD the smallest measurements recorded since the treatment started.

To assess the biochemical response rate (BRR), duration of biochemical response (DBR) 
and biochemical progression-free survival (BPFS) of pasireotide LAR and everolimus
alone or in combination in patients with well differentiated neuroendocrine tumor of the 
lung and thymus.
The endpoint “biochemical response rate (BRR)” is the percentage of patients showing 
normalization or a decrease of ≥ 30% from baseline of serum CgA compared to baseline.
The endpoint “duration of biochemical response (DBR)” is defined as the time from the 
first documentation of biochemical response to the first documentation of biochemical 
progression* or to death due to any cause, whichever occurs first.
* Biochemical progression is defined as an increase of serum CgA levels ≥25% versus
baseline.


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The endpoint “biochemical progression free survival (BPFS)” is the time from the first 
study drug administration to the first documentation of biochemical progression or to 
death due to any cause, whichever occurs first.
Additionally, the biochemical response on the basis of urine 5-hydroxyindole acetic acid 
(5HIAA) will be assessed

To assess the safety and tolerability of pasireotide LAR and everolimus alone or in 
combination as measured by rate and severity of adverse events in patients with a well 
differentiated neuroendocrine tumor of the lung or thymus. Safety will be assessed using 
the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Incidence 
of adverse events (AEs), serious adverse events (SAEs), changes from baseline in vital 
signs, ECG tracings and laboratory results (hematology, blood chemistry) will be 
reported.
4
Study design
4.1
Description of study design
This is a prospective, multicenter, randomized, open-label, 3-arm, phase II study with a 
single-stage design in each arm to evaluate the efficacy and safety of pasireotide LAR and 
everolimus alone or in combination in the treatment of patients with a well differentiated 
neuroendocrine carcinoma of the lung or thymus.
The number of patients enrolled is targeted to be 120 with 40 patients randomized to each arm 
as follows:

Arm 1: treatment with pasireotide LAR (SOM230) (60 mg/month i.m.),

Arm 2: treatment with everolimus (RAD001) (10 mg/day p.o.), and

Arm 3: treatment with pasireotide LAR (60 mg/month i.m.) and everolimus (10 mg/day 
p.o.).
4.1.1
Screening/Baseline phase
At screening visit (Visit 1) the investigator or his/her designee will assign a unique number to 
patients being considered for the study. The patient must provide a signed informed consent 
form (ICF) prior to any study related procedure. This study will use an Interactive voice 
response system (IVRS) for randomization to one of the three treatment arms. Once the 


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patient provides a signed ICF and eligibility is confirmed (all inclusion/exclusion criteria have 
been verified), the investigator and/or his designee can register the patient using the IVRS. A 
screening period of 28 days is allowed to assess eligibility.
Baseline tumor measurements will be based on screening triphasic CT/MRI tumor assessment,
according to RECIST Version 1.1 (assessment completed within 4 weeks prior to 
randomization can be used for baseline measurement). Non-tumor related assessments are 
also to be performed at screening.
4.1.2
Treatment phase
Upon completion of all screening tests and confirmation of eligibility, patients will be 
randomly assigned on a 1:1:1 basis to receive treatment with either pasireotide LAR or 
everolimus alone or a combined treatment with pasireotide LAR and everolimus.
Patients will receive treatment with study drug(s) for a period of 12 months or until 
radiologically documented disease progression, start of new cancer therapy, intolerable 
toxicity, withdrawal of consent or discontinuation due to any other reason.
Patients will be considered to have completed the core study after the 12-month evaluation 
has been performed.
During the study treatment, radiological and biochemical response assessments will be 
performed every 3 months.
Patients assigned to the pasireotide LAR treatment arm will be given a 60 mg i. m. depot 
injection every 28 days for 12 months. A dose decrease is permitted if tolerability issues arise 
(see Section 6.3.1.1).
Patients assigned to the everolimus treatment will receive a dose of 10 mg/day p.o. for 12 
months. A dose decrease is allowed if tolerability issues arise (see Section 6.3.1.2).
Patients assigned to receive a combined treatment with pasireotide LAR and everolimus will 
be treated with both regimens and dose modifications are applicable as in the monotherapy 
arms. It is the investigator’s decision to decrease one or both drugs depending on the profile 
of the adverse effects. If, however, condition for dose reduction in this arm is not clear (e.g. 
tolerability issue is not clearly attributable to one of the medications), the Novartis clinical 
team should be contacted.
4.1.3
Extension phase
Patients who are receiving clinical benefit from the treatment with the combination or the 
monotherapy with pasireotide LAR or everolimus and who are not experiencing unacceptable 
toxicity are permitted to continue treatment after the 12-month treatment period until they no 
longer demonstrate benefit or fulfill any of the study discontinuation criteria Disease control 
rate as well as progression-free survival (PFS) according to RECIST V. 1.1 will be evaluated 
during the extension phase All assessments which are required in the extension phase are 
listed in Table 7-2. Patients will have the option to receive therapy as long as they continue to 
demonstrate benefit and do not fulfill any of the study discontinuation criteria (see Section 
7.1.4.1 criteria for premature patient withdrawal) or as soon as the Clinical Trial ceases to be 
in the interests of the health of the Clinical Trial Subjects, based on the Data Monitoring 


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Committee (DMC) recommendations (see Section 8.6), or until the pasireotide and/or 
everolimus development programs is discontinued, whichever comes first (see reference to 
Section 4.4 early study termination).
All patients will have a safety follow-up visit at the end of the extension phase scheduled 56 
days after the last dose of the study treatment to follow up for AEs and SAEs that may have 
occurred after discontinuation from the study treatment.
Figure 4-1
Study design
Randomization
Arm 3: 40 patients
pasireotide LAR 60 mg 
q28d i.m.; everolimus 10 
mg/day p.o.
Arm 2: 40 patients
everolimus 10 mg/day 
po.
Arm 1: 40 patients
pasireotide LAR
60 mg q28d i.m.
Core study: 12-month treatment period
Extension phase - until they no longer demonstrate benefit or fulfill any of the study 
discontinuation criteria
120 patients with a well differentiated neuroendocrine carcinoma of the lung or thymus


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4.2
Timing of interim analyses and design adaptations
Not applicable.
4.3
Definition of end of the study
The end of the study is defined as when all patients have discontinued the study.
4.4
Early study termination
Patients will have the option to receive therapy as long as they continue to demonstrate 
benefit and do not fulfill any of the study discontinuation criteria (see Section 7.1.4.1: Criteria 
for premature patient withdrawal) or until the Clinical Trial ceases to be in the interests of the 
health of the Clinical Trial Subjects, based on DMC recommendations (see Section 8.6), or 
until the pasireotide and/or everolimus development programs are discontinued (whichever 
comes first). Should this be necessary, the patient should be seen as soon as possible and the 
same assessments should be performed as described in Section 7.1.4 for a prematurely 
withdrawn patient. The investigator may be informed of additional procedures to be followed 
in order to ensure that adequate consideration is given to the protection of the patient’s 
interests. The investigator will be responsible for informing IRBs and/or ECs of the early 
termination of the trial.
5
Population
5.1
Patient population
The target population is comprised of adult patients with an advanced (unresectable or 
metastatic) well differentiated neuroendocrine carcinoma (typical and atypical) of the lung or
thymus. It is expected that 120 patients (40 in each arm) will be enrolled into this study.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered enrollment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Histological confirmed advanced (unresectable or metastatic) well differentiated typical 
and atypical carcinoid tumors of lung or thymus. (Cytology by endobronchial ultrasound-
guided fine needle aspiration (EBUS) alone is not enough. Histopathology is required).
2. Patients of all treatment lines, including treatment naïve patients, can be enrolled.
3. At least one measurable lesion of disease on triphasic computed tomography (CT) scan or 
Magnetic Resonance Imaging (MRI) as defined by RECIST V. 1.1 criteria.
4. WHO Performance Status of 0, 1 or 2.
5. Radiological documentation of disease progression within 12 months prior to 
randomization. The triphasic CT or MRI confirming the progression according to RECIST 
V. 1.1 should not be older than 4 weeks to be used as baseline CT or MRI. CT scans and 
MRIs older than 4 weeks have to be repeated.


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6. Patients must have adequate liver, renal and bone marrow function:

Adequate bone marrow function:

ANC ≥ 1.5 × 109/L,

Platelets ≥ 100 × 109/L,

Hemoglobin > 9 g/dL.

Adequate liver function:

Total serum bilirubin ≤ 1.5 × ULN,

INR < 1.3,

ALT and AST ≤ 3 × ULN 

Adequate renal function: serum creatinine ≤ 1.5 × ULN.
7. Adult patients (male or female) >18 years old.
8. Patients must give a written informed consent prior to any trial-related procedures.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Poorly differentiated neuroendocrine carcinoma.
2. Non-neuroendocrine thymoma.
3. Prior treatment with any long-acting somatostatin analog within one month prior to 
randomization. Treatment with s.c. form of somatostatin analogs as “rescue” medication is 
allowed only until 48 hours prior to starting study treatment (continuation of “rescue” 
medication during the study is not allowed).
4. Patients with severe functional disease who require symptomatic treatment with 
somatostatin analogs can not be included in the protocol.
5. Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, everolimus).
6. Prior therapy with radioligand therapy (peptide receptor radionuclide therapy, PRRT)
within 6 months prior to starting study treatment or not recovered from the adverse effects 
of such therapy.
7. Prior cytotoxic chemotherapy or immunotherapy within 4 weeks or 5 half lives, whichever 
is longer, prior to starting study treatment or not recovered from the adverse effects of 
such therapy.
8. Patients with hepatic artery embolization, cryoablation or radiofrequency ablation of 
hepatic metastasis within the last 3 months prior to starting study treatment or not 
recovered from the adverse effects of such therapy.
9. Participation in a clinical trial to test an investigational drug within 4 weeks or 5 half lives 
whichever is longer prior to starting study treatment or not recovered from the adverse
effects of such therapy.
10. Sign of recurrence of prior or concomitant malignancies (within the last 3 years or 
requiring active treatment) other than NET with the exception of previous basal cell skin 
cancer, previous cervical carcinoma in situ.
11. Mixed tumours are excluded.


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12. Known intolerance or hypersensitivity to pasireotide, octreotide, or other somatostatin 
analogs and everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus).
13. Patients who have undergone major surgery/surgical therapy for any cause within 1 month 
or surgical therapy of loco-regional metastases within the last 3 months before recording 
baseline symptoms. Patients should have recovered from the treatment and have a good 
clinical condition before entering this study.
14. Patients who have received radiotherapy within the last 4 weeks prior to starting study 
treatment or not recovered from the adverse effects of such therapy.
15. Any of the following severe and/or uncontrolled medical conditions:

Severely impaired lung function (spirometry and DLCO ≤50% of normal and O2
saturation ≤88% at rest on room air)

Active bleeding diathesis

Cushing’s syndrome requiring medical treatment within 3 months.
16. Hepatic-related exclusion criteria

History of liver disease (such as cirrhosis) or chronic active hepatitis B and C.

Presence of Hepatitis B surface antigen (HbsAg) and/or of Hepatitis B Virus –
Deoxyribonucleic acid (HBV-DNA)

Presence of Hepatitis C virus-Ribonucleic acid-Polimerase Chain Reaction (HCV-
RNA-PCR)

History of or current alcohol misuse/abuse within the past 12 months

Known gallbladder or bile duct disease, acute or chronic pancreatitis.
17. Uncontrolled diabetes mellitus as defined by HbA1c ≥8% despite adequate therapy.
18. Patients unwilling or unable to comply with the requisites of the protocol.
19. Patients with symptomatic cholelithiasis.
20. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, 
sustained ventricular tachycardia, ventricular fibrillation, advanced heart block or a history 
of acute myocardial infarction within the 24 weeks preceding randomization.
21. QT-related exclusion criteria:

Patients with a baseline QTcF >470 msec

History of syncope or family history of idiopathic sudden death

Long QT syndrome

Sustained or clinically significant cardiac arrhythmias

Risk factors for Torsades de Pointes such as hypokalemia, hypocalcemia, 
hypomagnesemia (unless corrected prior to and during study), cardiac failure, 
clinically significant/symptomatic bradycardia, or high-grade AV block

Concomitant medications known to prolong the QT interval. A wash-out of 5 half 
lives from previous treatment with drugs known to induce QT prolongation is needed
prior to starting study treatmentConcomitant disease(s) that could prolong QT such as 
autonomic neuropathy (caused by diabetes mellitus or Parkinson’s disease), HIV, 
liver cirrhosis, uncontrolled hypothyroidism or cardiac failure.


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22. Patients with the presence of active or suspected acute or chronic uncontrolled infection or 
with a history of immunocompromise, including a positive HIV test result (ELISA and 
Western blot).
23. Patients who have any current or prior medical condition that may interfere with the 
conduct of the study or the evaluation of its results in the opinion of the Investigator or the 
Sponsor’s Medical Monitor.
24. 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.
25. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 8 weeks after stopping of study medication. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization: have had surgical bilateral oophorectomy with or without 
hysterectomy or tubal ligation at least six weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment

Male sterilization with appropriate post-vasectomy documentation of the absence of 
spermatozoa in the ejaculate (at least 6 months prior to screening). For female 
subjects on the study, the vasectomized male partner should be the sole partner for 
that subject.

Combination of any two of the following (a+b or a+c, or b+c):
a.
Use of oral, injected or implanted hormonal methods of contraception or other
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c.
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
26. Sexually active males must use a condom during intercourse while taking the treatment
and for 2 months after the last dose of study treatment and should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid. Female partners of male patients must be also 
advised to use one of the following contraception methods:

Use of oral, injected or implanted hormonal methods of contraception or other 
approved hormonal methods of contraception

Placement of an intrauterine device (IUD) or intrauterine system (IUS)

Total abstinence or patient sterilization (male or female).


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6
Treatment
6.1
Investigational treatment, other study treatment, supportive 
treatment
The investigational study drugs used in the course of this trial are pasireotide (SOM230) LAR 
and everolimus (RAD001). For the duration of the trial, pasireotide LAR and everolimus will 
be supplied by Novartis, or by local commercial stock, once available.
Therefore, if at any time during the study life pasireotide LAR and/or everolimus become 
commercially available in the Countries participating to the study the local commercial stock
should be used.
Definition of terms:

Study drug = pasireotide (SOM230) LAR or everolimus (RAD001)

Study treatment = pasireotide (SOM230) LAR or everolimus (RAD001) alone or a 
combination of pasireotide LAR and everolimus.
6.1.1
Dosing regimen
Patients will be randomized centrally on a 1:1:1 basis to receive treatment with either 
pasireotide LAR (arm 1) or everolimus (arm 2) or a combination of either regimen (arm 3).
A treatment cycle is defined as 28 days.
6.1.1.1
Pasireotide LAR administration
Pasireotide LAR 60 mg will be administered as an i.m. depot injection once every 28 days 
(+/- 3 days) starting at Day 1 (visit 2).
6.1.1.2
Everolimus administration
Everolimus will be dispensed by the study center personnel on an outpatient basis. Patients 
will be provided with an adequate supply of everolimus for self-administration at home.
Everolimus will be dosed starting on Day 1 (Visit 2). Patients will be instructed to take one 10 
mg tablet or, alternatively two 5 mg tablets taken together (QD), depending on the available 
strength of the commercial stock used. Everolimus tablets have to be taken orally with a glass 
of water, once daily at the same time each day either consistently with food or consistently 
without food. Any dietary habits around the time of everolimus intake should be as consistent 
as possible throughout the study. The tablet/tablets should be swallowed as a whole and not be 
chewed or crushed. In cases where the tablet/tablets cannot be swallowed, it/they should be 
disintegrated in water just prior being taken. Approximately 30 mL of water should be put 
into a glass. The tablet/tablets should then be added and the contents stirred gently (for a 
maximum of 7 minutes) until the tablet/tablets are disintegrated. The contents should then be 
drunk. Afterwards, the glass should be rinsed with an additional 30 mL of liquid and drunk.
If vomiting occurs, no attempt should be made to replace the vomited dose unless two 
everolimus tablets (or one 10 mg tablet) are clearly visible. If two everolimus tablets (or one 
10 mg tablet) are clearly visible, then the patient should replace the everolimus dose. Patients 


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should be instructed that if they miss a dose on one day, they must not take any extra dose the 
next day, but instead to immediately contact the study center as soon as possible to ask for 
advice.
If the patient misses a dose at the scheduled time, the administration of the study drug can:

occurr within 8 hours after the normal time of administration, and the new time of 
administration can be considered as a reference for the next administration (eg. if the 
normal time of administration is 8 am, the 8 am missing dose could be administered by 4 
pm of the same day)

or be skipped until the next day.
6.1.1.3
Combination of pasireotide LAR and everolimus
Patients randomized to the arm 3 will be given a combination therapy based on pasireotide 
LAR 60 mg i.m. every 28 days and everolimus 10 mg p.o. daily.
6.1.2
Ancillary treatments
Not applicable.
6.1.3
Rescue medication
See Section 6.1.4.
6.1.4
Handling of Specific Toxicities
6.1.4.1
Management of Infections
Everolimus has immunosuppressive properties and may predispose patients to infections, 
especially infections with opportunistic pathogens. Localized and systemic infections, 
including pneumonia, other bacterial infections and invasive fungal infections, such as 
aspergillosis, candidiasis or pneumocystis jirovecii pneumonia (PJP) have been described in 
patients taking everolimus. Some of these infections have been severe (e.g. leading to sepsis,
respiratory failure) and occasionally have had a fatal outcome. Physicians and patients must 
be aware of the increased risk of infections with everolimus, be vigilant for symptoms and 
signs of infection and, in case a diagnosis of infection is made, initiate appropriate treatment 
promptly and consider interruption or discontinuation of everolimus.
Treat pre-existing fungal infections prior to starting treatment with everolimus.
If a diagnosis of invasive systemic fungal infection is made, discontinue everolimus and treat 
with appropriate antifungal therapy.
Cases of PJP, some with fatal outcome, have been reported in patients who received 
everolimus. PJP may be associated with concomitant use of corticosteroids or other 
immunosuppressive agents. Prophylaxis for PJP should be considered when concomitant use 
of corticosteroids or other immunosuppressive agents are required.
6.1.4.2
Management of skin toxicity
Skin toxicity has been reported for patients receiving everolimus treatment.


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For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. 
Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with 
the following suggested supportive measures at the discretion of the investigator: oral 
minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, 
diphenhydramine, oral prednisolone (short course) or pimecrolimus.
6.1.4.3
Management of stomatitis / oral mucositis / mouth ulcers
Stomatitis, oral mucositis and mouth ulcers have been reported for patients receiving 
everolimus treatment.
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with 
gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal 
mucosa -e.g. gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis-
must be monitored more closely. Patients should be instructed to report the first onset of 
buccal mucosa irritation/reddening to their study physician immediately.
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral toxicities 
associated with everolimus as mouth ulcers, rather than mucositis or stomatitis. If your 
examination reveals mouth ulcers rather than a more general inflammation of the mouth, 
please classify the adverse event as such. The paradigm for treatment of stomatitis/oral 
mucositis/mouth ulcers, below reported, should be followed:
1. For mild toxicity (grade 1: minimal symtoms, normal diet), no dose adjustments are 
reguired. Use conservative measures such as non-alcoholic mouth wash or salt water 
(0.9%) mouth wash several times a day until resolution.
2. For moderate toxicity (grade 2: patients have pain but are able to maintain adequate oral 
alimentation), a temporary dose interruption until recovery to grade ≤1 is recommended.
Everolimus can be reinitiated at the same dose. If stomatitis recurs at grade 2, it is 
recommended to interrupt treatment untile recovery to grade ≤1, and reinitiate treatment at 
a lower dose. The suggested treatments are topical analgesic mouth treatments (i.e.,
local anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®).
3. For severe toxicity (grade 3: patients are symptomatic and cannot maintain adequate oral 
alimentation), a temporary dose interruption until recovery to grade ≤1 is recommended. 
Everolimus can be reinitiated at a lower dose. Manage with topical analgesic mouth 
treatments (i.e., local anesthetics such as, benzocaine, butyl aminobenzoate, 
tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids, 
such as triamcinolone oral paste 0.1% (Kenalog in Orabase®).
4. For more severe toxicity (grade 4: symptoms associated with life-threating consequences), 
discontinue everolimus and treat with appropriate medical therapy.
5. Agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents.
6. Antifungal agents should be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) 


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should be avoided in all patients due to their strong inhibition of everolimus metabolism, 
therefore leading to higher everolimus exposures. Therefore, topical antifungal agents are 
preferred if an infection is diagnosed.
6.1.4.4
Management of hyperlipidemia
Hyperlipidemia has been reported for patients receiving everolimus treatment.
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits of the patient. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) 
or grade 2 hypertriglyceridemia or higher (>2.5 × upper normal limit) should be treated with a 
3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g. atorvastatin, pravastatin, 
fluvastatin) or appropriate triglyceride-lowering medication, in addition to diet.
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death. The risk versus benefit of using this therapy should 
be determined for individual patients based on their risk of cardiovascular complications of 
hyperlipidemia.
6.1.4.5
Management of hyperglycemia
Hyperglycemia has been frequently reported in patients receiving everolimus and pasireotide 
therapy. 
Clinical studies of pasireotide in healthy volunteers and in patients with Cushing’s disease, 
acromegaly or NET with carcinoid syndrome have reported transient, asymptomatic increases 
in fasting and postprandial glucose levels. Although hyperglycemia was observed in healthy 
volunteers and across all disease populations receiving pasireotide, this AE was most 
prominent in patients with Cushing’s disease, a setting in which glucose metabolism is
inherently dysregulated. The majority of hyperglycemia events were grade 1 and 2. 
Some
patients developed grade 3 or 4 events, and SAEs related to 
hyperglycemia have been reported including diabetic ketoacidosis
(DKA). 
Hyperglycemia appears to be reversible upon pasireotide discontinuation.
In a phase III study [CSOM230B2305] assessing the safety and efficacy of pasireotide LAR 
s.c. over 6 months in patients with de novo or persistent/recurrent Cushing’s disease, two 
hyperglycemia-related emergencies occurred: one case of DKA, and one case of diabetic
hyperglycemic coma. The former patient discontinued from the study and the latter continued 
treatment with study drug while taking insulin to treat hyperglycemia. Both events were 
reported after pasireotide LAR dose was increased from 40 to 60 mg. However, it is important 
to highlight that in the patient with the SAE of DKA, pasireotide LAR was initiated when her 
underlying diabetes was poorly controlled (HbA1c 8.7% prior to first dose of pasireotide LAR 
and after cross-over from octreotide) while receiving no anti-diabetic therapy which in part 
could have contributed to the exacerbation of hyperglycemia resulting in DKA and 
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Two clinical studies have been conducted ([CSOM230B2216] and [CSOM230B2124]) in 
healthy volunteers to further understand the mechanism of pasireotide-induced hyperglycemia 
and to evaluate the potential clinical utility of antidiabetic agents in the management of 
pasireotide-induced hyperglycemia. Data from [CSOM230B2216] study indicate that 
pasireotide decreases insulin secretion, particularly in the postprandial period, as well as the 
glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) 
secretion. Results from [CSOM230B2124] study suggest that the incretin-based therapies 
(GLP-1 analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors) may have the best potential 
to manage the hyperglycemia associated with pasireotide. Some patients in [CSOM230B2305]
required insulin to treat their hyperglycemia. The mTOR pathway is related to the insulin 
signaling pathway, and it is likely that everolimus decreases insulin sensitivity whereas 
pasireotide-induced hyperglycemia is secondary to a decrease in insulin and incretin (such as 
GLP-1 and GIP) secretion. The combination of the two drugs (pasireotide LAR, which may 
alter insulin and glucagon secretion, and everolimus which may affect insulin sensitivity) may 
therefore result in a higher risk for hyperglycemia than each agent alone. Based on the 
currently available preliminary data regarding [CSOM230F2102] and [CSOM230I2201]
studies, it is hypothesized that one possible reason for the high rate of grade 3 hyperglycemia 
could be due to suboptimal monitoring of blood glucose.
It is important that optimal glycaemic control is achieved before starting a patient on study 
treatment, and that glucose levels are monitored during the trial.
The principal investigator is to educate the patient on the signs and symptoms of 
hyperglycemia. The principal investigator is to evaluate the risks for hyperglycemia in all 
patients. It is recommended to follow established guidelines by expert international diabetes 
associations such as the American Diabetes Association (ADA 2011) and European 
Association for the Study of Diabetes (EASD) (Nathan 2006, Nathan 2008, ADA 2011).
6.1.4.5.1 Monitoring of glucose levels
For patients in the pasireotide LAR monotherapy arm and in the pasireotide LAR and 
everolimus combination arm
All patients in the combination arm and in pasireotide LAR monotherapy arm must self-
monitor glucose levels.
Patients with normal glucose metabolism at baseline should self-monitor their fasting blood 
glucose level once daily by fingerstick for the first 2 months, then twice a week for the next 2 
months and once a week thereafter throughout the study.
Patients with a prior history or newly observed fasting hyperglycemia, impaired glucose 
tolerance or diabetes mellitus, or at risk of developing these conditions should self monitor 
their blood glucose by fingerstick twice daily (once fasting and once 2-hours post-prandial).
The site should call the patient after approximately 10 days after day 1 and day 29 visits (i.e. 
for the first 2 cycles) and should ask for the blood glucose results.
All patients should contact the site (or medical care, if the site is unavailable) if the fasting 
blood glucose level is >130 mg/dL (7.2 mmol/L) on any two separate occasions and come for 
an additional visit as soon as possible to confirm the values and to ensure early intervention.


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Any patient should contact the site (or medical care, if the site is unavailable) immediately if 
the fasting blood glucose value is ≥200 mg/dL (11.1 mmol/L) at any time. At this visit, fasting 
plasma glucose levels will be measured at local lab. Patients with confirmed fasting 
hyperglycemia should start self-monitoring of their blood glucose by fingerstick twice daily 
(once fasting and once 2-hours post-prandial), if not already done. They may be also be 
referred to a specialist for appropriate management of hyperglycemia. In order to ensure early 
intervention, if needed, glucose levels will be tested at the local lab at all visits.
All patients will keep a diary for appropriate detection and management of hyperglycemia
throughout the trial and present the collected data to their physician/diabetes specialist for 
evaluation. The sponsor will provide the patient diaries but this data will not be collected by 
the sponsor.
For patients in the everolimus monotherapy arm
All patients in the everolimus monotherapy arm showing ≥grade 3 hyperglycemia 
(>250mg/dL; >13.9 mmol/L) at any point visit throughout the study, should start monitoring 
their blood glucose by fingerstick twice daily (once fasting and once 2 hours post-prandial).
All patients should contact the site (or medical care, if the site is unavailable) if their fasting 
glucose value (during self monitoring) is >130 mg/dL (7.2 mmol/L) on any two separate 
occasions and come for an additional visit as soon as possible to confirm the values and to 
ensure early intervention. Any patient should contact the site (or medical care, if the site is 
unavailable) immediately if the fasting blood glucose value (during self monitoring) is ≥200 
mg/dL (11.1 mmol/L) at any time. At this visit, fasting plasma glucose levels will be 
measured at local lab. Patients may be referred to a specialist for appropriate management of 
hyperglycemia.
These patients should be encouraged to keep a diary for their blood glucose throughout the
trial and present the collected data to their physician/diabetes specialist for evaluation. The 
sponsor will provide the patient diaries but this data will not be collected by the sponsor.
In order to ensure early intervention, if needed, fasting glucose levels will be tested at the 
local laboratory at all visits, excluding visit 6 when glucose will not be assessed unless it is 
medically indicated.
For all patients
Any patient showing a fasting plasma glucose >130 mg/dL (7.2 mmol/L), or 2-hour post-
prandial capillary glucose (PPG) ≥180 mg/dL (10 mmol/L) on two separate occasions, and/or 
HbA1c >7% should be evaluated by a diabetes specialist for appropriate treatment (Position 
statement ADA 2011). In addition, these patients should be given information regarding 
diabetes disease management. Initiation or adjustment of antidiabetic treatment should be 
considered as early as possible. In addition, these patients should begin monitoring their blood 
glucose by fingerstick twice daily (fasting and 2 hours post-prandial) if not already done.
Appropriate management for the hyperglycemia includes:

The use of anti-diabetic agents for mild to moderate hyperglycemia such as incretin 
enhancers (e.g. GLP-1 analogues or DPP4 inhibitors or insulin secretagogues).


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
Insulin should be used for moderate to severe hyperglycemia.

Drugs like metformin may be used if the patient has history suggestive of insulin 
resistance or metabolic syndrome, who are taking everolimus and have/or have had fasting 
hyperglycemia. These agents may not be efficacious in patients with isolated post-prandial 
hyperglycemia as observed with pasireotide given its mechanism of action, but may be 
useful in patients with everolimus-induced hyperglycemia.
6.1.4.5.2 Dose adjustments
For patients on pasireotide LAR monotherapy
For patients showing ≥ grade 3 hyperglycemia (>250 mg/dL; >13.9 mmol/L) at any point 
throughout the study, pasireotide LAR treatment should be interrupted. 

If hyperglycemia recovers to grade ≤ 1, pasireotide LAR can be reinitiated at the lowest
dose level (20 mg). If hyperglycemia is well controlled, the dose of pasireotide LAR can 
be escalated in steps to the original dose with the appropriate monitoring of blood glucose 
levels. These patients should also begin monitoring their blood glucose by fingerstick 
twice daily (once fasting and once 2 hours post-prandial), if not already done;

If grade 3 hyperglycemia (>250 mg/dL; >13.9 mmol/L) persists despite interruption of 
pasireotide LAR treatment (≥56 days from last injection) and despite optimal antidiabetic 
treatment, the patient should be discontinued from the study.
For patients in the everolimus monotherapy arm
In addition to optimizing antidiabetic therapy, in patients showing ≥grade 3 hyperglycemia 
(>250 mg/dL; >13.9 mmol/L) at any point throughout the study, the dose of everolimus 
should be interrupted until recovery to grade ≤ 1. Then, everolimus should be reintroduced at 
one dose level lower. These patients should monitor their blood glucose by fingerstick twice 
daily (one fasting and one 2 hours post-prandial).
If grade 3 hyperglycemia (>250 mg/dL; >13.9 mmol/L) persists despite interruption of 
everolimus treatment (≥28 days from last dose) and in spite of optimal antidiabetic treatment,
the patient should be discontinued from the study (Table 6-1).
For patients in the pasireotide LAR and everolimus combination arm
For patients showing ≥grade 3 hyperglycemia (>250 mg/dL; >13.9 mmol/L) at any point 
throughout the study, pasireotide LAR treatment should be interrupted.

If hyperglycemia recovers to grade ≤ 1, pasireotide LAR can be reinitiated at the lowest 
dose level (20 mg). If hyperglycemia is well controlled, the dose of pasireotide LAR can 
be escalated in steps to the original dose with the appropriate monitoring of blood glucose 
levels. These patients should also begin monitoring their blood glucose by fingerstick 
twice daily (once fasting and once 2 hours post-prandial), if not already done.

If grade 3 hyperglycemia (>250 mg/dL; >13.9 mmol/L) persists despite interruption of 
pasireotide LAR treatment (≥56 days from last injection) and despite optimal antidiabetic 
treatment, the dose of everolimus should also be interrupted, i.e. this patient should be 
discontinued from the study (Table 6-1).


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Table 6-1
Dosing modification for hyperglycemia
CTCAE grade
Pasireotide LAR 
monotherapy arm
Everolimus monotherapy 
arm
Everolimus and 
pasireotide LAR 
combination arm
Grade ≤ 2 
(≤250 mg/dL; ≤13.9 
mmol/L)
No dose adjustment 
necessary. 
Consider start or 
adjustment of antidiabetic 
therapy.
No dose adjustment 
necessary. 
Consider start or 
adjustment of antidiabetic 
therapy.
No dose adjustment 
necessary. 
Consider start or adjustment 
of antidiabetic therapy.
Grade ≥ 3
(>250 mg/dL; >13.9 
mmol/L)
Interrupt pasireotide LAR 
until recovery to grade ≤ 1
Optimize antidiabetic 
therapy.
- If hyperglycemia recovers 
to grade ≤ 1, reinitiate 
pasireotide LAR at the 
lowest dose level (20 mg). 
If hyperglycemia is well 
controlled, the dose of 
pasireotide LAR can be 
escalated in steps to the 
original dose with the 
appropriate monitoring of 
blood glucose levels.
- If grade ≥3 hyperglycemia 
(>250 mg/dL; >13.9 
mmol/L) persists despite 
interruption of pasireotide 
LAR treatment (≥56 days 
from last injection) and 
despite optimal antidiabetic 
treatment, the patient 
should be discontinued 
from the study
Interrupt everolimus until 
recoveryto grade ≤ 1
Optimize antidiabetic 
therapy.
- If hyperglycemia recovers 
to grade ≤ 1, reintroduce 
everolimus at one dose 
level lower. 
- If grade 3 hyperglycemia 
(>250 mg/dL; >13.9 
mmol/L) persists despite 
interruption of everolimus 
treatment (≥28 days from 
last dose) and in spite of 
optimal antidiabetic 
treatment, the patient 
should be discontinued 
from the study
Interrupt pasireotide LAR 
until recovery to grade ≤ 1
Optimize antidiabetic 
therapy.
- If hyperglycemia recovers 
to grade ≤ 1 reinitiate 
pasireotide LAR at the 
lowest dose level (20 mg). If 
hyperglycemia is well 
controlled, the dose of 
pasireotide LAR can be 
escalated in steps to the 
original dose with the 
appropriate monitoring of 
blood glucose levels.
- If grade ≥3 hyperglycemia 
(>250 mg/dL; >13.9 mmol/L) 
persists despite interruption 
of pasireotide LAR 
treatment (≥56 days from 
last injection) and despite 
optimal antidiabetic 
treatment, interrupt 
everolimus and discontinue 
the patient from the study.
6.1.4.6
Management of diarrhea
Diarrhea has been reported for patients receiving everolimus and pasireotide treatment.
Appearance of diarrhea attributed to everolimus toxicity may be treated with loperamide. 
Other medications for diarrhea may be used as needed such as cholestyramine for the 
management of diarrhea due to short gut syndrome.
The investigator must report dose administered and frequency appropriately on the CRF.
6.1.4.7
Management of non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Both asymptomatic 
radiological changes (grade 1: radiological lung changes only) and symptomatic non-
infectious pneumonitis (grade 2: not interfering with activities of daily living or grade 3: 
interfering with activities of daily living and oxygen indicated) have been reported in patients 
receiving everolimus therapy.


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
Patients with non-symptomatic radiological changes suggestive of
non-infectious 
pneumonitis and few or no symptoms can generally continue everolimus therapy
without dose alteration.

Clinically significant toxicity associated with the use of mTOR inhibitors is typically 
associated with pulmonary symptoms including dyspnea, nonproductive cough, fatigue,
and fever. Patients with moderate symptoms may require interruption of therapy until 
symptoms improve, followed by re-introduction of everolimus at a lower dose (grade 2).
The use of corticosteroids may be indicated. Patients with severe symptoms (grade ≥3) 
require permanent discontinuation of everolimus. Corticosteroids may speed recovery in 
this group.
Individuals participating in this trial will be assessed for any signs of interstitial lung disease 
(ILD) indicative of pneumonitis at baseline and routinely questioned as to the presence of new 
or changed pulmonary symptoms consistent with lung toxicity. In addition, chest radiological 
imaging and pulmonary function tests (PFTs) will be conducted in the discretion of the 
investigator, if clinically indicated. If non-infectious pneumonitis develops during the study, 
the guidelines in Table 6-2 should be followed and consultation with a pulmonologist is 
recommended.
Overall, in light of evidence that the risk for non-infectious pneumonitis is related to 
everolimus, the drug interruption/discontinuation strategy will apply to everolimus only (see 
Table 6-2).
Table 6-2
Guidelines for management of non-infectious pneumonitis
Worst Grade
Pneumonitis
Required Investigations
Management of 
Pneumonitis
RAD001 Dose Adjustment
Grade 1
(asymptomatic,
radiographic 
findings only)
CT scans with lung windows.
Repeat at least every three 
cycles until return to normal
limits.
No specific therapy is
required.
Administer 100% of everolimus
dose.
Grade 2
(symptomatic,
not interfering 
with activities of 
daily living)
CT scan with lung windows.
Consider pulmonary function 
testing including spirometry,
DLCO, and room air O2 
saturation at rest. Repeat at least 
every three cycles until return to
normal limits. Consider a
bronchoscopy with biopsy and/or
BAL.
Symptomatic only. 
Prescribe 
corticosteroids if 
symptoms are 
troublesome.
Consider interruption of therapy, 
rule out infection and consider 
treatment with corticosteroids until 
symptoms improve to grade < 1.
Re-initiate everolimus at a lower 
dose.
Discontinue treatment if failure to 
recover within 4 wks.
Grade 3
(symptomatic,
interfering with 
activities of daily 
living; O2
indicated)
CT scan with lung windows and 
pulmonary function testing 
including spirometry, DLCO, and 
room air O2 saturation at rest.;
Repeat at least every two cycles 
until return to normal limits. 
Bronchoscopy with biopsy and/or
BAL is recommended.
Prescribe 
corticosteroids if 
infective origin is ruled
out. Taper as 
medically indicated.
Interrupt treatment until symptoms 
resolve to grade
≤ 1. May restart treatment at a
reduced dose (by one level), if 
evidence of clinical benefit.
Discontinue treatment, if failure to 
recover within 4 wks.
If toxicity recurs at grade 3, 
consider discontinuation.


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Worst Grade
Pneumonitis
Required Investigations
Management of 
Pneumonitis
RAD001 Dose Adjustment
Grade 4 (life-
threatening,
ventilatory 
support
indicated)
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 two cycles until return 
to within normal limits. 
Bronchoscopy with biopsy and/or
BAL is recommended if possible.
Prescribe 
corticosteroids if 
infective origin is ruled
out. Taper as 
medically indicated.
Discontinue treatment.
6.1.4.8
Management of hepatitis reactivation
6.1.4.8.1 Monitoring for hepatitis B reactivation
Hepatitis B reactivation has been observed in patients receiving everolimus treatment.
Table 6-3 provides details of monitoring according to screening/baseline results of viral load 
and serologic markers testing.
Table 6-3
Monitoring for positive baseline hepatitis B results
Test
Result
Result
Result
Result
Result
HBV-DNA
Positive
Positive or 
negative
Negative
Negative
Negative
HBsAg
Positive or 
negative
Positive
Negative
Negative
Negative
HBsAb
Positive or 
negative
Positive or 
negative
Positive and no 
prior HBV
vaccination
Positive or 
negative
Negative or 
positive with 
prior HBV
vaccination
HBcAb
Positive or 
negative
Positive or 
negative
Positive or 
negative
Positive
Negative
Recommendation
Patient does not qualify for the 
study.
No prophylaxis.
Monitor HBV-DNA every 4 weeks (±
1 week)*
No specific 
action
* The monitoring for hepatitis B reactivation has to be performed in all patients, irrespective of the treatment arm 
they have been assigned to (thus, not only in patients taking everolimus alone or in combination, but also in 
patients on pasireotide alone), taking into account the results arising from the four hepatitis B tests. However, in 
light of evidence that the risk for hepatitis B reactivation is related to everolimus, the drug 
interruption/discontinuation strategy (see Table 6-4) will apply to everolimus only.
For hepatitis B reactivation, definition and management guidelines see Table 6-4.
Table 6-4
Guidelines for management of hepatitis B
HBV reactivation (with or without 
clinical signs and symptoms)*
Actions
For patients with baseline results:
Negative HBV-DNA and HBs-Ag
AND
Positive HBs-Ab (with no prior history 
of vaccination against HBV), OR 
positive HBc-Ab
--------------------------------------------
Reactivation is defined as:
Treat: Start first antiviral medication
AND
Interrupt everolimus administration until resolution:
≤baseline HBV-DNA levels
If resolution occurs within <28 days, the study drug should be re-
started at one dose lower, if available. If the patient is already receiving 
the lowest dose of study drug according to the protocol, the patient 
should restart at the same dose after resolution. Antiviral therapy should 


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HBV reactivation (with or without 
clinical signs and symptoms)*
Actions
New appearance of measurable HBV-
DNA
continue at least 4 weeks after last dose of study drug.
If resolution occurs after ≥28 days, patients should discontinue study 
treatment but continue antiviral therapy for at least 4 weeks after last 
dose of study drug.
*All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-
activation), unless considered life threatening by the investigator; in this case, they should be recorded as grade 4 
(CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-activation). Date of viral reactivation is the date on which both 
DNA and ALT criteria were met (e.g. for a patient who was HBV-DNA positive on 01-JAN-10 and whose ALT 
reached ≥ 5 × ULN on 01-APR-10, the date of viral reactivation is 01-APR-10).
6.1.4.8.2 Monitoring for hepatitis C
At screening, all patients will be tested for the presence of HCV Ribonucleic acid-Polimerase 
Chain Reaction (HCV-RNA-PCR). If a patient tests positive for the presence of HCV-RNA-
PCR, he/she will be considered ineligible for the study according to Exclusion Criterion #16.
Patients known to have a history of HCV infection, despite a negative viral load test at
baseline (including those that were treated and are considered “cured”) should be monitored 
every 4 weeks (± 1 week) for the risk of hepatitis C reactivation.
The monitoring for hepatitis C reactivation has to be performed in all patients with a known 
history of HCV infection, irrespective of the treatment arm they have been assigned to (thus, 
not only in patients taking everolimus alone or in combination, but also in patients on 
pasireotide alone). However, in light of evidence that the risk for hepatitis C reactivation is 
related to everolimus, the drug interruption/discontinuation strategy (see Table 6-5) will apply 
to everolimus only.
For definition of hepatitis C reactivation and the management guidelines, see Table 6-5.
Table 6-5
Guidelines for management of hepatitis C
HCV reactivation*
Actions
For patients with baseline results: Knowledge of past hepatitis
C infection with no detectable HCV-RNA at screening.
Reactivation is defined as: New appearance of detectable 
HCV-RNA.
Discontinue study treatment.
*All reactivations of hepatitis C are to be recorded as grade 3 (CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-
activation), unless considered life threatening by the investigator; in this case, they should be recorded as grade 4
(CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-activation).
6.1.4.9
Management of ECG changes
SSAs have shown an influence on cardiac signal transduction.
Pasireotide administered subcutaneously has been shown to prolong the QT interval in healthy 
subjects based on two Phase I studies [CSOM230B2113] and [CSOM230B2125]. Additional 
analysis of thorough QT study data [CSOM230B2125], including quantitative ECG beat to beat 
restitution analysis, showed that pasireotide does not alter cardiac repolarization in the same 
manner as drugs known to prolong QT that are associated with pro-arrhythmia. 


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In clinical studies in Cushing’s disease patients, QTcF of >500 msec was observed in two out 
of 201 patients. These episodes were sporadic and of single occurrence with no clinical 
consequence observed. 
Episodes of torsade de pointes were not observed in any clinical study with pasireotide.
If at any visit a QTcF > 500 msec is observed, triplicate ECGs, each 2-3 minutes apart, need 
to be taken approximately 1 hour after the initial ECG. The mean QTcF from the triplicate 
ECGs will be determined. If the mean QTcF is > 500msec, the patient will need to be closely
monitored at the hospital and will have to postpone pasireotide LAR treatment until a 
cardiologist has re-evaluated the ECG (this can be done by the central cardiologist if the trial 
has one). If the cardiologist confirms a mean QTcF >500 msec, the patient has to discontinue. 
Otherwise and if the cardiologist confirms that at least one ECG shows a QTcF > 470msec, 
the cardiac assessments described for a confirmed QTcF > 470msec need to be followed (see 
Figure 6-1).
If at any visit a 470 msec < QTcF/mean QTcF ≤ 500msec is observed, the following steps 
need to be taken (refer to Figure 6-1):

postpone pasireotide LAR administration;

a cardiology consultation must be sought as soon as practical but within 7 days of the 
initial abnormal ECG and the cardiologist must re-evaluate the ECG (this can be done by 
the central cardiologist if the trial has one).

If a QTcF > 470msec is NOT confirmed, no further action needs to be taken, and 
pasireotide LAR can be restarted.

If a QTcF > 470msec is confirmed, a cardiologist must perform a thorough 
examination (such as reviewing baseline ECG, concurrent medications and 
performing a cardiovascular examination, including at least a cardiac auscultation) to 
assess the patient for cardiovascular risk factors.

If based upon the assessment by the cardiologist, the investigator considers that 
there is an acute cardiovascular safety risk and that the patient should not 
continue with study medication, the patient needs to be discontinued immediately 
(discontinuation criteria to be followed).

If following the examination by the cardiologist, the investigator considers that 
there is not an acute cardiovascular safety risk and that the patient could restart to 
receive study medication, a Holter ECG (24hr or 48hr depending on the study) 
must be recorded soon as practical but within 7 days after the initial abnormal 
ECG / at the next pasireotide LAR injection. The Holter-ECG must be started 
30min prior to an injection of study medication.
The results of the ECGs, cardiac examination, Holter-ECGs and the recommendation by the 
cardiologist must be evaluated by the investigator to determine whether the patient should 
continue the trial or not (discontinuation criteria to be followed).
Overall, the monitoring of ECG changes has to be performed in all patients, irrespective of the 
treatment arm they have been assigned to (thus, not only in patients taking everolimus alone or 
in combination, but also in patients on pasireotide alone), taking into account the observed 
QTcF value. However, in light of evidence that the risk for ECG changes is related to SSA 


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treatment, the drug interruption/discontinuation strategy (see Figure 6-1) will apply to 
pasireotide LAR only.
Figure 6-1
Procedure for QTcF prolongations


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6.1.4.10 Hepatic Safety Management
If any of the criteria below are observed at any scheduled or unscheduled visit the sponsor 
should be notified immediately upon awareness. 

ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN;

ALT or AST > 5 x ULN and < 8 x ULN;

ALT or AST > 8 x ULN.
ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN 
If this criterion is met with the presence of alkaline phosphatase < 2 X ULN, the patient has to 
discontinue the study and continue the safety evaluations.
If this criterion is met without the presence of alkaline phosphatase < 2 X ULN, the patient 
has to perform a safety follow-up procedure withing 72 hours of awareness of the 
abnormality (see Figure 6-2). According to the safety follow-up procedure, the investigator 
has to perform:

liver-directed medical history and physical examination (i.e. assess occupational hazards, 
concomitant medications including OTC medications, inter-current illness, etc);

liver function tests (LFT): ALT, AST, total bilirubin, (fractionate to direct/indirect 
bilirubin if total bilirubin is > 2.0 x ULN), Alb, PT (INR), ALP, and GGT;

hepatitis screening: anti-HAV, IgM (to confirm acute Hepatitis A), HbsAg, anti-HBc, anti-
HCV (if positive, PCR viral load should be assessed), anti-HEV, ANA antibodies, anti-
smooth muscle anti-bodies, CMV and EBV;

abdominal ultrasound (liver and biliary tree).
In addition, liver function tests have to be monitored every 3-4 days until resolution or return 
to baseline values.

If ALT or AST return to less than 5 x ULN study drug can be resumed at the original dose 
level and the patient can continue the study.

If ALT or AST rises above 5 x ULN at any time after study drug is resumed, then, the
study drug should be discontinued immediately.

If resolution or return to baseline does not occur after 2 weeks, the patient should be 
discontinued.
Overall, patients may need to be discontinued if the abnormal liver function criteria are met 
upon LFT retesting (See Section 6.3.2.1). Progress reports of the event should be maintained 
until resolution or stabilization (i.e. no further elevation after 2 consecutive assessments).
If any of these criteria are met and deemed an AE by the investigator, the event must be 
recorded on the AE CRF page; if the event is deemed serious by the investigator, then proceed 
with completing the SAE form. In addition, any significant findings from the physical 
examination should be recorded on the AE CRF page.


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ALT or AST > 5 x ULN and < 8 x ULN
If this criterion is met, the study treatment has to be temporarily interrupted, and the patient 
has to perform a safety follow-up procedure withing 72 hours of awareness of the 
abnormality, as above reported (see Figure 6-2).
ALT or AST > 8 x ULN
If this criterion is met, the study treatment has to be discontinued (see Figure 6-2).
Figure 6-2
LFT Management Algorithm
6.1.5
Guidelines for continuation of treatment
See Section 6.3.
6.1.6
Treatment duration
Patients will be treated with the assigned study treatment for 12 months or until radiologically 
documented disease progression, intolerable toxicity, start of new cancer therapy, withdrawal
of consent or discontinuation due to any other reason.
Patients who are presenting clinical benefit from the treatment with combination or 
monotherapy and who are not experiencing unacceptable toxicity are permitted to continue 
treatment after the 12-month treatment period. These patients will be followed until 


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radiologically documented disease progression, intolerable toxicity, start of new cancer 
therapy, withdrawal of consent or discontinuation due to any other reason.
The definition of end of the study is reported in Section 4.3.
6.2
Dose escalation guidelines (Phase 1 studies only)
Not applicable.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment.
6.3.1.1
Dose modifications for pasireotide LAR
Patients who do not tolerate the pasireotide LAR 60 mg i.m. dose are permitted to reduce the 
dose to 40 mg or to 20 mg. Patients requiring a dose reduction are to return to the higher dose 
once the tolerability issue is resolved.
All dose changes must be recorded on the CRF.
Table 6-6
Dosing modification criteria for suspected pasireotide LAR-related 
toxicities
Adverse Event
Action
CTCAE grade ≤2
CTCAE grade ≥3 and assessed as 
drug related
(except blood glucose changes see
Section 6.1.4.5,
LFT changes see Section 6.1.5,
QTc changes see Section 6.1.4.9
No drug adjustments
Reduce dose to 40 mg.
If the AE improves to grade ≤2 before the next administration, increase
dose to 60 mg.
If the dose is increased and the AE recurs at CTC grade ≥3 the dose 
will be reduced back to the lower dose and shall not be increased again 
during the study period.
If the AE does not improve to grade ≤2 on the lower dose before the 
next administration, reduce the dose to 20 mg. If re-escalation of 
pasireotide LAR to 40 mg is not possible*, the patient will be 
discontinued from the study and will be followed for safety.
If the AE does not improve to grade ≤ 2 on the lowest dose before the 
next administration, the patient will discontinue the study drug and be 
followed for safety.
* Re-escalation of pasireotide LAR from 20 to 40 mg has to be performed within 56 days.
The above guidance should be used for all AEs judged to be related to pasireotide LAR except 
for changes in blood glucose which should be followed-up as described in Section 6.1.4.5, for 
changes in LFTs which should be managed according to Section 6.1.5, and for changes in 
QTc which should be followed-up as described in Section 6.1.4.9.
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value must be followed at least weekly until resolution or stabilization 
of the event, whichever comes first. Patients must be discontinued from the study if they 


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require a dose delay of ≥56 days. All patients will be followed for adverse events and serious 
adverse events for 56 days following the last dose of pasireotide LAR.
6.3.1.2
Dose modifications for everolimus
Dose adjustments are permitted for any adverse event suspected to be related to everolimus in 
those patients unable to tolerate the once-daily oral dose of 10 mg. If the administration of 
everolimus must be interrupted because of unacceptable toxicity, study drug dosing will be 
interrupted or modified according to the guidelines in Table 6-7. If the toxicity is intolerable 
to the patient at the original 10 mg daily dose, interrupt everolimus until recovery to grade ≤1;
then, reintroduce everolimus at the initial dose or lower dose level depending on toxicity type 
and grade (Table 6-8).
If a patient has already decreased 2 dose level (i.e., to 5 mg every other day), no further dose 
reduction is permitted. Patients who need an additional dose reduction will be required to 
discontinue the study drug.
The lower dose level introduced after tolerability issues will be maintained throughout the 
study.
The initial once-daily oral dose of everolimus (10 mg) can be administered at two different 
strengths: either as two 5 mg tablets, taken together QD, or as a single 10 mg tablet. In case a 
dose reduction is required due to toxicity, patients initially receiving the 10 mg strength will 
be provided with the 5 mg strength. Thus, they will be able to take the reduced 5 mg dose as a 
single 5-mg tablet.
Table 6-7
Everolimus dose level modification guidelines
Dose level
Dose and schedule
0 (starting dose)
10 mg daily
Decrease 1 dose level
5 mg daily
Decrease 2 dose levels
5 mg every other day
Table 6-8
Dosing modification criteria for suspected everolimus-related toxicity
Toxicity
Action
Non-hematological toxicity
Grade 2
(except pneumonitis – refer to Table 6-2)
(except blood glucose changes – refer to Table 6-1)
(except Hepatitis B and C management – refer to Table 
6-4 and Table 6-5)
(except hepatic toxicity – refer to Figure 6-2)
If the toxicity is tolerable to the patient, maintain the 
same dose. Initiate appropriate medical therapy and 
monitor.
If the toxicity becomes intolerable to patient, interrupt 
everolimus until recovery to grade ≤1. Then,
reintroduce everolimus at the initial dose. 
If the toxicity recurs at grade 2, interrupt everolimus
until recovery to grade ≤1. Then, reintroduce 
everolimus at the lower dose level.
Grade 3
(except hyperlipidemia*)
(except blood glucose changes – refer to Table 6-1)
(except Hepatitis B and C management – refer to Table 
6-4 and Table 6-5)
(except hepatic toxicity – refer to Figure 6-2)
Interrupt everolimus until recovery to grade ≤1. Initiate 
appropriate medical therapy and monitor. Then 
reintroduce everolimus at the lower dose level. For 
pneumonitis consider the use of a short course of 
corticosteroids.
If the toxicity recurs at grade 3, consider 
discontinuation.


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Toxicity
Action
Grade 4
(except Hepatitis B and C management – refer to Table 
6-4 and Table 6-5)
Discontinue everolimus, and treat with appropriate 
medical therapy.
Hematological toxicity
Grade 2 Thrombocytopenia (platelets <75, ≥50×109/L)
Interrupt everolimus until recovery to grade ≤1 
(>75×109/L). Then, reintroduce everolimus at the initial 
dose.
If thrombocytopenia again returns to grade < 2, 
interrupt everolimus until recovery to grade ≤1. Then,
reintroduce everolimus at the lower dose level.
Grade 3 Thrombocytopenia (platelets <50, ≥25×109/L)
Interrupt everolimus until recovery to grade ≤1 
(platelets ≥ 75×109/L). Then, resume everolimus at 
one dose level lower. If grade 3 thrombocytopenia 
recurs, discontinue everolimus.
Grade 4 Thrombocytopenia (platelets <25×109/L)
Discontinue everolimus.
Grade 3 Neutropenia (neutrophils <1, ≥0.5×109/L)
Interrupt everolimus until recovery to grade ≤1 
(neutrophils ≥1.5×109/L). Then, resume everolimus at 
the initial dose. If ANC again returns to Grade 3, hold 
everolimus until the ANC ≥1.5×109/L. Then, resume 
everolimus dosing at the lower dose level. Discontinue 
patient from study therapy for a third episode of grade 
3 neutropenia.
Grade 4 Neutropenia (neutrophils < 0.5×109/L)
Interrupt everolimus until recovery to grade ≤1 
(neutrophils ≥1.5×109/L). Then, resume everolimus at 
the lower dose level. If grade 3 or grade 4 neutropenia 
occurs despite this dose reduction, discontinue 
everolimus.
Grade 3 febrile neutropenia (not life-threatening)
Interrupt everolimus until resolution of fever and 
neutropenia to grade ≤1. Hold further everolimus until 
the ANC ≥1,500/mm3 and fever has resolved. Then,
resume everolimus at the lower dose level. If febrile 
neutropenia recurs, discontinue everolimus.
Grade 4 febrile neutropenia (life-threatening)
Discontinue everolimus.
Any hematological or non-hematological toxicity 
requiring interruption for ≥4 weeks (28 days)
Discontinue everolimus.
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed using medical 
therapies
Investigator should manage anemia as medically indicated per local standards.
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value must be followed at least weekly until resolution or stabilization 
of the event, whichever comes first. The patients must be discontinued from the study if they 
require a dose delay of ≥28 days. All patients will be followed for adverse events and serious 
adverse events for 56 days following the last dose of everolimus. All interruptions or dose 
modifications must be recorded on the relevant section of the CRF.
6.3.2
Treatment interruption and treatment discontinuation
Patients experiencing unacceptable toxicity (AE of grade 3 or higher, including laboratory
value changes of grade 3 or higher) that the investigator considers directly attributable to the
study drugs should have their dose reduced or be withdrawn from the study. Section
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experiencing adverse events which are judged to be drug-related. Any deviation from
these guidelines should be discussed and approved by the sponsor.
For patients treated in the pasireotide LAR monotherapy arm or in the combination arm, in 
case the re-escalation from 20 to 40 mg of pasireotide LAR is not possible due to toxicity 
issues, the patient will be discontinued (Table 6-9). For patients treated in the combination 
arm, the patient will be maintained on study treatment unless the 20 mg pasireotide LAR dose
cannot be re-escalated (Table 6-9). If one drug of the combination is discontinued, the 
combination treatment will be discontinued.
Table 6-9
Recommendations for patient discontinuation following study drug 
adjustment
Dose levels reached after tolerability issues
Action
Pasireotide LAR 20 mg
If re-escalation to 40 mg* is not possible, the patient will 
be discontinued and followed for safety
Pasireotide LAR 40 mg
Patient can be maintained on study treatment 
Pasireotide LAR 20 mg and everolimus 5 mg e.o.d.
If re-escalation of pasireotide LAR to 40 mg* is not 
possible, the patient will be discontinued and followed for 
safety
Pasireotide LAR 40 mg and everolimus 5 mg e.o.d.
Patient can be maintained on study treatment
Pasireotide LAR 60 mg and everolimus 5 mg e.o.d
Patient can be maintained on study treatment
Pasireotide LAR 20 mg and everolimus 5 mg daily
If re-escalation of pasireotide LAR to 40 mg* is not 
possible, the patient will be discontinued and followed for 
safety
Pasireotide LAR 40 mg and everolimus 5 mg daily
Patient can be maintained on study treatment
Pasireotide LAR 60 mg and everolimus 5 mg daily
Patient can be maintained on study treatment
Pasireotide LAR 20 mg and everolimus 10 mg daily
If re-escalation of pasireotide LAR to 40 mg is not 
possible, the patient can not be maintained on study 
treatment
Pasireotide LAR 40 mg and everolimus 10 mg daily
Patient can be maintained on study treatment
* Re-escalation of pasireotide LAR from 20 to 40 mg has to be performed within 56 days.
All patients must have evaluations for 56 days after the last dose of study treatment. Patients 
lost to follow up should be recorded as such on the CRF. Patients who discontinue study
drug before completing the study should be scheduled for a visit as soon as possible, at
which time all of the assessments listed for the final study visit will be performed. At a
minimum, all patients who discontinue study treatment, including those who refuse to return
for a final visit, will be contacted for safety evaluations during the 56 days following the last
dose of study drug.
Patients who discontinue study drug should be considered withdrawn from the study after the
final visit assessments are performed or when it is clear that the patient will not return
for these assessments.
6.3.2.1
Hepatic-related discontinuation criteria
If any of the discontinuation criteria below are met, study medication should be discontinued 
immediately. In addition, proper safety follow-up management should be performed as 
outlined in Section 6.1.5. Re-challenge of study medication is prohibited once discontinuation 
criteria are met.


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
ALT or AST > 3 x ULN and Total Bilirubin ≥2 x ULN and ALP < 2 x ULN;

ALT or AST > 5 x ULN and ≤8 x ULN persistent for more than 2 weeks;

ALT or AST > 8 x ULN.
6.4
Concomitant medications/therapies
As underscored in Section 1.2.2.3, everolimus is a substrate of CYP3A4, being metabolized 
by this enzyme in the liver and, to some extent, in the intestinal wall. In addition, it is a 
substrate and moderate inhibitor of the multidrug efflux pump P-glycoprotein (PgP). 
Therefore, extent of absorption and subsequent elimination of systemically absorbed 
everolimus may be influenced by agents that are substrates, inhibitors, or inducers of 
CYP3A4 and/or PgP. For example, inhibitors of PgP may decrease the efflux of everolimus 
from brain or tumor and therefore increase everolimus concentrations in these tissues. 
Table 6-10 reports a comprehensive list of relevant inducers and inhibitors of CYP3A. A
strong inhibitor may cause ≥5-fold increase in AUC or ≥80% decrease in clearance of
sensitive CYP substrates (including everolimus) whereas a moderate inhibitor may cause 2 to 
5-fold increase in AUC values or 50-80% decrease in clearance of sensitive CYP substrates. 
Distinction is not always categorical as the interaction can vary according to certain 
conditions.
Table 6-10
Clinically relevant drug interaction: inducers & inhibitors of 
isoenzyme CYP3A4
Inducers
Strong inducers:
avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John's wort
(hypericum perforatum)
Moderate inducers:
bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, ritonavir, [talviraline], thioridazine, tipranavir
Weak inducers:
amprenavir, aprepitant, armodafinil (R-modafinil), bexarotene, clobazam, danshen, dexamethasone, Echinacea,
garlic (allium sativum), gingko (ginkgo biloba), glycyrrhizin, methylprednisolone, nevirapine, oxcarbazepine,
pioglitazone, prednisone, [pleconaril], primidone, raltegravir, rufinamide, sorafenib, telaprevir, terbinafine,
topiramate, [troglitazone], vinblastine
Inhibitors
Strong inhibitors:
boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, nefazodone, nelfinavir, posaconazole (Krishna, et al 2009), ritonavir, saquinavir, telaprevir, 
telithromycin, tipranavir, troleandamycin, voriconazole.
Moderate inhibitors:
amprenavir, aprepitant, atazanavir, casopitant, cimetidine, ciprofloxacin, cyclosporine, darunavir, diltiazem, 
dronedarone, erythromycin, fluconazole, fosamprenavir, grapefruit juice (citrus paraside fruit juice), imatinib, 
schisandra sphenanthera, tofisopam, verapamil.
A comprehensive list of cytochrome P450 isoenzymes and CYP3A4 inhibitors, inducers, and substrates can be 
found at http://medicine.iupui.edu/clinpharm/ddis/. This website is continually revised (Version 5.0 released on 
January 12, 2009) and should be checked frequently for updates.
The list of relevant substrates, inhibitors or inducers of PgP and PgP/CYP3A dual inhibitors is 
included in Table 6-11.


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Table 6-11
Clinically relevant drug interactions: substrates, inducers, and 
inhibitors of PgP and PgP/CYP3A dual inhibitors
PgP Substrates
PgP Inhibitors and PgP/CYP3A dual inhibitors
PgP Inducers
colchicine, digoxin,
fexofenadine, indinavir,
paclitaxel, talinolol,
topotecan, vincristine,
everolimus
amiodarone, azirhromycin, captopril, carvedilol, 
clarithromycin, conivaptan, diltiazem, dronedarone, 
elacridar, erythromycin, felodipine, fexofenadine, 
fluvoxamine, ginko (ginko
biloba) indinavir, itraconazole, lopinavir, mibefradil, milk 
thistle
(silybum marianum), nelfinavir, nifedipine, nitrendipine, 
paroxetine, quercetin, quinidine, ranolazine, rifampin,
ritonavir, saquinavir, Schisandra chinensis, St John’s wort 
(Hypericum perforatum), talinolol, telaprevir, telmisartan, 
ticagrerol, tipranavir, tolvaptan, valspodar, verapamil,
rifampin, St John’s
wort
Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Oct. 29, 2012, which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug Interaction Studies”, 
the University of Washington’s Drug Interaction Database, and Indiana University School of Medicine’s Drug 
Interaction Table.
In addition, in vitro studies showed that everolimus is a competitive inhibitor of CYP3A4 and 
a mixed inhibitor of CYP2D6, potentially increasing the concentrations of products eliminated 
by these enzymes. Thus, caution should be exercised when co-administering everolimus with 
CYP3A4 and CYP2D6 substrates with a narrow therapeutic index.
In contrast, pasireotide has little or no capacity to inhibit the major P450 enzymes as a direct 
acting (metabolism independent) reversible inhibitor, or as an irreversible metabolism 
dependent inhibitor. Pasireotide was found to be a weak in vitro inhibitor of CYP1A2, 
CYP2B6, CYP2C8, CYP2C19, CYP2E1 and CYP3A4/5 with IC50 values ranging from 10 
to >100 μM. However, based on the low therapeutic levels, no drug-drug interaction between 
pasireotide and comedications (as CYP450 substrates) is expected.
Pasireotide was also shown to be able to inhibit PgP (IC50 = 0.85 μM) in vitro in the inside-out
membrane vesicle system, at concentrations of up to 10 μM. However, with the low 
therapeutic levels (plasma Cmax.ss <0.1) and no inhibition in cell system, as well as the 
permeability-limited drug concentrations at the PgP active site, a drug-drug interaction
between pasireotide and PGP substrates is not expected in vivo.
6.4.1
Permitted concomitant therapy
The patients must be instructed not to take any additional medications (over-the-counter
products) during the course of the study without prior consultation with the investigator.
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. At each visit, the patient must be asked about any new
medications he/she is or has taken.
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy and blood transfusions) administered during the study must be reported in the CRF.
All medications taken ≤30 days prior to study entry should be reported on the relevant
section of the CRF. The investigator or his/her designee will continue collecting
information on the initiation of additional anticancer therapies up to 56 days after the last 
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Women of childbearing potential will be allowed to use hormonal contraception, as indicated 
in exclusion criterion #25.
Palliative radiotherapy or surgery may be allowed during the study but they should be 
discussed with Novartis Clinical Team prior to administration.
6.4.2
Permitted concomitant therapy requiring caution and/or action
The following medications should be used with caution during the study:

Concomitant treatment with moderate inhibitors of CYP3A4 (including but not limited to 
amprenavir, 
fosamprenavir, 
cyclosporine, 
aprepitant, 
erythromycin, 
fluconazole, 
verapamil or diltiazem) or moderate PgP inhibitors requires caution. If a patient requires 
co-administration of moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of 
everolimus to 5 mg. If well tolerated for two weeks, the everolimus dose can be increased 
to 10 mg/day. Additional dose reductions to every other day may be required to manage 
toxicities. If the inhibitor is discontinued, consider a washout period of at least 2-3 days 
(average for most commonly used moderate inihibitors) beforeeverolimus dose is 
increased to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor.

Concomitant treatment with strong CYP3A4/PgP inducers should be avoided. If patients 
require co-administration of a strong CYP3A4/PgP inducer (like rifampicin and rifabutin), 
an everolimus dose increase from 10 mg daily up to 20 mg daily should be considered 
(based on pharmacokinetic data), using 5 mg increments. Enzyme induction usually 
occurs within 7-10 days; therefore, study drug dose should be increased by one increment 
7 days after the start of the inducer therapy. If no safety concerns are seen with the next 7 
days, the dose can be increased again one additional increment up to a maximum of twice 
the daily dose used prior to the initiation of the strong CYP3A4 inducer. This dose of 
everolimus is predicted to adjust the AUC to the range observed without inducers. 
However, there are no clinical data with this dose adjustment in patients receiving strong
CYP3A4 inducers. If the strong inducer is discontinued, consider a washout period of at 
least 3-5 days (reasonable time for significant enzyme de-induction) beforeeverolimus 
dose is returned to the dose used prior to initiation of the strong CYP3A4 inducer.

Concomitant treatment with a substrate of CYP3A4 doesn’t require dose modification; 
however, patients should be closely monitored for toxicity (Only patients receiving 
everolimus).
6.4.3
Prohibited concomitant therapy
The following concomitant treatments are not allowed during the study:

Other investigational drug or therapy.

Medication known to affect GH or IGF-1 levels.

Medications that might lead to QT prolongation (the discontinuation of the patient is 
required prior to starting the respective QT prolonging medication).
A comprehensive list of drugs that prolong the QT interval and/or induce Torsades de 
Pointes can be found at: http://crediblemeds.org/everyone/composite-list-all-
qtdrugs/?rf=All


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
Investigational or commercial anticancer agents other than pasireotide LAR and 
everolimus (including chemotherapy, hormone therapy, targeted therapy, targeted or 
biological agents). If such agents are required for a patient, the patient must first be 
withdrawan from the study. The initiation of any non-protocol specific anti-tumor 
treatment or surgery is considered an indication of disease progression and should be 
recorded appropriately.

Use of prescription medication for diarrhea. Exceptions may be made if the medication is 
to treat an adverse event.

Use of dexamethasone therapy administered for nausea and/or vomiting, is prohibited 
during the study.

Use of the anticoagulant medication warfarin should be avoided. Warfarin should be 
replaced by the use of selective Factor Xa inhibitors (rivaroxaban, apixaban, dabigatran) 
which are acceptable from a safety point of view since they have no effect on 
prothrombin time (PT), and partial thromboplastin time (PTT)

The following drugs should also be avoided from 5 days before through to the end of the 
5-HIAA collection, given their potential to affect 5-HIAA: chlorpromazine, imipramine, 
isoniazid, levodopa, monoamine oxidase inhibitors, methenamine, methyldopa, 
phenothiazines, promethazine, and tricyclic antidepressants, acetanilid, phenacetin, 
glyceryl guaiacolate (component of many cough syrups), methocarbamol, and reserpine.

Leukocyte growth factors (e.g. G-CSF and GM-CSF) are not permitted prophylactically 
but may be prescribed by the investigator for severe neutropenia if deemed appropriate.

Prolonged (>2 weeks in duration) treatment with systemic corticosteroids.

Strong CYP3A4 inhibitors and strong PgP inhibitors are not allowed (see Table 6-10).
In addition, patients should refrain from grapefruit juice, Seville oranges, and star fruit as
well as the juice of these fruits which are potent CYP3A4-inhibitor and also affect PgP
activity.
Everolimus may affect patient response to vaccinations making the vaccination less 
effective. As everolimus is an immunosuppressant, live vaccines should be avoided while a 
patient is treated with everolimus. Examples of live vaccines are: intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a thypoid 
vaccines.
6.5
Patient numbering, treatment assignment and randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Subject No. consists of the 4-
digit Center Number (Center No.) (as assigned by Novartis to the investigational site) with a 
5-digit sequential patient number suffixed to it, so that each subject is numbered uniquely 
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Upon signing the ICF, the patient number is assigned by the investigator. At each site, the first 
patient is assigned patient number 00001, and subsequent patients are assigned consecutive 
numbers (e.g. the second patient is assigned patient number 00002, the third patient is 
assigned patient number 00003).
Once assigned, the Subject No. must not be reused for any other subject and the Subject No. 
for that individual must not be changed, even if the patient is re-screened.
6.5.2
Treatment assignment and randomization
Patients will be assigned to one of the 3 treatment arms (Section 4.1 and Section 6.1) in a ratio 
of 1:1:1.
Stratification: Randomization will be stratified by typical carcinoid tumor (TC) vs. atypical 
carcinoid tumor (AC) according to WHO classification and line of study treatment (1st line vs. 
others). In case of naïve patients, the study treatment will be considered as 1st line. The 
randomization scheme will be reviewed by a Biostatistics Quality Assurance Group.
Randomization: The randomization numbers will be generated using the following procedure 
to ensure that treatment assignment is unbiased and concealed from patients and investigator 
staff. A patient randomization list will be produced by the IVRS provider using a validated 
system that automates the random assignment of patient numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms.
The patient number will be entered into the IVRS system by the site, the randomization 
number and treatment arm linked to this patient number will be allocated by the system; IVRS 
will communicate to the site personnel only the treatment arm assigned while the 
randomization number linked to this will not be communicated. The randomization number 
will be stored in the IVRS databases and only provided to authorised trial personnel on 
request. Prior to dosing and at the end of the screening period, all patients who fulfill all 
inclusion/exclusion criteria will be randomized via IVRS/IWRS to one of the treatment arms. 
The investigator or his/her delegate will call or log on to the IVRS/IWRS and confirm that the 
patient fulfils all the inclusion/exclusion criteria. The IVRS will assign the patient one of the 
treatment arm.
6.5.3
Treatment blinding
Not applicable.
6.6
Study drug supply
6.6.1
Study drug preparation and dispensation
Study medication will be dispensed by an authorized person at the investigator’s site. Patients 
will receive either pasireotide LAR alone and everolimus alone or a combination of 
pasireotide LAR and everolimus depending on the treatment arm they were randomized to.
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the CRF.


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Table 6-12
Preparation and dispensing
Study drugs
Dispensing
Preparation
Pasireotide LAR
i.m. injection performed by study nurse or study physician every 28 days 
(+/- 3 days) on an outpatient basis
See below
Everolimus
Tablets including instructions for administration are dispensed by study 
personnel on an outpatient basis.
Patients will be provided with adequate supply of study treatment for 
self-administration at home until at least their next scheduled study visit.
Not applicable
6.6.1.1
Preparation procedure for pasireotide LAR
The reconstitution of pasireotide LAR has to be performed just prior to administration. The 
i.m. injection must be given immediately after the withdrawal of the reconstituted suspension 
from the vial in the syringe.
Table 6-13
Handling and preparation of pasireotide LAR dose
Dose (mg)
Volume to be injected
20
1 x 20 mg vial + 2 mL vehicle: whole volume to be injected
20
1 × 40 mg vial + 2 mL vehicle: 0.9 mL of volume to be injected
40
1 × 40 mg vial + 2 mL vehicle: whole volume to be injected
60
1 × 60 mg vial + 2 mL vehicle: whole volume to be injected
60 mg dosage strength (60 mg per vial)

Take one (1) pasireotide LAR 60 mg vial.

Remove the transparent flip-off cap from the vial.

Take one vehicle ampoule and break off the upper part.

Withdraw the content of the vehicle ampoule with a needle and the 3 mL syringe (or 2.5 
mL syringe, in case the 3mL syringe is not available).

Remove air bubbles by pushing the piston and wipe the needle with a sterile pad and
adjust the volume to 2 mL.

Inject 2 mL of vehicle into the vial containing the powder (60 mg)

Shake the vial up and down for at least 30 seconds in order to get a homogenous 
suspension.

Withdraw the whole volume of suspension from the vial with a needle and the 3 mL (or 
2.5 ml) syringe.

Reverse the syringe and aspirate in the suspension contained in the needle to the syringe.

Change the needle with a standard i.m. injection needle.

Remove air bubbles by pushing the piston and wipe the needle with a sterile pad.

Immediately, inject the whole volume of suspension intra-muscularly to the patient.
40 mg dosage strength (40 mg per vial)

Take one (1) pasireotide LAR 40 mg vial.

Remove the transparent flip-off cap from the vial.


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
Take one vehicle ampoule and break off the upper part.

Withdraw the content of the vehicle ampoule with a needle and the 3 mL syringe (or 2.5 
mL syringe, in case the 3 mL syringe is not available).

Remove air bubbles by pushing the piston and wipe the needle with a sterile pad and 
adjust the volume to 2 mL.

Inject 2 mL of vehicle into the vial containing the powder (40 mg).

Shake the vial up and down for at least 30 seconds in order to get a homogenous 
suspension.

Withdraw the whole volume of suspension from the vial with a needle and the 3 m L (or 
2.5 mL) syringe.

Reverse the syringe and aspirate in the suspension contained in the needle to the syringe.

Change the needle with a standard i.m. injection needle.

Remove air bubbles by pushing the piston and wipe the needle with a sterile pad.

Immediately inject the whole volume of suspension intra-muscularly to the patient.
20 mg dosage strength (20 mg per vial)

Take one (1) pasireotide LAR 20 mg vial.

Remove the transparent flip-off cap from the vial.

Take one vehicle ampoule and break off the upper part.

Withdraw the content of the vehicle ampoule with a needle and the 3 mL syringe (or 2.5 
mL, in case the 3 mL syringe is not available).

Remove air bubbles by pushing the piston and wipe the needle with a sterile pad and 
adjust the volume to 2 mL.

Inject 2 mL of vehicle into the vial containing the powder (20 mg)

Shake the vial up and down for at least 30 seconds in order to get a homogenous 
suspension.

Withdraw the whole volume of suspension from the vial with a needle and the 3 m L (or 
2.5 mL) syringe.

Reverse the syringe and aspirate in the suspension contained in the needle to the syringe.

Change the needle with a standard i.m. injection needle.

Remove air bubbles by pushing the piston and wipe the needle with a sterile pad.

Immediately, inject the whole volume of suspension intra-muscularly to the patient.
20 mg dosage strength (40 mg per vial)

Take one (1) pasireotide LAR 40 mg vial.

Remove the transparent flip-off cap from the vial.

Take one vehicle ampoule and break off the upper part.

Withdraw the content of the vehicle ampoule with a needle and the 3 mL syringe (or 2.5 
ml, in case 3ml syringe is not available).


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
Remove air bubbles by pushing the piston and wipe the needle with a sterile pad and 
adjust the volume to 2 mL.

Inject 2 mL of vehicle into the vial containing the powder (40 mg).

Shake the vial up and down for at least 30 seconds in order to get a homogenous 
suspension.

Withdraw the whole volume of suspension from the vial with a needle and the 3 m L (or 
2.5 mL) syringe.

Reverse the syringe and aspirate in the suspension contained in the needle to the syringe.

Adjust the volume in the syringe to 0.9 mL.

Change the needle with a standard i.m. injection needle.

Remove air bubbles by pushing the piston and wipe the needle with a sterile pad.

Immediately, inject the whole volume of suspension intra-muscularly to the patient.
6.6.1.2
Everolimus administration
Everolimus will be dispensed by the study center personnel on an outpatient basis. Patients 
will be provided with an adequate supply of everolimus for self-administration at home.
The investigator should instruct the patient to take the study drug exactly as p rescribed 
(promote compliance).
The patient will take the first dose of everolimus at the center. Everolimus will be dosed 
starting on Day 1 (Visit 2). Patients will be instructed to take one 10 mg tablet or, 
alternatively, two 5 mg tablets of everolimus QD orally with a glass of water, at the same time 
each day either consistently with food or consistently without food. Any dietary habits around 
the time of everolimus intake should be as consistent as possible throughout the study. The 
tablet/tablets should be swallowed as a whole and not be chewed or crushed. In cases where
the tablet/tablets can not be swallowed, it/they should be disintegrated in water just prior 
being taken. Approximately 30 mL of water should be put into a glass. The tablet/tablets 
should then be added and the contents stirred gently (for a maximum of 7 minutes) until the 
tablet/tablets are disintegrated. The contents should then be drunk. Afterwards, the glass 
should be rinsed with an additional 30 mL of liquid and drunk. 
If vomiting occurs, no attempt should be made to replace the vomited dose unless two 
everolimus tablets (or one 10 mg tablet) are clearly visible. If two everolimus tablets (or one 
10 mg tablet) are clearly visible, then the patient should replace the everolimus dose. Patients 
should be instructed that if they miss a dose on one day, they must not take any extra dose the 
next day, but instead to immediately contact the study center as soon as possible to ask for 
advice.
If the patient misses a dose at the scheduled time, the administration of the study drug can:

occurr within 8 hours after the normal time of administration, and the new time of 
administration can be considered as a reference for the next administration (eg. if the 
normal time of administration is 8 am, the 8 am missing dose could be administered by 4 
pm of the same day)
or


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
be skipped until the next day. 
On days on which there are visits scheduled, patients should be reminded not to take their 
study drug until advised to do so during the visit. At visits, when laboratory blood samples are 
drawn, patients should not take the daily study drug dose until the blood sample has been 
drawn and after all safety assessments have been performed.
Patients are to bring their unused everolimus, as well as the empty blister packs, to the clinic 
on each visit, and a new pack of everolimus will be dispensed on that visit. Compliance 
should be verified by the investigator’s staff by counting the number of tablets consumed 
between visits.
The investigator (or his/her designee) will document dosage administration and all dose 
changes during the study in the CRF. The site must maintain an overall drug accountability 
log for the study, as well as individual accountability records for each patient. The dose, 
amount dispensed, amount received, and amount remaining unused must be recorded in the 
source document. Drug accountability will be noted by the field monitor during site visits and 
at the completion of the study.
The patient will be asked to return all unused everolimus tablets at eachstudy visit.
Patients will receive treatment with study drug during the duration of the study, or until 
progressive disease occurs, or until the occurrence of unacceptable toxicity, or until the 
investigator or patient decides that continuation is not in the best interest of the patient.
Interruption for toxicity should follow the instructions in Table 6-8.
6.6.1.3
Combination therapy pasireotide LAR and everolimus
Patients assigned to this treatment arm will be given a combination therapy based on 
pasireotide LAR 60 mg i.m. and everolimus 10 mg p.o. q.d. as described for each study drug 
above.
6.6.2
Study drug packaging and labeling
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug but no information about the 
patient.
6.6.3
Drug supply and storage
Study drugs must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, pasireotide LAR and everolimus should be 
stored according to the instructions specified on the drug labels. Clinical supplies are to be 
dispensed only in accordance with the protocol. Details are listed in Table 6-14.


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Table 6-14
Supply and storage of study treatments
Study treatments
Supply
Storage
Pasireotide LAR
Centrally supplied by Novartis
Refer to study treatment label
Everolimus
Centrally supplied by Novartis, or by local 
commercial stock, once available
Refer to study treatment label
6.6.3.1
Pasireotide LAR
Study drug pasireotide LAR i.m. depot injections will be supplied in open-label packaging by 
Novartis as a powder in vials containing 20 mg, 40 mg and 60 mg, with ampules containing 
2 mL of vehicle (for reconstitution). No syringes or needles will be provided with the 
pasireotide study drug supplies.
6.6.3.2
Everolimus
Study drug everolimus will be supplied in open-label packaging by Novartis (centrally or by 
local commercial stock, once available) as tablets of either 10 mg or 5 mg strength, blister-
packed under aluminium foil in units of 10 tablets and dosed on a daily basis. Everolimus
tablets should be opened only at the time of administration as the drug is both hygroscopic 
and light-sensitive.
6.6.4
Study drug compliance and accountability
6.6.4.1
Study drug compliance for everolimus
Compliance will be assessed by the investigator and/or study personnel at each visit using tablet
counts. Records of study medication used, treatment administered, and intervals between visits 
will be kept during the study. This information should be captured in the source document at 
each patient visit.

Patients will be requested to bring their unused medication including empty packaging to 
the clinic at each visit, at the end of the study and at the time of study treatment 
discontinuation.

All doses taken by the patient and all dose changes during the study must be recorded on 
the CRF.
6.6.4.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability ledger (overall drug accountability log for the 
study as well as individual study drug accountability records for each patient) of tablets 
administered, tablets used, dose changes, dates dispensed and intervals between visits. Drug 
accountability will be noted by the field monitor during site visits and at the completion of the 
study.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.


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6.6.5
Disposal and destruction
The drug supply can be destroyed at the local Novartis facility, Drug Supply group or third 
party, as appropriate. Study drug destruction at the investigational site will only be permitted 
if authorized by Novartis in a prior agreement and if permitted by local regulations.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X” the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category column”).


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Table 7-1
CORE STUDY – Visit evaluation schedule (12 months)
Visit Name
Category
Reference to 
Section 7.2
Screening 
Baseline
Core study
End of core 
study/Early 
withdran
(EOS)
Safety FU 
visit **
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Study Day
-28 
to-1
1
15
21
29
49
57
85
113
141
169
197
225
253
281
309
337
Week
2
3
4
7
8
12
16
20
24
28
32
36
40
44
48
52
Obtain Informed 
Consent
D
X
Patient history
D
X
Demography
D
X
Relevant medical 
history/current 
medical conditions 
incl. cancer-related 
conditions and 
symptoms
D
X
Diagnosis and extent 
of cancer
D
X
Prior antineoplastic 
therapies, therapy 
for lung/thymus NET
D
X
Inclusion/exclusion 
criteria
S
X
Prior/concomitant 
medications
D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Visit Name
Category
Reference to 
Section 7.2
Screening 
Baseline
Core study
End of core 
study/Early 
withdran
(EOS)
Safety FU 
visit **
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Study Day
-28 
to-1
1
15
21
29
49
57
85
113
141
169
197
225
253
281
309
337
Week
2
3
4
7
8
12
16
20
24
28
32
36
40
44
48
52
WHO Performance 
status
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-ray, or chest 
CT scan
D
7.2.2.6.1
As medically indicated
Hepatitis screening 
(HBV-DNA, HBsAg, 
HBsAb, HBcAb, 
HCV RNA-PCR)
D
7.2.2.5.10
X
Monitoring for HBV-
DNA, HCV RNA-
PCR every 4 weeks
(if applicable)
D
7.2.2.5.10
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-HAV, IgM, 
HbsAg, Anti-HBc, 
anti-HCV (if positive, 
PCR viral load 
should be 
assessed), Anti-
HEV, ANA 
antibodies, anti-
smooth muscle anti-
bodies, CMV and 
D
If LFTs meet criteria reported in Section 6.1.5


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Visit Name
Category
Reference to 
Section 7.2
Screening 
Baseline
Core study
End of core 
study/Early 
withdran
(EOS)
Safety FU 
visit **
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Study Day
-28 
to-1
1
15
21
29
49
57
85
113
141
169
197
225
253
281
309
337
Week
2
3
4
7
8
12
16
20
24
28
32
36
40
44
48
52
EBV
Laboratory 
evaluations
7.2.2.5
   Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  Coagulation (INR)
D
7.2.2.5.2
X
X
X*
X
X*
X
X
X
X
X
X
X
   Coagulation (PTT)
7.2.2.5.2
X
   Biochemistry
D
7.2.2.5.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
   Fasting 
glucose/insulin/ 
HbA1c (everolimus 
monotherapy)
D
7.2.2.5.4
X
X
X
X
X
If 
medically 
indicated
X
X
X
X
X
X
X
X
X
X
X
X
   Fasting 
glucose/insulin/ 
HbA1c
(combination)
D
7.2.2.5.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
   Fasting 
glucose/insulin/ 
HbA1c pasireotide 
LAR monotherapy
D
7.2.2.5.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  Blood glucose self 
monitoring (if 
applicable)
7.2.2.5.4
Continuous
   Liver Function 
Tests
D
7.2.2.5.5
X
X
X
X*
X
X*
X
X
X
X
X
X
X
X
X
X
X
X


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Visit Name
Category
Reference to 
Section 7.2
Screening 
Baseline
Core study
End of core 
study/Early 
withdran
(EOS)
Safety FU 
visit **
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Study Day
-28 
to-1
1
15
21
29
49
57
85
113
141
169
197
225
253
281
309
337
Week
2
3
4
7
8
12
16
20
24
28
32
36
40
44
48
52
   ACTH 
D
7.2.2.5.3
X
Every 3 months, if ACTH hypersecretion at baseline
   Serum lipid profile
D
7.2.2.5.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
   Thyroid function 
test
D
7.2.2.5.7
X
X
X
X
   Urinalysis
D
7.2.2.5.8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
   Pregnancy test
D
7.2.2.5.9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
   CgA and 5HIAA
D
7.2.1.2
X
X
X
X
X
X
Imaging/Other assessments
Tumor evaluation 
D
7.2.1.1
X
X
X
X
X
X
   Gallbladder 
assessment
D
7.2.2.6.4
X
X*
X*
X*
X*
X*
   Pulmonary 
Function Test
D
7.2.2.6.2
As medically indicated
   Bronchoscopy
D
7.2.2.6.3
As medically indicated
   ECG
D
7.2.2.7.1
X
X
X
X
X
X
X
X
   Cardiac imaging 
(ECHO or MUGA 
scan)
D
7.2.2.7.2
X
As medically indicated
Safety
   Adverse events
D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Visit Name
Category
Reference to 
Section 7.2
Screening 
Baseline
Core study
End of core 
study/Early 
withdran
(EOS)
Safety FU 
visit **
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Study Day
-28 
to-1
1
15
21
29
49
57
85
113
141
169
197
225
253
281
309
337
Week
2
3
4
7
8
12
16
20
24
28
32
36
40
44
48
52
Contact IVRS for 
randomization
X
Pasireotide LAR 
injections (q28d)
D
X
X
X
X
X
X
X
X
X
X
X
X
X
X***
Everolimus 
administration (daily)
D
Daily***
Core study 
completion
D
X
*Only for patients treated with pasireotide LAR
** The safety FU visit should be performed only for patients who prematurely discontinue study treatment or experience disease progression at week 52. The visit 
should be performed 56 days after the last dose of pasireotide LAR or everolimus, whichever comes last.
***Pasireotide LAR injection and everolimus should be given at V18 only to patients that continue the extension phase


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Table 7-2
EXTENSION PHASE - Visit evaluation schedule 
Visit No.
Category
Reference to 
Section 7.2
Extension phase
End of extension
phase /Early 
withdrawn
Safety FU visit**
1
2
3
4
Month of extension phase
3
6
9
12
Every 3 mos
Vital signs
D
7.2.2.2
X
X
X
X
X
X
Physical examination
S
7.2.2.1
X
X
X
X
X
X
Weight
D
7.2.2.3
X
X
X
X
X
X
WHO performance status
D
7.2.2.4
X
X
X
X
X
X
Tumor evaluation, frequency at investigator’s 
discretion***
D
7.2.1.1
X
X
X
X
X
X
Gallbladder assessment, frequency as per tumor 
evaluation at investigator’s discretion
D
7.2.2.6.4
X*
X*
X*
X*
X*
X*
Pulmonary Function Test
D
7.2.2.6.2
As medically indicated
Bronchoscopy
D
7.2.2.6.3
As medically indicated
Chest X-ray, or Chest CT scan
D
7.2.2.6.1
As medically indicated
ECG
D
7.2.2.7.1
X
X
X
X
X
X
Cardiac imaging (ECHO or MUGA scan)
D
7.2.2.7.2
As medically indicated
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
Biochemistry
D
7.2.2.5.3
X
X
X
X
X
X
Fasting glucose/insulin/HbA1c (everolimus 
monotherapy)
D
7.2.2.5.4
X
X
X
X
X
X
Fasting glucose/insulin/HbA1c (combination)
D
7.2.2.5.4
X
X
X
X
X
X
Fasting glucose/insulin/HbA1c pasireotide LAR 
monotherapy
D
7.2.2.5.4
X
X
X
X
X
X
Blood glucose self monitoring (if applicable)
7.2.2.5.4
Continuous
Liver Function Tests
D
7.2.2.5.5
X
X
X
X
X
X


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Visit No.
Category
Reference to 
Section 7.2
Extension phase
End of extension
phase /Early 
withdrawn
Safety FU visit**
1
2
3
4
Month of extension phase
3
6
9
12
Every 3 mos
Coagulation (INR)
D
7.2.2.5.2
X
X
X
X
X
X
CgA and 5HIAA****
D
7.2.1.2
X
X
Urinalysis
D
7.2.2.5.8
X
X
X
X
X
X
Serum lipid profile
D
7.2.2.5.6
X
X
X
X
X
X
Pregnancy test
D
7.2.2.5.9
X
X
X
X
X
X
Monitoring of HBV-DNA, HCV RNA-PCR (if 
applicable)
D
Every 4 weeks as indicated in Section 
6.1.4.8
Anti-HAV, IgM, HbsAg, Anti-HBc, anti-HCV (if 
positive, PCR viral load should be assessed), Anti-
HEV, ANA antibodies, anti-smooth muscle anti-
bodies, CMV and EBV
D
If LFTs meet criteria reported in Section 
6.1.5
Pasireotide LAR injections (q28d)
D
Every 28 days from V18 of Core phase
Everolimus administration (daily)
D
Daily from V18 of Core phase
Adverse events
D
X
X
X
X
X
X
X
Concomitant medications
D
X
X
X
X
X
X
X
Study completion
D
X
*Only for patients treated with pasireotide LAR
**The safety follow up visit should be performed 56 days after the last dose of pasireotide LAR or everolimus, whichever comes last.
*** Patients who discontinue study treatment after 12 months of treatment without evidence of progression or for reasons other than disease progression will continue to 
have tumor evaluation assessments until disease progression or last patient last visit (LPLV) whichever occurs first.
**** CgA and 5HIAA will only be collected until extension visit 4.


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7.1.1
Pre-screening assessments
Not applicable.
7.1.2
Screening
7.1.2.1
Eligibility screening 
The principal investigator is responsible for patient’s eligibility.
7.1.2.2
Information to be collected on screening failures
Patients who complete the informed consent process and do not meet all entry criteria and 
therefore who do not receive first dose of study drug(s) will be considered screen failures. For 
screening failure patients, no data will be entered in the clinical database, except for the reasons 
of screening failure.
7.1.2.3
Patient demographics and other baseline characteristics
Patient demographics and baseline characteristics will include the following: demography, 
medical history/current medical conditions (including cancer-related conditions and symptoms), 
diagnosis and extent of cancer, prior anticancer therapies taken, disease-related symptoms, 
prior/concomitant medication taken, physical examination, WHO performance status, vital signs, 
weight and height, hepatitis B and C screening, hematology, blood chemistry, coagulation panel, 
urinalysis, pregnancy test required for women of childbearing potential, ECG.
7.1.3
Treatment period
This study has a treatment duration of 12 months (core study). Patients will either start 
pasireotide LAR or everolimus treatment or a combined treatment of both pasireotide LAR and 
everolimus regimens at visit 2.
7.1.4
End of core study visit, including premature withdrawal and study 
discontinuation visit
Patients who discontinue study treatment should be scheduled for a visit as soon as possible, 
at which time all of the assessments listed for the end of core study visit/early withdrawn will 
be performed. Study treatment discontinuation in the pasireotide LAR plus everolimus arm is 
defined as the withdrawal of both study drugs; the date and reason for stopping the study 
treatment should be reported in the CRF. At a minimum, all patients who discontinue study 
treatment, including those who refuse to return for a final visit, will be contacted for safety 
evaluations 56 days after the last dose of pasireotide LAR or everolimus, whichever comes 
last.


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7.1.4.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time. Patients may be withdrawn from the study if any of the following 
occur:
1. Disease progression
2. Unacceptable toxicity / adverse events which are not listed below
3. Clinically significant abnormal lab values
4. Clinically significant abnormal test procedure results
5. Protocol violation
6. Administrative problems
7. Pregnancy
8. Patient withdrawing informed consent
9. New anticancer therapy
10. Patient lost to follow-up
11. Death
In addition to the general withdrawal criteria, the following study specific criteria will also 
require study treatment discontinuation:
1. Patients experiencing unacceptable toxicity as described in Table 6-1, Table 6-2, Table 6-4, 
Table 6-5, Table 6-6 and Table 6-7.
2. Patient with blood glucose values consistently in excess of 250 mg/dL persisting after 
interruption of study drug in spite of continuous, appropriate therapeutic intervention(s).
3. Confirmed QTcF >470 msec and discontinuation recommended by a cardiologist after 
examination of cardiovascular risk factors.
4. Mean QTcF >500 msec measured by triplicate ECGs, and discontinuation recommended 
by a cardiologist, after ECG re-evaluation and confirmation of a mean QTcF value >500
msec.
5. Significant arrhythmia findings from Holter monitoring such as:

Any ventricular or supra-ventricular tachyarrhythmia associated with symptoms of 
hemodynamic compromise

Sustained ventricular tachycardia (>30 sec) irrespective of symptoms

Recurrent non-sustained VT (≥ 3 beats) during any 24-hour monitoring period

Torsades de Pointes (TdP)

Cardiac arrest

Pause >5 seconds

Second or third degree AV block.
6. New occurrence of clinically significant/symptomatic bradycardia.
7. Increased risk of QT prolongation by use of QT prolonging medication.
8. Hypokalemia (<3.5 mmol/L) or hypomagnesaemia (<0.7 mmol/L or below the LNR as 
provided by the laboratory) confirmed by repeat testing that is either a new finding or 
accompanied by vomiting or diarrhea and not corrected by treatment.


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9. Abnormal Liver Function Tests such as:

ALT or AST > 3 x ULN and Total Bilirubin ≥ 2 x ULN and ALP < 2 x ULN;

ALT or AST > 5 x ULN and ≤ 8 x ULN persistent for more than 2 weeks;

ALT or AST > 8 x ULN.
If such withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and
record this information on the CRF.
All patients who discontinue study treatment must have safety evaluations 56 days after the 
last dose of pasireotide LAR or everolimus, whichever comes last.
All cancer medications/therapies given to a patient up to 56 days after the last dose of study
treatment must be recorded in the CRF.
7.1.4.2
Replacement policy
Not applicable.
7.1.5
Extension period
Patients who are presenting clinical benefit from the treatment with combination or 
monotherapy with pasireotide LAR or everolimus and who are not experiencing unacceptable 
toxicity are permitted to continue treatment after the 12 month treatment period. Patients will 
have the option to receive therapy as long as they continue to demonstrate benefit and do not 
fulfill any of the study discontinuation criteria (see Section 7.1.4.1 criteria for premature 
patient withdrawal) or until the Clinical Trial ceases to be in the interests of the health of the 
Clinical Trial Subjects, based on the DMC recommendations (see Section 8.6), or until the 
pasireotide and/or everolimus development programs are discontinued, whichever comes first 
(see reference to Section 4.4 “Early study termination”) .
All patients who discontinue study treatment must have safety evaluations 56 days after the 
last dose of pasireotide LAR or everolimus, whichever comes last.
All cancer medications/therapies given to a patient up to 56 days after the last dose of study
treatment must be recorded in the CRF.
Patients who discontinue study treatment after 12 months of treatment, without evidence of 
progression or for reasons other than disease progression will continue to have tumor 
evaluation assessments until disease progression or LPLV whichever occurs first.as described 
in Section 7.2.1.
Patients lost to follow up should be recorded as such in the CRF. For these patients, the
investigator should show "due diligence" by documenting in the source documents steps taken 
to contact the patient, e.g., dates of telephone calls, registered letters, etc.


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7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Primary efficacy assessment
The primary efficacy endpoint is defined as the proportion of patients who are progression
free (i.e. disease control rate) at 9 months according to RECIST V. 1.1 criteria (Eisenhauer 
et al. 2009).
7.2.1.1.1 Tumor Evaluation
Tumor evaluation (chest, abdomen and pelvis) will be assessed at baseline by means of
triphasic CT or MRI. CT scan is the preferred modality and should be used wherever
possible. Measurable lesions -i.e., target lesions and the non-target lesions by which
subsequent response assessments will be judged- must be identified during tumor
assessment at baseline; the disease must be staged and progression confirmed at this time.
The tumor evaluation is to be repeated every 3 months or at EOS if reached earlier. During
the extension period, tumor evaluation is recommended every 3 months
All images will be read locally at the site by the reviewer. Clinical decisions will be
done locally by the investigator with the local radiologist.
All images will be saved on a CD-rom and locally stored at the site in order to allow any 
future double check of the tumor assessment, if needed.
Evaluation of the endpoints will be done by a local radiologist together with the investigator.
All patients with bone pain or bone uptake at Octreoscan guided imaging at baseline should 
repeat the assessment while on treatment (including MRI).
7.2.1.1.2 Response evaluation by RECIST V. 1.1
The same method of assessment and the same technique should be used throughout the study 
to characterize each identified and reported lesion at baseline and during follow-up.
Each center must have a designated radiologist or other physician responsible for the 
interpretation of X-rays, MRI or CT scans and the response evaluation according to RECIST
V . 1.1 criteria. The same physician should perform the evaluation for the entire duration
of the study. All radiology evaluations will be performed by the local physician.
Scans to allow measurement of all target lesions will be performed routinely every 3
months. If an initial observation of partial or complete response is made, a confirmation
scan should be obtained no less than 4 weeks and no more than 6 weeks after the initial
observation.
Response evaluation will be performed according to the RECIST V. 1.1 criteria (Eisenhauer 
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7.2.1.1.3 Baseline requirement
All patients should have at least one measurable disease lesion. Measurable disease lesions 
must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with minimum lesion size of:

10 mm by CT scan (irrespective of scanner type and MRI) (no less than double the slice
thickness and a minimum of 10 mm).
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
7.2.1.1.4 Measurement technique
All measurements should be taken and recorded in metric notation, using a ruler or calipers.
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 28 days before the beginning of the treatment.
7.2.1.1.5 Target lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total,
representative of all involved organs should be identified as target lesions and recorded
and measured at baseline. Target lesions should be selected on the basis of their size (lesions
with the longest diameter) and their suitability for accurate repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the longest diameter for all target lesions will be
calculated and reported as the baseline sum of the longest diameter. The baseline sum of
the diameters will be used as reference by which to characterize the objective tumor 
response.
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumour. Pathological lymph nodes can be 
identified as target lesions when measurable (i.e. short axis ≥ 15mm by CT scan). Only the 
short axis (perpendicular to longest diameter) of these nodes will contribute to the baseline 
sum.
7.2.1.1.6 Response assessment
Regarding the target lesions:

partial response (PR) requires at least a 30% decrease in the sum of the diameter of all 
target lesions, taking as reference the baseline sum of diameters;

complete response (CR) requires disappearance of all target lesions. Any pathological 
lymph nodes must have a reduction in short axis to <10 mm. To be assigned a status of 
PR or CR, changes in tumour measurements must be confirmed by repeated 
assessments that should be performed not less than 4 weeks after the criteria for 
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
progressive disease (PD) requires at least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered progression).
Regarding the non-target lesions:

complete response (CR) is defined as the disappearance of all non-target lesions, and 
normalisation of tumour marker level. All lymph nodes must be non-pathological in 
size (<10mm short axis);

non-CR/non-PD is defined as the persistence of one or more non-target lesion(s) and/or 
maintenance of tumour marker level above the normal limits;

progression is is defined as unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression).
For more details on tumor response criteria, please look at RECIST V. 1.1 evaluation criteria 
(Eisenhauer et al. 2009), and at Appendix 1 (Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival and Overall Survival - based on RECIST V. 
1.1).
7.2.1.2
Secondary efficacy assessment
7.2.1.2.1 Response assessment
Regarding the response assessment for the secondary efficacy endpoints, please look at the 
previous section for the primary endpoint (“Response assessment”) for more details.
7.2.1.2.2 Biochemical response rate (BRR)
The biochemical response rate (BRR) and biochemical progression will be evaluated on the 
basis of serum chromogranin A (CgA) levels.
Additionally, the biochemical response on the basis of urine 5-hydroxyindole acetic acid
(5HIAA) will be assessed.
Response of CgA is defined as normalization or a ≥30% reduction of serum CgA levels
compared to baseline (Kouvaraki et al. 2004; Yao et al. 2010).
Response of 5HIAA is defined as normalization or a ≥50% reduction of urinary 5HIAA
levels compared to baseline (Bajetta et al. 1993; Bajetta et al. 2006).
Biochemical progression is defined as an increase of serum CgA levels ≥25% vs. baseline 
(Bajetta et al. 1999; Brizzi et al. 2009).
CgA / 5HIAA
The serum parameter CgA and urine 5HIAA will be assessed for all patients at screening, on 
visits 8, 11 14, 17 and at the end of core study visit/early withdrawn. In patients treated in the 
extension phase, serum and urine samples will be collected on visits 2, 4. In the course of 
the study, CgA and 5HIAA are collected at the same time points. In case of an unscheduled
tumor evaluation, an additional blood and urine sample will be collected.


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For CgA measurements in serum, 5.5 mL blood will be collected. For 5HIAA measurements,
urine will be collected for 24 h. From this measurement, 10 mL urine will be analyzed.
Serum and urine samples will be analyzed centrally.
It is worth underlining that some foods contain significant amounts of hydroxyindoles that may 
influence 5HIAA measurements. Thus, patients will be asked to amend their diet for three days 
before starting urine collection and during the collection to avoid interference with the test. 
Specifically, patients should avoid food containing high levels of indoles such as avocados, 
bananas, tomatoes, plums, walnuts, peanuts, almonds, pineapples, eggplants, and smoked fish. 
Patients will be also asked not to consume coffee, tea, alcohol, vanilla, chocolate, and tobacco 
for three days before and during urine collection.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing hematology, blood chemistry, vital signs, ECG tracings, 
WHO performance status, gallbladder assessment (at baseline for all patients, on treatment only 
for patients treated with pasireotide LAR), and physical conditions as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8.
These assessments should be performed ± 7 days during monthly visit period and ± 2 days 
during the weekly visit period as outlined in Table 7-1, and in Table 7-2 except for adverse 
events that will be evaluated continuously throughout the study.
Safety and tolerability will be assessed according to the NIH/NCI CTC guidelines
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf).
7.2.2.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions CRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
Adverse Event page of the patient’s CRF.
7.2.2.2
Vital signs
Vital signs include blood pressure, pulse, respiration rate and temperature measurements. 
They will be measured as indicated in Table 7-1 and in Table 7-2 and will be recorded on 
source documents, repeated at each visit. Other vital signs will be recorded on the CRF if they 
represent an adverse event.
After the patient has been sitting for five minutes, with back supported and both feet placed 
on the floor, systolic and diastolic blood pressure will be measured three times using an 
automated validated device, e.g. OMRON, with an appropriately sized cuff. The repeat sitting 


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measurements will be made at 1 - 2 minute intervals and the mean of the three measurements 
will be used. In case the cuff sizes available are not large enough for the patient's arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used.
7.2.2.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. Height will be measured at screening visit only; 
weight will be recorded on the case report form at screening visit and at each visit.
7.2.2.4
Performance status
WHO performance status will be measured as indicated in the assessment schedules
(Table 7-1, and Table 7-2), and recorded on the CRF and in the source documents.
Performance status WHO grade
Grade
Status
Grade 0
Fully active, able to carry out all normal activity without restriction.
Grade 1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
Grade 2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours
Grade 3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
Grade 4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
Grade 5
Dead
7.2.2.5
Laboratory evaluations
All standard clinical laboratory analyses described below are to be performed by the local 
laboratory as outlined in Table 7-1 and in Table 7-2. Unscheduled abnormal laboratory 
evaluations which are clinically relevant (e.g. require dose modification and/or interruption of 
study drug, indicate changes in previously abnormal values) must be recorded on the Adverse 
Event page of the CRF. For clinically relevant laboratory values from different local labs, 
please record actual laboratory value and provide local lab ranges on the CRF, as appropriate.
7.2.2.5.1 Hematology
Hematology tests are to be performed at each scheduled visit (± 7 days during monthly visit 
period and ± 2 days during the weekly visit period) as indicated in Table 7-1 and in Table 7-2.
These must include: hemoglobin, hematocrit, platelets, total white blood cell (WBC) count 
(absolute and, if available, differential including neutrophils, lymphocytes, monocytes, 
eosinophils, basophils).
If the hematology tests of Visit 1 have been done less than 7 days before treatment start, they 
should not be repeated on Cycle 1 Day 1.
7.2.2.5.2 Coagulation
The international normalized ratio (INR) will be determined at screening/baseline, at Visits 2, 
5, 7, 8 and every 8 weeks thereafter and reported in CRF. It will be determined also at Visits 4 
and 6 for patients treated with pasireotide LAR. During the Extension phase, the INR will be 


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determined every three months. The partial thromboplastin time (PTT) will be determined 
only at screening/baseline.
7.2.2.5.3 Biochemistry
The following tests will be performed at each scheduled visit (± 7 days during monthly visit 
period and ± 2 days during the weekly visit period) as indicated in Table 7-1 and in Table 7-2
and will include sodium, potassium, chloride, bicarbonate, creatinine, total protein, uric acid, 
BUN (or urea, if BUN cannot be directly evaluated), calcium, magnesium, phosphate. If the 
biochemistry tests of Visit 1 have been done less than 7 days before treatment start, they 
should not be repeated on Cycle 1 Day 1.
One pre-dose, blood draw for plasma ACTH will be taken at visit 1 (baseline). In patients 
with ACTH hypersecretion at baseline, ACTH will be tested during the study every 3 month 
(± 7 days).
7.2.2.5.4 Glucose, Insulin and HbA1c
Glucose, insulin, and glycated hemoglobin (HbA1c) will be assessed in fasting conditions at 
the visits outlined in Table 7-1 and in Table 7-2.
Blood glucose will not be assessed at visit 6 in patients treated with everolimus monotherapy, 
unless medically indicated.
Please refer to Section 6.1.4.5 for additional detailed guidance on the combination and 
pasireotide LAR monotherapy arms.
For patients in the combination and pasireotide LAR monotherapy arms with normal glucose 
metabolism at baseline, fasting blood glucose will be self-measured once daily for the first 2 
month, then twice a week for the next 2 months and once a week thereafter throughout the 
study.
All patients with abnormal glucose metabolism or at risk to develop this condition at 
screening or later at any time will self-measure blood glucose by fingerstick twice daily (one 
fasting and one 2-hour post-prandial). All patients will enter the results in the patient diary. 
Patient diaries will not be collected by the sponsor.
7.2.2.5.5 Liver Function Tests
The following tests will be performed at each scheduled visit (± 7 days during monthly visit 
period and ± 2 days during the weekly visit period) as indicated in Table 7-1, and in Table 7-2
and will include albumin, SGOT (AST), SGPT (ALT), total bilirubin (fractionate to 
direct/indirect bilirubin if total bilirubin is > 2.0 x ULN), alkaline phosphatase and GGT.
For patients treated with pasireotide LAR: the Day 21 and Day 49 LFTs should be available 
and assessed prior to dosing on Day 29 (2nd LAR injection) and Day 57 (3rd LAR injection).
7.2.2.5.6 Lipid profile
A lipid profile (cholesterol, triglycerides, LDL,
HDL) will be determined at 
screening/baseline, at visit 3 and repeated every month (± 7 days). During the Extension phase,


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lipide profile will be determined every three months. The patient must be in a fasting status at 
the time of blood sampling for this evaluation.
7.2.2.5.7 Thyroid Function Test
Thyroid function test (TSH, free T3 and T4), and B12 vitamin will be collected at 
screening/baseline, at week 12 (visit 8) (± 7 days), at week 24 (visit 11) (± 7 days) and at EOS.
7.2.2.5.8 Urinalysis
A standard urinalysis assessment (pH, protein, glucose, blood, ketones, and leukocytes) using 
a dipstick will be performed at screening/baseline and at each scheduled visit as indicated in
Table 7-1, and in Table 7-2. If any positive findings, a microscopic laboratory urinalysis has to 
be performed.
7.2.2.5.9 Pregnancy and assessments of fertility
All females of childbearing potential should have a negative serum pregnancy test at 
screening (i.e., within 14 days of randomization) and a negative urine/serum pregnancy test at 
visit 2 (i.e., randomization visit). Highly effective contraception must be used while on 
study and up to 56 days (8 weeks) after last dose of pasireotide LAR and/or everolimus 
treatment, whichever comes last.
Postmenopausal women must have been amenorrheic for at least 12 months or have a serum 
FSH >40 mIU/ml to be considered “of non-childbearing potential” or 6 weeks post surgical 
bilateral oophorectomy with or without hysterectomy.
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception;

Female sterilization: have had surgical bilateral oophorectomy with or without 
hysterectomy or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment;

Male sterilization: with appropriate post-vasectomy documentation of the absence of 
sperma in the ejaculateat least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.

Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other
forms of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception;
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS);
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.


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Sexually active males must use a condom during intercourse while taking the treatment and 
for 2 months after the last dose of study treatment and should not father a child in this period. 
A condom is required to be used also by vasectomized men in order to prevent delivery of the 
drug via seminal fluid. Female partners of male patients must be also advised to use one of the 
following contraception methods: 

Use of oral, injected or implanted hormonal methods of contraception or other approved 
hormonal methods of contraception;

Placement of an intrauterine device (IUD) or intrauterine system (IUS);

Total abstinence or patient sterilization (male or female).
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications.
Consent to report information regarding these pregnancy outcomes should be obtained from 
the mother.
A serum/urine pregnancy test should be repeated every month while on treatment and at the 
end of the core study visit. If the patient continues treatment in the extension phase, a 
serum/urine pregnancy test should be repeated at each scheduled visit, i.e., every 3 months.
7.2.2.5.10
Hepatitis screening
Screening for Hepatitis B
Prior to randomization, all patients must be tested for Hepatitis B viral load and serologic 
markers, that is: Hepatitis B Virus –Deoxyribonucleic acid (HBV-DNA), Hepatitis B surface 
antigen (HBsAg), Hepatitis B surface Antibody (HBsAb), and Hepatitis B core Antibody 
(HBcAb).
If a patient tests positive for the presence of HbsAg and/or HBV-DNA, he/she will be 
considered ineligible for the study according to Exclusion Criterion #16. In case of eligibility, 
the results from the other two tests (HBsAb and HBcAb) will detect which patients have to be 
monitored for the risk of hepatitis B reactivation approximately every 4 weeks (± 1 week)
during the study.
Please note that patients whose test is negative for HBV-DNA, HBsAg, and HBcAb but 
positive for HBsAb with prior history of vaccination against Hepatitis B will be eligible. The 
fact that the patient had been vaccinated should be entered in the patient’s eCRF (“Medical 
history” page).
Management guidelines for the risk of hepatitis B reactivation are provided in Section 6.1.4.8
according to the results of the baseline assessments of viral load and serological markers for 
hepatitis B.
Screening for Hepatitis C
Prior to randomization, all patients will be tested for the presence of HCV-RNA-PCR..


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If a patient tests positive for HCV-RNA-PCR, he/she will be considered ineligible for the 
study according to Exclusion Criterion #16.
Patients known to have a history of HCV infection, despite a negative viral load test at
baseline (including those that were treated and are considered “cured”) should be monitored 
every 4 weeks (± 1 week) for the risk of hepatitis C reactivation.
Management guidelines for the risk of hepatits C reactivation are provided in Section 6.1.4.8..
7.2.2.6
Radiological examinations
7.2.2.6.1 Monitoring for pneumonitis
If the baseline scan shows signs suggestive of interstitial lung disease (ILD)/non-infectious 
pneumonitis, it is at the discretion of the investigator to follow the patient with appropriate 
chest imaging. For all other patients, chest X-ray or chest CT scans are to be performed during 
the study if clinically indicated e.g. if there is suspicion of non-infectious pneumonitis, in the 
investigator’s discretion.
7.2.2.6.2 Monitoring for Pulmonary Function Test
At screening/baseline, prior to administration of study drug, pulmonary function tests (PFT) 
can be performed, if clinically indicated. During study treatment, all PFTs (spirometry, DLCO 
and room air O2 saturation at rest) must be performed if the patient develops non-infectious 
pneumonitis, according to the management guidelines addressed in Table 6-2.
7.2.2.6.3 Bronchoscopy
A bronchoscopy with biopsy and/or bronchoalveolar lavage (BAL) will be performed only 
when medically necessary for ensuring patient care. When non-infectious pneumonitis is 
diagnosed, consultation with a pulmonologist should be considered. Further details are 
provided in Section 6.1.4.7.
7.2.2.6.4 Gallbladder Assessment
The gallbladder evaluation (MRI/CT) will be performed together with the radiological tumor 
assessment at baseline for all patients, on treatment only for patients treated with pasireotide 
LAR as outlined in Table 7-1 and in Table 7-2.
If the patient discontinues treatment, an EOS visit MRI/CT scan has to be performed only if 
the EOS visit occurred 3 months or more after the previous MRI/CT scan.
Significant findings that are present prior to the start of study treatment must be included in 
the Relevant Medical History/Current Medical Conditions CRF. Significant findings made 
after the patient signed the ICF or worsening of those reported at screening/baseline and 
which meet the definition of an AE must be recorded on the AE CRF.


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7.2.2.7
Cardiac assessments
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12-lead ECG will be performed at baseline and at the visits outlined in Table 7-1
and in Table 7-2.
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG CRF page. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported in CRF. Clinically significant findings must be discussed with the 
Novartis Medical Monitor prior to enrolling the patient in the study.
ECG may be repeated at the discretion of the investigator at any time, as clinical indicated. 
New or worsened clinically significant findings occurring after informed consent must be 
recorded on the Adverse Events CRF page.
Safety data captures should include the following:

Any abnormal ECG findings (please refer to Section 6.1.4.9);

Abnormal vital signs;

All arrhythmias, including: Torsades de Pointes, ventricular tachycardia, ventricular 
fibrillation, and ventricular flutter;

Syncope, near-syncope and fainting;

Convulsions or loss of central function (sudden incontinence, dizziness, vision 
disturbances).
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
All patients will have an echocardiogram or MUGA scan at screening and when it is indicated 
clinically during the study.
7.2.3
Pharmacokinetics
Not applicable.


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7.2.5
Other assessments
No additional tests will be performed on patients entering this study.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. Abnormal laboratory values or test results occurring 
after informed consent constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy (e.g., hematologic 
abnormality that requires transfusion or hematological stem cell support), or require changes 
in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the CRF. Adverse event monitoring should be 
continued for at least 56 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1-4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected through the “Study evaluation completion – Core”form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:
1. The severity grade (CTCAE grade 1-4);
2. Its duration (Start and end dates);
3. Its relationship to pasireotide LAR or everolimus or combination pasireotide LAR and 
everolimus (Reasonable possibility that AE is related: No, Yes);
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable);
5. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy);


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6. Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown);
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (as per RECIST criteria), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
Information about common adverse effects already known about the investigational drug can
be found in the [Investigator’s Brochure] or will be communicated between IB updates in
the form of Investigator Notifications. This information will be included in the patient
informed consent and should be discussed with the patient during the study as needed.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol and is still, by definition, an adverse event.
8.1.3
Adverse events of special interest 
Not applicable.


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8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening;

Results in persistent or significant disability/incapacity;

Constitutes a congenital anomaly/birth defect;

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above;

Requires inpatient hospitalization or prolongation of existing hospitalization, 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 signing the informed consent

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

Protocol exempt SAEs: SAEs specifically defined in the protocol and where there has 
been a clear agreement with regulators not to collect these SAEs in the safety database, 
provided the information is collected elsewhere. For example, this may include serious 
adverse events that are also a primary outcome measure, such as mortality, survival rate or 
number of flares of the condition being studied.
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 56 days after the patient received the last dose
of treatment, respectively must be reported to Novartis within 24 hours of learning of its 
occurrence. Any SAEs experienced after this period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE Report Form in 
English, and send the completed, signed form by fax within 24 hours to the oncology Novartis 
Drug Safety and Epidemiology (DS&E) department.
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E), specific to the site, are listed in the investigator folder 


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provided to each site. The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated 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 Clinical 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.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
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 
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.
Preclinical data regarding reproductive toxicity of everolimus is described in the most recent 
Investigator Brochure. Based on non-clinical findings (rats), male and female fertility may be 
compromised by treatment with everolimus. In addition, this agent crosses the placenta and is
toxic to the conceptus. In rats, everolimus caused embryo/fetotoxicity at systemic exposure 
below the therapeutic level. This was manifested as mortality and reduced fetal weight.
The potential for everolimus to cause infertility or reproductive risk in male and female 
patients is unknown. However, due to the observed malformations in rats, everolimus should 
be considered potentially teratogenic. In addition, menstrual irregularities, amenorrhea 
(including secondary amenorrhea), and associated luteinizing hormone (LH)/follicle 
stimulating hormone (FSH) imbalance has been observed.


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Regarding pasireotide, there are no adequate and well-controlled studies in pregnant women. 
Studies in animals have shown reproductive toxicity, and effects on female reproductive 
parameters when pasireotide was administered via the subcutaneous route; however, the 
potential risk for humans is not known.
Women of childbearing potential should be advised to use highly effective contraception 
methods while they are receiving everolimus or pasireotide and up to 8 weeks after treatment 
has been stopped. If a pregnancy occurs while on study treatment, the newborn will be 
followed for at least 12 months.
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.
It is not known whether everolimus and pasireotide are excreted in human breast milk. 
However, in in vivo studies everolimus (and/or its metabolites) and pasireotide readily passed
into the milk of lactating animals. Women taking everolimus should therefore not breast-feed. 
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
An external Data Monitoring Committee (DMC) will be instituted before study start. It is 
expected that the DMC will consist of at least two physicians and one independent statistician. 
The DMC will review safety-related issues and will be entitled to make recommendations for
changes in study conduct. Details on the function of the DMC will be laid out in a separate
DMC Charter prepared and approved by both Novartis and the DMC.
Member of the DMC will not be involved in patient recruitment or trial conduct.
8.7
Steering Committee
The general role of the study Steering Committee (SC) is to oversee and provide guidance 
on study conduct and to help ensure delivery of study data. The SC will support the Novartis
clinical team on a continuous basis when questions arise in the trial. The SC will monitor
and supervise the progress of the trial towards its objectives. The members of the SC will 
be appointed by Novartis and comprise of three investigators. The SC will also include two 
Novartis physicians (one covering the role of Clinical Trial Head), a statistician, and the
Clinical Trial Manager. Clinical experts not directly involved in the clinical trial may be
added after consultation with the SC. The committee will be chaired and co-chaired by an
external (non-Novartis) expert.
The SC chair will play a specific role in controlling the flow of the trial information, in
being the primary contact to receive the recommendations from the IDMC at any safety data


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review and at the interim analyses, and in further communicating this information as
appropriate.
Additional details on the safety monitoring and the role of the Steering Committee will be 
provided in the Steering Committee charter.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.


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The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
No information in source documents about the identity of the patients will be disclosed.
9.3
Data collection
The designated investigator staff will enter the data required by the protocol into the
Electronic Case Report Forms (eCRF). The eCRFs have been built using fully validated 
secure web-enabled software that conforms to 21 CFR Part 11 requirements; Investigator site 
staff will not be given access to the EDC system until they have been trained. Automatic 
validation programs check have been created to detect data discrepancies in the eCRFs and to 
allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
9.4
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
10
Statistical methods and data analysis
This is a multicenter, phase II trial evaluating the treatment of pasireotide LAR and 
everolimus in patients with well differentiated neuroendocrine carcinoma of the lung and
thymus randomized to one of the following arms:


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
Arm 1: pasireotide LAR alone;

Arm 2: everolimus alone;

Arm 3: pasireotide LAR and everolimus.
The study is designed to assess the activity, safety, and tolerability of the therapy with
pasireotide LAR and/or everolimus in each arm separately following a Fleming single-stage
design. Each arm is independently evaluated using the decision rules given in the sample
size calculation (see Section 10.8). If 2 or 3 arms are accepted the selection of the best arm 
will be based on a risk/benefit evaluation including the incidence of grade 3-4 adverse events, 
the incidence of serious adverse events, the frequency of treatment modifications as key 
safety parameters to be taken into account in the final decision.
The data will be analyzed by Novartis and/or by the designated CRO. Any data analysis 
carried out independently by the investigator(s) should be submitted to Novartis before 
publication or presentation. It is planned that the data from participating centers in this 
protocol will be combined within each of the arms, so that an adequate number of patients 
will be available for analysis.
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements. Categorical data will 
be presented as absolute frequencies and percentages. For continuous data, N, mean, standard 
deviation, minimum, median, and maximum will be presented. Time to event data will be 
analyzed using the Kaplan-Meier methodology and will be presented as Kaplan-Meier plots 
and/or Kaplan-Meier estimates.
Efficacy and safety analyses will be conducted on all patient data at the time all patients who 
are still receiving study drug will have completed 12 months of treatment. The additional 
data for any patients continuing to receive study drug past this time, as allowed by the 
protocol, will be further summarized in a report once these patients completed the study 
(extension phase of the clinical study report).
10.1
Analysis sets
The following analysis sets will be defined for each study arm separately:
10.1.1
Full Analysis Set
The full analysis set (FAS) consists of all patients who received at least one dose of study 
drug. Following the intent-to-treat (ITT) principle, patients will be analyzed according to the 
treatment and stratum they were assigned to at randomization.
10.1.2
Safety Set
It consists of all patients who received at least one dose of study drug and had at least
one post-baseline safety assessment. Please note: the statement that a patient had no
adverse events (on the Adverse Event CRF) constitutes a safety assessment. Patients who
have received at least one dose of study drug but who have no post-treatment safety data
of any kind would be excluded from the safety set. Patients will be analyzed according to the 
study treatment (regimen) they actually received.


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10.1.3
Per-Protocol Set
It consists of all FAS patients without major protocol violations, such as: (1) no 
histologically 
confirmed 
diagnosis 
of 
unresectable 
advanced 
well 
differentiated 
neuroendocrine carcinoma, (2) prior therapy with mTOR inhibitors (e.g sirolimus, 
temsirolimus, everolimus) (3) prior treatment with long-acting somatostatin analogs (not as 
rescue medication) within one month prior randomization (4) sign of recurrence of prior or 
concomitant malignancies (within the last 3 years or requiring active treatment) other than 
NET with the exception of previous basal cell skin cancer, previous cervical carcinoma in 
situ (5) any current or prior medical condition that may interfere with the conduct of the 
study, (6) study treatment received different from treatment assigned by randomization. 
Further protocol violations leading to exclusion from the per-protocol (PP) set will be 
eventually specified in the Novartis Validation and Planning (VAP) document.
The PP set will be identified prior to database lock.
10.1.4
Dose-determining analysis set
Not applicable.
10.1.5
Pharmacokinetic analysis set
Not applicable.
10.1.6
Other analysis sets 
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be summarized
descriptively for the FAS. Categorical data will be presented as frequencies and percentages.
For
continuous
data,
the
number
of
valid observations,
the
number
of
missing
observations, mean, standard deviation, minimum, median, and maximum will be presented.
Baseline characteristics include prior medication, past/current medical conditions, diagnosis 
and extent of cancer, ECOG performance status and tumor evaluation at baseline.
Medical history will be coded using MedDRA and will be presented by system organ class 
and MedDRA preferred term. Separate tables will be provided for past medical condition and 
current medical condition. Prior medication will be coded according to WHO Drug 
Reference List.
10.3
Treatments (study treatment, concomitant therapies, compliance)
The duration of study treatment exposure, dose intensity and relative dose intensity will be 
summarized descriptively. Frequency of dose reduction (including temporary dose 
interruption) will be presented together with the reasons for dose adjustments/interruptions.
Concomitant medications and significant non-drug therapies after the start of the study drug 
will be coded according to the WHO Drug Reference List and will be summarized by ATC 
class and ATC preferred term.


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10.4
Primary objective
The primary objective of this trial is to evaluate the efficacy of pasireotide LAR and 
everolimus alone or in combination in patients with a well differentiated neuroendocrine 
tumor of the lung or thymus.
10.4.1
Variable
The primary efficacy endpoint is defined as the proportion of patients who are progression
free at Month 9, based on RECIST 1.1.
All CT scans and MRI will be assessed and validated at the local sites throughout the trial.
10.4.2
Statistical hypothesis, model, and method of analysis
Let p0 be the highest proportion of patients progression-free at Month 9 which would indicate 
that the procedure or treatment is clearly ineffective, and p1 be the minimum required 
proportion of patients progression-free. The trial tests the null hypothesis H0 that the 
proportion of patients progression-free, p, is less than or equal to p0 against the alternative 
hypothesis H1 that p is greater than or equal to p1. It consists of entering a predetermined 
number of subjects and deciding in favor of p0 or p1 based on the success rate observed by 
using an appropriate cut-off between p0 or p1. In a single-stage design, if the number of 
responses is greater than or equal to R+1, the hypothesis that p is less than or equal to p0 is 
rejected. If the number of responses is less than or equal to R, the hypothesis that p is greater 
than or equal to p1 is rejected. Details on p0, p1 and R are reported in Section 10.8.
The number and percentage of patients progression-free at Month 9 will be presented for the 
FAS together with the appropriate exact confidence interval.
10.4.3
Handling of missing values/censoring/discontinuations
The definition of the primary variable is based on RECIST 1.1 criteria.
The evaluation of overall lesion response at each assessment is a composite of the target
lesion response, nontarget lesion response and presence of new lesions as shown below in
Table 10-1.
Table 10-1
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall lesion response
CR
CR
No
CR
1
CR
Non-CR/Non-PD
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR
1
SD
Non-PD and not UNK
No
SD
1, 2
UNK
Non-PD or UNK
No
UNK
1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, PR, SD
UNK
No
UNK


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Target lesions
Non-target lesions
New Lesions
Overall lesion response
1This overall lesion response also applies when there are no non target lesions identified at baseline.
2Once confirmed PR was achieved, all these assessments are considered PR.
The evaluation of overall lesion response at Month 9 will be used for the assessment of the 
primary efficacy endpoint.
Patients discontinuing the study for any reason prior to the 9 month assessment, or with 
missing tumor assessment, or with overall lesion response “unknown” will be considered as 
“non progression-free”. Only patients in CR, PR or SD at Month 9 will be considered as 
“progression-free”. Therefore, the proportion of patients who are progression free at 9 months 
is equivalent to the disease control rate (DCR).
10.4.4
Supportive analyses
The number and percentage of patients progression-free will be presented additionally for the 
PP set together with the appropriate exact confidence interval. Results of supportive analyses 
will be interpreted purely exploratory.
10.5
Secondary objectives
Secondary efficacy variables will be analyzed in the FAS. Time to event endpoints will be 
analyzed by Kaplan-Meier (KM) method. Frequencies will be reported together with the 
appropriate exact confidence intervals. All listings and tables will be presented by study arm
10.5.1
Key secondary objective(s)
Not applicable.
10.5.2
Other secondary efficacy objectives
Progression-free survival (PFS) is defined as the time from first study drug administration to 
objective tumor progression or death from any cause. If a patient has not had an event, PFS is 
censored at the date of the last adequate tumor assessment. PFS will be analysed in the FAS 
and PP set by presenting the Kaplan-Meier curve and estimators.
Disease control rate (i.e. the proportion of patient showing a best overall response of CR, PR 
or SD) at 12 months. It will be calculated and displayed with 95 percent exact confidence 
intervals.
Time to response will be defined as the time from start of treatment to the first objective 
tumor response (PR or CR) observed according to RECIST V. 1.1 criteria. Patients who did 
not achieve a confirmed PR or CR will be censored using one of the following options:

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case, the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond;

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding.
Time to response will be explored by presenting the Kaplan-Meier curve and estimators.


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Duration of response is defined as the time from onset of the first objective tumor response 
(CR/PR) to objective tumor progression or death from any cause. Patients not experiencing 
progression or death will be censored with the date of their last adequate tumor assessment. 
Duration of response will be explored by presenting the Kaplan-Meier curve and estimators.
Objective response rate is defined as the proportion of patients showing a best overall 
response of CR or PR at 9 and 12 months, according to RECIST V. 1.1 criteria.The objective 
response rate will be calculated and displayed with 95 percent exact confidence intervals for 
the full analysis set.
Best overall response is defined as the best response recorded from the start of the treatment 
until disease progression/recurrence, taking as reference for PD the smallest measurements 
recorded since the treatment started.
Biochemical response (BR) is defined in Section 7.2.1.2. BR rate (BRR) is the percentage of 
patients showing a ≥30% decrease or normalization of serum CgA levels compared to 
baseline. Additionally, parameters of biochemical response as well as absolute and relative 
changes from baseline in these parameters will be descriptively summarized .
Additionally, the biochemical response on the basis of urine 5-hydroxyindole acetic acid 
(5HIAA) will be assessed, with a response being defined as normalization or a ≥ 50% 
reduction of 5HIAA levels from baseline
Duration of biochemical response (DBR) is defined as the time from the first documentation 
of biochemical response to the first documentation of biochemical progression or to death due 
to any cause, whichever occurs first. Biochemical progression is defined as an increase of 
serum CgA levels ≥25% versus baseline. DBR data will be censored on the date of the last 
tumor marker assessment on study for subjects who do not have biochemical progression and 
who do not die due to any cause while on study.
Biochemical progression free survival (BPFS) is the time from first study drug 
administration to the first documentation of biochemical progression or to death due to any 
cause, whichever occurs first. BPFS data will be censored on the date of the last tumor marker 
assessment on study for subjects who do not have biochemical progression and who do not 
die due to any cause while on study.
10.5.3
Safety objectives
10.5.3.1 Safety parameters and analyses
Safety will be evaluated using assessment of adverse events and laboratory data. The 
assessment of safety will be based mainly on the frequency of adverse events. Other safety 
data (e.g. vital signs) will be considered as appropriate.
10.5.3.1.1
Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by
study arm
The overall observation period will be divided into three mutually exclusive segments:


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1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. On-treatment period: from day of first dose of study medication to 56 days after last dose 
of study medication
3. Post-treatment period: starting at day 56+1 after last dose of study medication.
10.5.3.1.2
Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period will be flagged.
Adverse events will be coded using MedDRA. The incidence of treatment-emergent adverse 
events will be summarized by system organ class, severity (based on CTC grades), type of 
adverse event, and relation to the study drug by study arm. Deaths reportable as SAEs and 
non-fatal serious adverse events will be listed by patient and tabulated by type of adverse 
event and study arm.
All information pertaining to AE noted during the study will be listed by treatment group and 
patient, detailing verbatim given by the investigator, the preferred term, the body system, 
start/end dates, severity, seriousness, relationship to study drug and action taken. The AE 
onset will also be displayed relative (in number of days) to the day of the first dose of study 
medication. AE occurring before start of study drug or 57 or more days after the 
discontinuation of study medication will not be considered as treatment-emergent and will not 
be included in AE summary tables but will be listed only.
10.5.3.1.3
Laboratory abnormalities
All laboratory values will be converted into SI units; for laboratory tests covered by the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (see NCI 2009), the 
study’s biostatistical and reporting team will grade laboratory data accordingly. For laboratory 
tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 
1 or higher. Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

Frequency table for newly occurring on-treatment grades 3 or 4. 

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high /(low and high) classification to compare baseline to the worst on-
treatment value.

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.


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10.5.3.1.4
Other safety data
ECG

Data from ECG will be listed and notable values will be flagged.

Shift table from baseline to worst on-treatment result and summary statistics of changes 
from baseline will be provided for QTcF.
Number and percentage of patients with clinically notable QTcF interval values will be 
summarized.
Vital signs
Vital signs variables include measurements of oral body temperature, systolic and diastolic 
blood pressures, pulse and body weight.
Data on vital signs will be descriptively analysed and listed. Notable values will be flagged; 
definitions of notably abnormal results will be specified in the statistical analysis plan.
10.5.3.1.5
Supportive analyses for secondary objectives
Not applicable.
10.5.3.1.6
Tolerability
Not applicable.
10.5.4
Pharmacokinetics
Not applicable.


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10.7
Interim analysis
Not applicable. No interim analysis will be performed.
10.8
Sample size calculation
A Fleming single stage design will be employed for each arm. Let p0 be the highest proportion 
of patients progression-free at Month 9 which would indicate that the treatment is clearly
ineffective, and p1 be the minimum required proportion of patients progression-free. The trial
tests the null hypothesis H0 that the observed proportion of patients progression-free, p, is
less than or equal to p0 against the alternative hypothesis H1 that p is greater than or
equal to p1. It consists of entering a predetermined number of subjects and deciding in
favor of p0 or p1 based on the success rate observed by using an appropriate cut-off
between p0 and p1. If the number of responses is greater than or equal to R+1, p0 is rejected.
If the number of responses is less than or equal to R, p1 is rejected.
In this trial, p0 and p1 have been set equal to 0.20 and 0.45, respectively. Forty (40) 
patients are planned to be randomized in each treatment group. If the number of responses 
is 13 or more, the hypothesis that p ≤p0 = 20% is rejected with a target alpha error rate of 
5% and an actual alpha error rate of 4.3%; if the number of responses is 12 or less, the 
hypothesis that p ≥ p1 = 45% is rejected with an actual beta error rate of 4%.
Table 10-2
Design features for single-arm trials
p0
p1
Target
Cut-Off
R + 1
N
Actual
alpha
beta
13
40
alpha
beta
20%
45%
5%
10%
4.3%
4%
10.9
Power for anal ysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 


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protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs and 
regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. The date when a subject’s Informed Consent was actually obtained will be 
captured in their CRFs.
Novartis will provide investigators in a separate document with a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
 
 
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Other specific conditions for terminating the study are outlined in 
Section 4.4.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.


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11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.


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11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who is directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the 
study site should be informed within 10 working days.


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sorting of somatostatin receptor subtypes. J Biol Chem; 279 (20):21374-21382.
Van der Hoek J, Waaijers M, van Koetsveld PM, et al (2005) Distinct functional properties of 
native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH 
release by corticotroph tumor cells. Am J Physiol Endocrinol Metab; 289(2):E278-E287.
Van Gompel JJ, Chen H (2004). Insulin-like growth factor 1 signaling in human 
gastrointestinal carcinoid tumor cells. Surgery; 136(6):1297-1302.
Von Wichert G, Jehle PM, Hoeflich A, et al. (2000). Insulin-like growth factor-I is an 
autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor
cells. Cancer Res; 60(16):4573-4581.
Weckbecker G, Raulf F, Stolz B, et al (1993) Somatostatin analogs for diagnosis and 
treatment of cancer. Pharmacol Ther; 60(2):245-264.
Weckbecker G, Briner U, Lewis I, et al (2002) SOM230: A New Somatostatin 
Peptidomimetic with Potent Inhibitory Effects on the Growth Hormone/Insulin-Like Growth 
Factor-I Axis in Rats, Primates, and Dogs. Endocrinol; 143(10):4123-4130.


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Yao JC (2007) Molecular targeted therapy for carcinoid and islet-cell carcinoma. Best Pract 
Res Clin Endocrinology & Metabolism; 21:163-172.
Yao JC, Eisner MP, Leary C, et al (2007) Population-based study of islet cell carcinoma.
Ann Surg Oncol; 14:3492-3500.
Yao JC, Hassan M, Phan A, et al (2008a) One Hundred Years After “Carcinoid”: 
Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the
United States. J Clin Oncol; 26:3063-3072.
Yao JC, Lombard-Bohas C, Baudin E, et al (2010) Daily oral everolimus activity in patients
with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a
phase II trial. J Clin Oncol; 28(1):69-76. Epub 2009 Nov 23.
Yao JC, Manisha HS, Tetshuido, I et al (2011) Everolimus for Advanced Pancreatic 
Neuroendocrine Tumors. New Engl J Med; 364:514-23.
Yao JC, Phan A, Chang DZ, et al (2007) Phase II study of RAD001 (everolimus) and depot
octreotide (sandostatin LAR) in advanced low grade neuroendocrine carcinoma (LGNET).
Abstract No. 4503. ASCO Annual Meeting 2007.
Yao JC, Phan AT, Chang DZ, et al (2008b). Efficacy of RAD001 (everolimus) and
octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a
phase II study. J Clin Oncol; 26(26):4311-8. Erratum in: J Clin Oncol 2008; 26(34):5660.
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Lawrence TS, Rosenberg S. DeVita, Hellman, and Rosenberg’s Cancer Principles &
Practice of Oncology. Lippincott Williams & Wilkins, Philadelphia, PA, USA.


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14
Appendices
14.1
Appendix 1
Guidelines for Response, Duration of Overall Response, 
TTF, TTP, Progression-Free Survival and Overall Survival 
(based on RECIST 1.1) – RECIST Guidelines version 3.1, 
released on November 29, 2011
Document type:
TA Specific Guideline
Document status:
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
29-Nov-2011
Authors (Version 3.1):
 
 
Authors (Version 3):
 
Authors (Version 2):
Authors (Version 1):


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14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.2 and the definition of best response in
Section 14.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.3.2 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) 
European Journal of Cancer; 45:228-247.
14.1.2.1 Definitions
14.1.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in 
order to classify lesions appropriately at baseline. In defining measurability, a distinction also 
needs to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.1.3.2.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at baseline, 
regardless of the slice thickness, are normal and not considered indicative of disease.


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
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
14.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the 
study in some situations (e.g. in Phase III studies where PFS is the primary endpoint). 
However, it is recommended that patients be excluded from trials where the main focus is on 
the Overall Response Rate (ORR). Guidance on how patients with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses is 
given in Section 14.1.3.2.8.
14.1.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.


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


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
Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.1.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.1.2.1.1.

Nodal target: See Section 14.1.2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. 
Each target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.


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14.1.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 14-3) as well as the presence or absence of new lesions.
14.1.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for 
the evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate 
lesion evaluation data are examined by the investigator in order to derive the overall visit 
response. Therefore all such data applicable to a particular visit should be associated with the 
same assessment number.
14.1.2.4.1.1 Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance 
of the cut from the longest diameter; such lesions may appear to have responded or progressed 
on subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm,
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
14.12.4.1.2
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are 
not expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.


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However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
14.1.2.4.2
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3
1.
SOD for CR may not be zero when nodal lesions are part of target lesions
2.
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR
3.
Methodology change See Section 14.1.2.2.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance 
(i.e., the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually 
present and/or not visualized for technical reasons in this previous assessment. If it is not 
possible to change the 0 value, then the investigator/radiologist has to decide between the 
following three possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.


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


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14.1.2.4.3
Determination of non-target lesion response
Table 14-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than baseline.
1.
Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of 
the treating physician does prevail and the progression status should be confirmed later on by the review panel 
(or study chair).
Notes on non-target lesion response

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.2.4.2 for assigning PD following a CR for 
thenon-target lesion response in the presence of non-target lesions nodal lesions should be 
pplied.
14.1.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
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
If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.2.2.
14.1.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in 
Table 14-3.
Table 14-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1.
This overall lesion response also applies when there are no non-target lesions identified at baseline.
2.
Once confirmed PR was achieved, all these assessments are considered PR.
3.
As defined in Section 14.1.2.4.
If there are no baseline scans available at all, then the overall lesion response at each 
assessment should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.1.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.


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


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


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Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be 
at 8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with 
an unknown (UNK) assessment at that time point and no PD before, will not be counted as 
early progressors in the analysis but may be included in the denominator of the EPR rate, 
depending on the analysis population used. Similarly when examining overall response and 
disease control, patients with a best overall response assessment of unknown (UNK) will not 
be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT approach).
14.1.3.2 Time to event variables
The protocol should state which of the following variables is used in that study.
14.1.3.2.1
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.1.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date 
the patient was last seen alive / last known date patient alive, the date of death and the reason 
of death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be 
censored at the date of last known date patient alive.
14.1.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which 
indicates progression. In this case the variable “Time to progression” might be used. TTP is 
defined as PFS except for death unrelated to underlying cancer.


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Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate 
tumor assessment.
14.1.3.2.4
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation 
is typically related to intolerance of the study drug. In some protocols, time to treatment 
failure may be considered as a sensitivity analysis for time to progression. The list of 
discontinuation reasons to be considered or not as treatment failure may be adapted according 
to the specificities of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation 
due to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to 
treatment failure for patients who did not experience treatment failure will be censored at last 
adequate tumor assessment.
14.1.3.2.5
Duration of response
The analysis of the following variables should be performed with much caution when 
restricted to responders since treatment bias could have been introduced. There have been 
reports where a treatment with a significantly higher response rate had a significantly shorter 
duration of response but where this probably primarily reflected selection bias which is 
explained as follows: It is postulated that there are two groups of patients: a good risk group 
and a poor risk group. Good risk patients tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk patients tend to 
be difficult to achieve a response, may have a longer time to respond, and tend to relapse 
quickly when they do respond. Potent agents induce a response in both good risk and poor 
risk patients. Less potent agents induce a response mainly in good risk patients only. This is 
described in more detail by Morgan (1988).
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then 
interpreted with caution by evaluating the results in the context of the observed response 
rates... If an inferential comparison between treatments is required this should only be 
performed on all patients (i.e. not restricting to “responders” only) using appropriate statistical 
methods such as the techniques described in Ellis et al (2008). It should also be stated in the 
protocol if duration of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. 
(Specific definitions for an all-patient analysis of these endpoints are not appropriate since the 
status of patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end 
date and censoring is defined the same as that for time to progression.


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The following two durations might be calculated in addition for a large Phase III study in 
which a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to 
be confirmed) or SD the start and end date as well as censoring is defined the same as that for 
time to progression.
14.1.3.2.6
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be 
confirmed depending on the type of study and its importance. Where the response needs to be 
confirmed then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be 
performed on the “responders” subset only, in which case the results should be interpreted 
with caution and in the context of the overall response rates, since the same kind of selection 
bias may be introduced as described for duration of response in Section 14.1.3.2.5. It is 
recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. Where an 
inferential statistical comparison is required, then all patients should definitely be included in 
the analysis to ensure the statistical test is valid. For analysis including all patients, patients 
who did not achieve a response (which may have to be a confirmed response) will be censored 
using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
14.1.3.2.7
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 


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assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.1.3.2.8
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered 
into the study, either because of a protocol violation or by design (e.g. in Phase III studies 


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with PFS as the primary endpoint). In such cases the handling of the response data requires 
special consideration with respect to inclusion in any analysis of endpoints based on the 
overall response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-4.
Table 14-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.1.2.4
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with 
only non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular patients. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from patients with only non-
measurable disease.
14.1.3.2.9
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after a 
long period of a patient being lost to follow-up? It is important that the protocol and RAP
specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed.


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Based on definitions outlined in Section 14.1.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered:
Table 14-5
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently 
in the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3 Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim
(1) N/A
(2) Date of discontinuation (visit date at 
which clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored (only 
TTP and 
duration of 
response)
1.
=Definitions can be found in Section 14.1.3.2.7.
2.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 
14.1.3.2.7.
3.
=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.


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Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as patients without 
documented PD should be followed for progression after discontinuation of treatment.
However, option (2) may be used as sensitivity analysis. If progression is claimed based on 
clinical deterioration instead of tumor assessment by e.g. CT-scan, option (2) may be used for 
indications with high early progression rate or difficulties to assess the tumor due to clinical 
deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for 
potential bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for 
censoring and events only at scheduled visit dates. The latter could be handled by replacing in 
Table 14-5 the “Date of last adequate assessment” by the “Date of previous scheduled 
assessment (from baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on 
the individual requirements for the specific study and disease area and have to be specified in 
the protocol or RAP documentation.
14.1.4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
14.1.4.1 Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.1.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 


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documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
The end of treatment visit and its associated assessments should occur within 7 days of the 
last study treatment. 
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
14.1.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study 
treatment and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor


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14.1.4.4 Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) 
and not available evaluations (i.e. if any target or non-target lesion was not evaluated the 
whole overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on 
RECIST criteria. This may be queried for clarification. However, the investigator or central 
reader’s response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion 
response at that specific assessment is to be kept in a dataset. This must be clearly 
documented in the RAP documentation and agreed before database lock. This dataset should 
be created and stored as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.1.4.5 Programming rules
The following should be used for programming of efficacy results:
14.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.1.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.


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14.1.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.1.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.1.4.5.6
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 3-2)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.1.3.2.7. This reason is applicable when 
adequate evaluations are missing for a specified period prior to data cut-off (or prior to any 
other censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason 
should also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-


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cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
14.1.5
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16

SAP_001.pdf: 
Clinical Development & Medical Affairs
SOM230 (Pasireotide) LAR and RAD001 (Everolimus)
CSOM230DIC03 / NCT01563354  
Multicenter 3-arm trial to evaluate the efficacy and safety of 
Pasireotide LAR or Everolimus alone or in combination in 
patients with well differentiated neuroendocrine carcinoma of 
the lung and thymus -LUNA Trial
RAP Module 3 – Detailed Statistical Methodology
Author:
, 
 Trial Statistician
, 
 Trial Statistician
, Novartis 
, Novartis Trial Statistician
, Novartis 
Document type:
RAP Documentation
Document status:
Final 1.0
Release date:
1st April 2020
Number of pages:
48
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
Amendment 1.0
09-Feb-2016
Section 3.4.1 (Core phase analysis) – clarification is added on 
safety follow up data inclusion for patients who do not enter 
extension phase.
Amendment 1.0
09-Feb-2016
 
Amendment 1.0
09-Feb-2016
 
 
Amendment 1.0
09-Feb-2016
 
 
Amendment 1.0
09-Feb-2016
Section 10.15 (Vital signs): Clarification is added on the value 
classification (low/normal/high) for baseline and post-baseline 
measurements. This classification is needed for the shift table
output.
Amendment 1.0
09-Feb-2016
Sections 3.2, 7.4, 7.5 – Clarification added that for tumor 
response related assessments, confirmation of response is 
required.
Amendment 1.0
09-Feb-2016
 
Amendment 1.0
09-Feb-2016
Section 5.3 – Clarified that partial end dates will be imputed to 
derive prior/concomitant status.
Amendment 1.0
09-Feb-2016
Section 6.3.3 – Table 5 - Brackets for posterior probability 
intervals updated for consistency with cumulative distribution 
function. Specified seed to be used for random draws.
Amendment 1.0
09-Feb-2016
 
 
Amendment 1.0
09-Feb-2016
 
Amendment 1.0
09-Feb-2016
Section 10.1 – Changed terminology ‘clinically notable adverse 
events’ to ‘adverse events of special interest’.
Amendment 2.0
10-Oct-2018
Sections 1 and 9.6.2 – Updated using latest version of 
protocol.
Amendment 2.0
10-Oct-2018
 
Amendment 2.0
10-Oct-2018
Section 3.4.2 – Updated to clarify that PFS endpoint will be 
analyzed on PP Set as well in extension phase analyses. 
Amendment 2.0
10-Oct-2018
Section 3.5 – Updated to indicate that protocol deviations will 


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Version
Date
Changes
be re-evaluated and PP Set will be used in extension phase 
analyses as well.
Amendment 2.0
10-Oct-2018
Section 5.2 – Amended list of outputs which will be repeated 
based on subset of patients entering extension phase.
Amendment 2.0
10-Oct-2018
Section 7.1 – Updated to clarify that PFS endpoint will be 
analyzed on PP Set as well in extension phase analyses.
Amendment 2.0
10-Oct-2018
Section 7.3 – Clarification added that endpoint is analyzed up 
to 12 month only.
Amendment 2.0
10-Oct-2018
Section 7.4 – Updated to indicate that endpoint will be rerun 
during extension phase analyses based on cumulative data.
Amendment 2.0
10-Oct-2018
Section 7.5 – Clarification added that endpoint is analyzed up 
to 12 month only.
Amendment 2.0
10-Oct-2018
Section 7.6 – Clarification added that endpoint is analyzed up 
to 12 month only.
Amendment 2.0
10-Oct-2018
Section 7.7 – Updated to indicate that endpoint will be rerun 
during extension phase analyses based on cumulative data.
Amendment 2.0
10-Oct-2018
Section 7.8 – Updated to indicate that endpoint will be rerun 
during extension phase analyses based on cumulative data.
Amendment 2.0
10-Oct-2018
 
 
Amendment 2.0
10-Oct-2018
Section 10 - Updated general statement on extension phase 
analyses to clarify that analyses performed after extension 
phase will include cumulative data.
Amendment 2.0
10-Oct-2018
Section 10.1 – Added description of two new AE summary 
tables. 
Amendment 2.0
10-Oct-2018
Section 10.1 – Updated process of groupings of adverse 
events of special risk.
Amendment 2.0
10-Oct-2018
Section 11 – Clarification added that DMC analyses were 
performed during core phase only.
Amendment 3.0
15-Aug-2019
Section 3.4.2 – Removed duration of response analysis from 
extension phase analysis and added clarification that all 
analyses and data reporting after extension phase will be 
reported in the extension phase CSR only.
Amendment 3.0
15-Aug-2019
Section 3.6 – Added note on the subset of patients who 
entered extension phase and listed the analyses for which this 
subset will be used.
Amendment 3.0
15-Aug-2019
Section 5.2 – Removed prior therapy analyses from the list of 
analyses that are repeated for extension phase analysis.
Amendment 3.0
15-Aug-2019
Section 5.4.2 – Removed duration of exposure categories.
Amendment 3.0
15-Aug-2019
Section 5.4.3 – Updated the description of relative dose 
intensity summary table.
Amendment 3.0
15-Aug-2019
Section 7.4 – Removed statement of repeating duration of 
response endpoint analysis at the time of extension phase 
analysis.
Amendment 3.0
15-Aug-2019
 
 
 


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Version
Date
Changes
 
Amendment 3.0
15-Aug-2019
 
 
Amendment 3.0
15-Aug-2019
Section 10.9 – Removed shift table of ECHO or MUGA scan 
and added clarification that only baseline results will be 
presented in a summary table.
Amendment 3.0
15-Aug-2019
Section 10.16 – Added description of bar chart displaying the 
percentage distribution of ECOG performance score.
Amendment 3.0
15-Aug-2019
Section 5.4.3 – Relative dose intensity categories have been 
added.
Amendment 3.0
15-Aug-2019
Section 10.16 – Slight update in sentence describing bar 
charts provided for ECOG performance score.
Amendment 3.0
15-Aug-2019
Section 3.8 – Further details added on review of protocol 
deviations before extension phase database lock.
Amendment 3.0
15-Aug-2019
Section 5.2 – Clarification added that prior long acting 
analogue therapy and prior antineoplastic therapy summaries 
will be repeated during extension phase analyses based on the 
subset of Full Analysis Set who entered extension phase 
where prior therapy data is collected in core phase.
Amendment 4.0
01-Apr-2020
Section 5.3 – Added statement that concomitant medication 
table created as part of extension phase analyses will be 
repeated excluding any patient with missing Safety Follow-up 
assessments during Extension phase.
Amendment 4.0
01-Apr-2020
 
 
 
 
 
Amendment 4.0
01-Apr-2020
Section 10.5 – Added statement that tables created as part of 
extension phase analyses will be repeated excluding any 
patient with glucose, insulin and HbA1c assessment missing 
page during Extension study phase.


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Table of contents
Table of contents ........................................................................................................................5
List of Abbreviations..................................................................................................................8
1
Statistical methods planned in the protocol.......................................................................11
2
Discrepancies between RAP and protocol-specified analyses ..........................................12
3
Statistical and analytical plans...........................................................................................12
3.1
Primary objective...................................................................................................12
3.2
Secondary objectives .............................................................................................12
14
3.4
Data included in the analysis .................................................................................14
3.4.1
Core phase analysis...............................................................................14
3.4.2
Extension phase analysis.......................................................................15
3.5
Patients and treatments ..........................................................................................15
3.6
Full Analysis Set (FAS).........................................................................................16
3.7
Safety Set...............................................................................................................16
3.8
Per-Protocol Set.....................................................................................................16
3.9
Assessment windows, baseline and post-baseline definitions, missing data 
handling .................................................................................................................16
3.9.1
Assessment windows ............................................................................16
3.9.2
Baseline and post-baseline definitions..................................................18
3.9.3
Missing data handling ...........................................................................18
4
General Strategies of Data Presentation............................................................................18
5
Patient Disposition, background and demographic characteristics ...................................18
5.1
Patient disposition..................................................................................................18
5.2
Demographics and baseline characteristics variables............................................19
5.3
Concomitant Medications......................................................................................20
5.4
Study Medication...................................................................................................20
5.4.1
Dose reductions or interruptions...........................................................20
5.4.2
Duration of exposure.............................................................................21
5.4.3
Relative dose intensity ..........................................................................22
6
Efficacy evaluation............................................................................................................23
6.1
Implementation of RECIST...................................................................................23
6.2
Source for overall lesions response .......................................................................24
6.3
Primary efficacy evaluation...................................................................................24


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6.3.1
Variable.................................................................................................24
6.3.2
Statistical Hypothesis, model and analysis ...........................................24
6.3.3
Supportive analyses...............................................................................26
7
Secondary efficacy evaluations .........................................................................................27
7.1
Progression-free survival (PFS).............................................................................27
7.2
Disease Control Rate .............................................................................................27
7.3
Time to Response ..................................................................................................28
7.4
Duration of Response ............................................................................................28
7.5
Objective Response Rate .......................................................................................28
7.6
Biochemical Response Rate ..................................................................................29
7.7
Duration of Biochemical Response .......................................................................29
7.8
Biochemical Progression-free Survival (BPFS)....................................................29
30
30
30
31
31
32
32
32
32
33
33
33
35
36
10 Safety evaluation ...............................................................................................................37
10.1
Adverse Events ......................................................................................................38
10.2
Laboratory values ..................................................................................................40
10.3
Hepatitis screening and evaluation........................................................................41
10.4
Liver function tests ................................................................................................41
10.5
Glucose, insulin & HbA1c.....................................................................................42
10.6
Serum lipid profile.................................................................................................43
10.7
Thyroid function ....................................................................................................43
10.8
Electrocardiograms (ECGs)...................................................................................43
10.9
ECHO or MUGA scan...........................................................................................44


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10.10 Gallbladder assessment..........................................................................................44
10.11 Pulmonary function test.........................................................................................45
10.12 Bronchoscopy ........................................................................................................45
10.13 Chest X-ray or chest CT-scan................................................................................45
10.14 Hepatic assessment ................................................................................................45
10.15 Vital signs..............................................................................................................46
10.16 Eastern Cooperative Oncology Group (ECOG) performance status (WHO)........46
11 Interim analyses.................................................................................................................47
12 Other topics .......................................................................................................................47
13 Determination of sample size............................................................................................47
14 References .........................................................................................................................47


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List of Abbreviations
5-HIAA 
5-Hydroxyindoleacetic acid
AC
Atypical carcinoid 
ACTH 
Adrenocorticotropic hormone
AE 
Adverse Event
ALT 
Alanine aminotransferase
AST 
Aspartate aminotransferase
ATC 
Anatomical Therapeutic Chemical
BAL 
Bronchoalveolar lavage
BOR
Best overall response
BPFS 
Biochemical progression free survival
BR
Biochemical response
BRR 
Biochemical response rate
BUN 
Blood urea nitrogen
CgA 
Chromagranin A
CR 
Complete response
CRF 
Case Report/Record Form
CRO 
Contract Research Organization
CSR 
Clinical Study Report
CT
Computer tomography
CTC/CTCAE Common Toxic Criteria/Common Toxic Criteria for Adverse Events
DBL
Database lock
DBR 
Duration of biochemical response
DCR
Disease control rate
DI
Dose intensity
DLCO 
Diffusing capacity of the lung for carbon monoxide
DMC 
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG 
Electrocardiogram
eCRF
electronic Case Report/Record Form
ECHO
Echocardiogram


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ECOG 
Eastern Cooperative Oncology Group
EOCS 
End of core study
EOEP
End of extension phase
EOT
End of treatment
FAS 
Full Analysis Set
FEV1
Forced expiratory volume in 1 second
FPFV
First patient, first visit
FVC
Forced vital capacity
GGT
Gamma-glutamyl transpeptidase
H0
null hypothesis
H1
alternative hypothesis
HbA1c 
Hemoglobin A1c subtype (glycated hemoglobin)
HDL 
High density lipoprotein
IGF 
Insulin-like growth factor
IHC
Immunohistochemistry
ILD 
Interstitial Lung Disease
i.m.
Intramuscular
INR 
Internation Normalized Ratio
ITT
Intent-to-Treat
K-M
Kaplan-Meier
LAR 
Long-Acting Release
LDL
Low density lipoprotein
LLN
Lower limit normal
LPLV
Last patient, last visit
MedDRA 
Medical Dictionary for Regulatory Activities
MRI 
Magnetic Resonance Imaging
mTOR 
mammalian target of rapamycin
MUGA 
Multiple-Gated Acquisition
NA
Not Applicable
NCI
National Cancer Institute
NET 
Neuroendocrine Tumor
NEU
Neutrophils


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p.o. 
per os/by mouth/orally
PD 
Progressive Disease
PFR-9
Progression-free at Month 9
PFS 
Progression-free survival
PFT
Pulmonary function test
PI3K 
Phosphoinositide 3-kinase
PP
Per-Protocol
PR 
Partial Response
PTT
Partial prothrombin Time
RAP 
Reporting Analysis Plan
RDI
Relative dose intensity
RECIST 
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic acid
SAE 
Serious Adverse Event
SD 
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase SSC
TC
Typical carcinoid 
T3
Tri-iodothyronine
T4
Levothyroxine
TEAE
Treatment-emergent adverse event
TSH 
Thyroid stimulating hormone
TTP
Time to progression
ULN 
Upper Limit Normal
Unsch
Unscheduled visit
UNK
Unknown
WBC 
White Blood Cell
WHO 
World Health Organization


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1
Statistical methods planned in the protocol
This Report Analysis Plan (RAP) contains details of the statistical methods that will be 
applied for the final analyses to be incorporated into the CSR. This document is based on the 
clinical trial protocol version no. 5 dated November 7, 2016.
The purpose of this study is to assess the efficacy and safety of pasireotide long-acting release 
(LAR) and everolimus alone or in combination.
The rationale for this study is based on both preclinical and clinical considerations:

Combined inhibition of the IGF-1-, the PI3K- and the mTOR-pathways by pasireotide 
and everolimus may control tumor growth more effectively than either compound 
alone.

Combination of everolimus with sandostatin LAR seems to improve progression free 
survival in NET patients. Thus the combination of everolimus with pasireotide LAR 
might result in even better tumor control.
This is a prospective, multicenter, randomized, open-label, 3-arm, phase II study with a 
single-stage design in each arm to evaluate the efficacy and safety of pasireotide LAR and 
everolimus alone or in combination in the treatment of patients with well differentiated 
neuroendocrine carcinoma of lung and thymus.
The number of evaluable patients enrolled is targeted to be 120 with 40 patients randomized 
to each arm as follows:

Arm 1 treatment with pasireotide LAR (SOM230) (60 mg/month i.m.),

Arm 2 treatment with everolimus (RAD001) (10 mg/day p.o.), and

Arm 3 treatment with pasireotide LAR (60 mg/month i.m.) and everolimus (10 mg/day 
p.o.)
Randomization is stratified by histological grade of well-differentiated tumor (typical 
carcinoid (TC) vs. atypical carcinoid (AC)) according to the World Health Organization
(WHO) classification and line of treatment (1st line vs. others). 
The study is designed to assess the activity, safety, and tolerability of the therapy with 
pasireotide LAR and/or everolimus in each arm separately following a Fleming single-stage 
design. Each arm is independently evaluated using the decision rules given in the sample size 
calculation (see Section Determination of sample size). 
This study consists of a core study and an extension phase. Patients will receive treatment 
with study drug(s) for a period of 12 months or until one of the following occur:

radiologically documented disease progression

start of new cancer therapy

intolerable toxicity

withdrawal of consent


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
discontinuation due to any other reason. 
Patients will be considered to have completed the core study after the 12 month evaluation has 
been performed. Patients who are presenting clinical benefit from the treatment with 
combination or monotherapy with pasireotide LAR and everolimus are permitted to continue 
treatment after the 12 month treatment period until progression as long as they do not fulfill 
any of the study discontinuation criteria or as long as the Clinical Trial ceases to be in the 
interests of the health of the Clinical Trial Patients, or until the pasireotide and/or everolimus 
development programs is discontinued, whichever comes first.
The end of the study is defined as the last visit two years after treatment start of the last 
randomized patient or when all patients have progressed whichever comes earlier.
Data will be analyzed by
 according to the data analysis section 10 of the study protocol 
which will be available in Appendix 16.1.1 of the Clinical Study Report (CSR). 
2
Discrepancies between RAP and protocol-specified 
analyses
The following discrepancy exists between the Reporting Analysis Plan (RAP) and the study 
protocol version 05, dated 7th November 2016. This discrepancy has become apparent during 
development of the RAP.
 
 
 At the RAP review stage it was decided that 95% confidence intervals 
will be displayed instead following template conventions and presentation methods for other 
parameters.
3
Statistical and analytical plans
3.1
Primary objective

To evaluate the efficacy of pasireotide LAR and everolimus alone or in combination in 
progressive patients with a well differentiated neuroendocrine tumor of the lung or
thymus. The primary endpoint is defined as the proportion of patients who are 
progression-free at 9 months, according to response evaluation criteria in solid tumors 
(RECIST V.1.1).
3.2
Secondary objectives

To assess overall progression-free survival (PFS) throughout the study in patients with
a well differentiated neuroendocrine tumor of the lung or thymus. The endpoint 
“progression-free survival (PFS)” is defined as the time from first study drug
administration to objective tumor progression or death from any cause, according to
RECIST V. 1.1.

To assess the disease control rate of pasireotide LAR and everolimus alone or in
combination, at 12 months, in patients with a well differentiated neuroendocrine tumor 


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of the lung or thymus. Disease control rate is defined as the proportion of patients 
showing a best overall response of complete (CR) or partial (PR) response or stable 
disease (SD) according to RECIST V.1.1

To assess the time to response, duration of response, objective response rate and best 
overall response of pasireotide LAR and everolimus alone or in combination during 12 
months of treatment in patients with a well differentiated neuroendocrine tumor of the 
lung or thymus. The endpoint “time to response” is defined as the time from start of 
treatment to the first objective tumor response (PR or CR) observed, according to 
RECIST V.1.1. The endpoint “duration of response” is defined as the time from 
onset of the first objective tumor response (CR/PR) to objective tumor progression or 
death from any cause. Tumor response will be analyzed using the criteria of 
confirmation, i.e. patients will need to have confirmed CR or PR overall assessment 
before PD or end of core phase measured at least 4 weeks apart each other to be 
included in the subset of responders. The endpoint “objective response rate” is 
defined as the percentage of patients showing a best overall response of CR or PR
according to RECIST V.1.1. criteria. Objective response rate will be summarized at 9 
months and again at 12 months. The endpoint of “best overall response” is defined as 
the best response recorded from the start of the treatment until disease 
progression/recurrence, taking as a reference for PD the smallest measurements 
recorded since the treatment started.

To assess the biochemical response rate (BRR), duration of biochemical response 
(DBR) and biochemical progression-free survival (BPFS) of pasireotide LAR and 
everolimus
alone or in combination in patients with a well differentiated 
neuroendocrine tumor of the lung or thymus. The endpoint “biochemical response 
rate (BRR)” is the percentage of patients showing normalization, i.e. return to within 
normal ranges, or a decrease of ≥ 30% from baseline of serum Chromogranin A (CgA) 
concentrations compared to baseline. The endpoint of “duration of biochemical 
response (DBR)” is defined as the time from the first documentation of biochemical 
response to the first documentation of biochemical progression (defined as an increase 
of serum CgA levels ≥ 25% versus baseline) or to death due to any cause, whichever 
occurs first. The endpoint of “biochemical progression free survival (BPFS)” is the 
time from the first study drug administration to the first documentation of biochemical 
progression or to death due to any cause, whichever occurs first. Biochemical 
progression is defined as an increase of serum CgA levels ≥ 25% versus baseline. 
Additionally, the biochemical response on the basis of urine 5-hydroxyindole acetic 
acid (5HIAA) will be assessed.

To assess the safety and tolerability of pasireotide LAR and everolimus alone or in
combination as measured by rate and severity of adverse events in patients with a well
differentiated neuroendocrine tumor of the lung or thymus. Safety will be assessed 
using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 
Incidence of adverse events (AEs), serious adverse events (SAEs), changes from 
baseline in vital signs, ECG tracings and laboratory results (hematology, blood 
chemistry) will be reported.


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3.4
Data included in the analysis
The data will be analyzed by Novartis and/or 
 Any data analysis carried out 
independently by the investigator(s) should be submitted to Novartis before publication or 
presentation. It is planned that the data from participating centers in this protocol will be 
combined within each of the arms, so that an adequate number of patients will be available for 
analysis.
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, 
, where applicable. Time to event data will be analyzed using the Kaplan-Meier 
methodology and will be presented as Kaplan-Meier plots and Kaplan-Meier estimates.
Efficacy and safety analyses will be conducted on all patient data, both from the core study 
and extension phase. Note that the analysis carried out at the end of the core study will be of
primary importance with analysis at the end of the extension phase being exploratory only.
3.4.1
Core phase analysis
For the core analysis, the data cutoff will be the 12 month or end of core phase evaluation and 
the analysis will take place after the last randomized patient has completed the 12 Month 
evaluation, or discontinued the study treatment due to progression or start of new anti-cancer 
therapy.
Only data from the 12 month core phase will be used in the core analyses, any data from the 
extension phase will be excluded. For patients who do not enter extension phase, safety follow 
up data (if available) will be included in the core analyses.
All events with start date before or on the 12 month evaluation date and with an end date after 
the 12 month end date will be reported as ‘continuing at the end of the core phase’. The same 
rule will be applied to events starting before or on the 12 month evaluation date and not 
having documented end date. This approach applies, in particular, to adverse event and
concomitant medication reports. For these events, the 12 month evaluation date will not be 
imputed and therefore will not appear in the listings.


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Imputation of end date will be performed with the 9 or 12 month evaluation date when needed 
for specific analyses e.g. exposure and dose intensity computation.
3.4.2
Extension phase analysis
For each arm, a final analysis on all data collected, including data from the core phase –
unless otherwise specified - will be performed once the last patient discontinues the study 
treatment. All this data will be listed.
Only PFS analyses and all safety analyses will be repeated at the end of the extension phase 
since no changes are expected to the core data after the core analysis is performed. A formal 
check will be carried to demonstrate no change, or to document if any changes. All TLFs will 
not be rerun during the formal check, if any change is detected in the data, then it will be 
documented in the CSR. All analyses and data reporting performed after extension phase is 
completed will be reported in the extension phase CSR only.
3.5
Patients and treatments 
The number and percentage of patients in each analysis set and each stratum split by treatment 
group will be summarized using the total number of patients randomized as the denominator 
for percentages. A listing of this information will also be provided based on all randomized 
patients. This will include the population flags, whether they were included or excluded from 
that specific population.
Protocol deviations severity codes defined in VAP Module 3 will lead to patient classification 
into the analysis sets as follows:
Severity Codes
Actions
0
Exclude from all efficacy analysis (including FAS)
1
Exclude from Per-Protocol analysis
Table 1 - Analysis set exclusions based on severity codes
Analysis set
PD severity codes that cause 
a patient to be excluded
Non-PD criteria that cause a 
patient to be excluded
Full
0
Did not receive at least one 
dose of study drug
Safety
NA
Did not receive at least one 
dose of study drug, or did 
not have at least one post-
baseline safety assessment
Per-Protocol
0, 1
NA
A frequency tabulation of the protocol deviations leading to exclusion from analysis sets will 
be presented based on the number of patients in the full analysis set along with an associated 
listing for the core phase analyses. This listing will include the severity, the deviation code 
and the related description. Protocol deviations will be re-evaluated at the end of extension 
phase, therefore frequency table will be rerun at the end of extension phase based on 


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cumulative data. A listing will also be created displaying all protocol deviations recorded 
during the whole study.
3.6
Full Analysis Set (FAS)
The full analysis set consists of all patients who received at least one dose of study drug. 
Following the intent-to-treat (ITT) principle, patients will be analyzed according to the 
treatment and stratum they were assigned to at randomization. Disposition, demography and 
analyses of disease history will be repeated at the time of extension phase analysis based on 
those subset of full analysis patients, who started extension phase.
3.7
Safety Set
The safety set consists of all patients who received at least one dose of study drug and had at 
least one post-baseline safety assessment. Please note: the statement that a patient had no
adverse events (on the Adverse Event CRF) constitutes a safety assessment. Patients who
have received at least one dose of study drug but who have no post-treatment safety data of 
any kind would be excluded from the safety set. Patients will be analyzed according to the
study treatment (regimen) they actually received. Patients who received, during the whole 
treatment period, a treatment different from the one assigned at randomization will be 
analyzed according to the actual treatment received. Patients who received a non-randomized 
treatment for part of the trial will be analyzed as having received both treatment arms i.e. will 
be counted in the Pasireotide LAR and everolimus group.
3.8
Per-Protocol Set
The per-protocol set consists of all patients from the full analysis set without major protocol 
violations. Appendix 1 of VAP module 3 lists all major protocol violations. 
The per-protocol set definition will be finalized prior to database lock and might be revised 
prior to extension phase database lock after the review of protocol violations collected during 
the whole study.
3.9
Assessment windows, baseline and post-baseline definitions, 
missing data handling
3.9.1
Assessment windows
Patients will be assessed at baseline (day -28 to -1) and will then attend up to 16 visits during 
the core study with a separate assessment being completed at the end of the core study 
(EOCS) (12 months), either completion or early withdrawal. Those patients presenting with 
clinical benefit and not experiencing unacceptable toxicity at the 12 month visit will continue 
into the extension phase until progression occurs. They will attend visits every 3 months with 
a separate assessment being completed at the end of the extension phase (EOEP) when 
progression occurs, patient withdraws or two years after treatment start of the last evaluable 
patient. All patients who discontinue study treatment must have safety evaluations 56 days 
after the last dose of pasireotide LAR or everolimus, whichever comes last. This includes 
those who didn’t enter extension phase due to disease progression at week 52. Endpoints (i.e. 
EOCS and EOEP) will be summarized as per scheduled visits.  Any data from unscheduled 


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visits (Unsch), will be listed. Early withdrawal visits will continue to be displayed at the 
EOCS visit i.e. it will not be re-mapped to the most appropriate visit.  
Visits will be labeled as follows: Baseline, Day 1, Day 15, Day 21, Day 29, Day 49, Day 57, 
Day 85, Day 113, Day 141, Day 169, Day 197, Day 225, Day 253, Day 281, Day 309, Day 
337, EOCS, 3 Mths Extn, 6 Mths Extn, 9 Mths Extn, 12 Mths Extn, 15 Mths Extn,…., EOEP,  
Safety FU, Unsch.
The tumor assessments will be time-slotted using the time windows displayed in Table 2. 
Table 2 - Time windows for tumor assessments
Time Window
Planned Visit Timing 
Time Window Definition
Week 12
Study Day 85
(Week 12)
]0; 126] 
days
or
]0; 18]
weeks
Week 24
Study Day 169 (Week 24)
]126; 210] days
or
]18; 30]
weeks
Week 36
Study Day 253 (Week 36)
]210; 294] days
or
]30; 42]
weeks
Week 48
Study Day 337  (Week 48)
]294; 351]   days        or     ]42; 50]      weeks
Week 52
Study Day 365 (Week 52)
]351; 379]   days        or     ]50; 54]      weeks
Week 64
Study Day 449 (Week 64)
]379; 491]   days        or     ]54; 70]      weeks
Week k 
Study Day x
(Week y)
x= k*7+1 ; 
y=k
]x-43; x+41] days
or
]y-6; y+6] weeks
                  
Study Day 1 = start of study treatment date
Similarly to tumor assessments, week-based time windows 
 
. If more non-missing results fall into a specific time window, then the one will 
be chosen which is closer to the optimal study day of the specific time window.


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3.9.2
Baseline and post-baseline definitions
For efficacy evaluations, the last available assessment before or at date of start of study 
treatment is taken as “baseline” value or “baseline” assessment. In the context of baseline 
definition, the efficacy evaluations include also ECOG performance status.  
For safety evaluations (i.e. laboratory and vital signs), the last available assessment before or 
at date of start of study treatment is taken as “baseline” assessment.
If patients have no value as defined above, the baseline result will be missing.
3.9.3
Missing data handling
Throughout the study reasonable attempts will be made to limit the amount of missing data. 
However the majority of missing data will not be imputed. The only exceptions to this are for 
the RECIST calculations, see the table in the Primary efficacy evaluation section and 
censoring for the time to analyses detailed in the secondary efficacy evaluation sections. 
4
General Strategies of Data Presentation 
All categorical data will be summarized by frequencies and percentages. Where categorical
data is missing, a ‘Missing’ row will be included at the bottom with frequencies and 
percentages for it also presented.
Continuous data will be summarized with either standard descriptive statistics (i.e. the number 
of non-missing data points, arithmetic mean, standard deviation, minimum, median and
maximum), or will be collapsed into categorical data and summarized as categorical data. 
Day 1 is relative to the treatment start date and is calculated as date of interest – treatment 
start date + 1. For visits/events occurring prior to treatment start date the ‘+1’ will be excluded, 
so the day before day 1 is day -1.
5
Patient Disposition, background and demographic 
characteristics
5.1
Patient disposition
All patient disposition outputs will be performed on the full analysis set.
The number of patients who received study drug, completed the core study and entered 
extension phase will be summarized. For patients who discontinued their reason for 
discontinuing will be presented. This will be summarized for the core study and the extension 
phase separately. 
A listing will include details of patients’ last known date of study medication, whether they 
completed or discontinued and the primary reason for any discontinuation for both the core 
study and extension phase (if applicable), whether the patient is followed up for post 
treatment evaluation and death date if applicable.
A separate listing will also be presented which only includes screening failure patients. This 
will include the reason for screening failure. 


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5.2
Demographics and baseline characteristics variables
Demographics and baseline characteristics will be summarized using the full analysis set. The 
demographics of age (both numeric and categorical (<65 & >=65)), sex, race, body mass 
index and Eastern Cooperative Oncology Group (ECOG) performance status (World Health 
Organization (WHO)) at baseline will be summarized. A listing will also be provided 
summarizing this information along with the height (cm), weight (kg) and child-bearing 
potential for women.
An additional listing will provide details of the pregnancy test, both at screening and post-
baseline (including extension phase pregnancy test results as well). This will include the visit, 
sample date, the method (serum, urine) and the result (negative, positive).
The baseline stratification factors (i.e. histologic grade and treatment line) will be cross-
classified, tabulated and listed against the stratification factors actually used at randomization 
(contained in the IVRS dataset).
Diagnosis and extent of cancer will also be summarized and listed. This will include primary 
site of cancer (lung, thymus), KI67 index categories, functional status of tumor (functioning, 
non-functioning), histologic grade as recorded on the eCRF (typical, atypical), treatment line 
(first line, others) time since initial diagnosis of primary site in months, type of lesions at 
baseline (target only, non-target only, both target and non-target), the presence of metastatic 
disease (yes, No) and if present the location of this. Time since initial diagnosis of primary 
site will be calculated as the date of the baseline visit minus the dates of initial diagnosis of 
primary site divided by 30.4375.  Partial dates will be handled in the following way: where 
the day is missing e.g. XXAPR74 then the day will be imputed as 01, e.g. 01APR74, where 
the date and month are missing XXXXX73 then the day will be imputed as 01 and the month 
as JAN, e.g. 01JAN73. A listing will also present this information along with the date of first 
diagnosis.
Relevant medical history/current medical conditions will be coded using the latest version of 
the Medical Dictionary for Regulatory Activities (MedDRA) and will be presented by system 
organ class and MedDRA preferred term. Separate summary tables will be provided for past 
medical condition and current medical condition. A current medical condition will be those on 
the CRF that are flagged as an active problem. A listing of all relevant medical history/current 
medical conditions will be presented. This will include reported term, preferred term and 
system organ class, the diagnosis/surgery date and whether or not it is still an active problem.
History of prior long-acting somatostatin analogue therapy will be summarized, identifying 
any use of octeotride or lanreotide, as well as summarizing exposure to prior somatostatin 
analogues, in terms of both summary statistics and categorical frequencies (<6 months, >6 
months - <2 years, >2 years - <5 years, >5 years). Duration of exposure (months) will be 
calculated as (end date of somatostain analogue therapy – start date of somatostatin analogue 
therapy + 1) / 30.4375. A listing summarising the long-acting somatostatin therapies will also 
be presented.
Prior antineoplastic therapies will also be summarized overall, and separately by therapy type 
(Medications (solid tumor), Radiotherapy, Surgery/local or regional therapy).
The 
medications (solid tumor) table will include if any prior antineoplastic regimens occurred and 


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if so the number, setting and best response at last treatment. The radiotherapy table will 
summarize if any prior radiotherapy occurred and if so the location, along with the setting and 
best response at last radiotherapy. The surgery/local or regional therapy table will include if 
any prior surgery occurred, the time since last surgery, procedure at last surgery and whether 
there was any residual disease. All these summaries will be based on the full analysis set.
Listings will also be provided for each of the therapy types separately. The listing for 
medications (solid tumor) will include regimen number, medication, route, setting, number of 
cycles, start date, end date, best response, the duration of response and the date of progression. 
The listing for Radiotherapy will include location, start date, end date, cumulative dose and 
unit, setting, best response, method and whether or not the patient had received radiotherapy 
to 30% or more of their bone marrow. The listing for Surgery/local or regional therapy will 
include the procedure, the date of surgery and the residual disease.
Basic demographic data, disease history, prior long acting somatostatin analogue therapy and 
prior antineoplastic therapy summaries (overall, surgery, radiotherapy and medication, where 
data is collected in core phase) will be repeated for extension phase analyses displaying data 
on only the subset of patients entering extension phase.
5.3
Concomitant Medications
Prior and concomitant medications will be collected throughout the study and will be coded 
according to the latest version of the WHO Drug Reference List. The actual medication listed 
on the CRF along with the coded name, Anatomical Therapeutic Chemical (ATC) classes, 
reason, start date, stop date, dose, unit, frequency, route and a flag for prior/concomitant status 
will be listed. The prior/concomitant flag will be identified using the end date of the 
medication; if the end date is prior to the start of study treatment then the medication is 
defined as prior, otherwise it is concomitant. Partial end dates will be imputed and flagged in 
the listing. Details are provided in RAP Module 8.1. A frequency tabulation for the 
concomitant medications will be presented for each of the ATC levels and coded medications
for both core phase and extension phase analyses. This will be based on the full analysis set.
Table will be repeated during extension phase analyses excluding patients missing Safety 
Follow-up assessments during Extension study phase.
5.4
Study Medication
5.4.1
Dose reductions or interruptions
Exposure to study treatment, relative dose intensity, dose reductions and interruptions will be 
summarized after completion of core phase and extension phase. Dosages may be adjusted for 
a number of reasons, see the protocol for details.
The number of patients who have dose reductions or interruptions, the number of dose 
reductions or interruptions, as well as their reasons, will be summarized by treatment. This 
will be done for all reductions or interruptions together and then summarized just for 
reductions and again just for interruptions. The number of dose reductions/interruptions will 
be the sum of the number of reductions and the number of interruptions. A patient who 
reduced their dose to zero will be counted only once in the dose reduction/interruption 
summaries, i.e. not counted once as a reduction and counted again as an interruption. 


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If a patient moves from a higher than protocol planned dose down to the planned dose then 
this is not be counted as a reduction, however if they move directly from a higher than 
planned dose down to a lower than protocol planned dose or the planned dose on a less 
frequent regimen, then this is counted as a reduction.
Everolimus
Interruption: An interruption is defined as a 0mg/0tablets dose given on one or more days or a 
0mg/0tablets record entered for a weekly dosing schedule.
Reduction: A reduction is defined as a decrease in dose from the protocol planned dose or a 
decrease from the previous non-zero dose, even if this decrease has been directly preceded by 
an interruption. A decrease to zero will not be counted as a reduction. For example, in the 
sequence 10mg – 0mg – 5mg, only the 5mg dose will be counted as a reduction.  A decrease 
in frequency of administration which results in a lower cumulative dose is also counted as a 
reduction, e.g. in the sequence 10mg od – 5mg od – 5mg qod, two reductions will be counted.
Pasireotide LAR
Interruption: An interruption is defined as a 0mg dose entered for a monthly dosing schedule 
or the time between two Pasireotide LAR administrations being more than 31 days (28 days + 
3 days).
Reduction: A reduction is defined as a decrease in dose from the protocol planned dose or a 
decrease from the previous non-zero dose, even if this decrease has been directly preceded by 
an interruption. A decrease to zero will not be counted as a reduction.  
Combination arm
Dose reductions and interruptions will be calculated separately for both Pasireotide LAR and 
Everolimus treatments.
5.4.2
Duration of exposure
Everolimus
The following algorithm will be used to calculate the duration of Everolimus exposure:
Duration of exposure (weeks) = (min(date of last administration of Everolimus, date of data 
cut-off) – (date of first administration of Everolimus + 1)) / 7.
The duration includes the periods of temporary interruption.
Pasireotide LAR
The following algorithm will be used to calculate the duration of Pasireotide LAR exposure:
Duration of exposure (weeks) = (min(date of last administration of Pasireotide LAR +27, date 
of death, date of data cut-off) – date of first administration of Pasireotide LAR + 1) / 7.
Combination arm 
The duration of exposure in the combination arm will be computed for the individual 
components separately and combined. The exposure for the individual components will be 


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calculated using the methods above. The duration of exposure to the study treatment for the 
combined treatment will be calculated as follows:
Duration of exposure (weeks) = (last date of exposure to any study treatment component– date 
of first administration of study treatment + 1) / 7.
With the last date of exposure to any study treatment component defined as: max (min(date of 
last administration of Pasireotide LAR +27, date of death, data cut-off date) for Pasireotide 
LAR, min(date of last Everolimus administration, data cut-off date) for Everolimus).
Summaries of the exposure to each treatment i.e. duration (weeks) of application of study 
medication will be presented for the safety set. 
The total number of patients who received each component will be summarized, with the 
combination arm being split into three (Pasireotide LAR, Everolimus and Both). Duration of 
study treatment exposure will be summarized with means of descriptive statistics.
5.4.3
Relative dose intensity
Relative dose intensity (RDI) will be summarized separately for each study drug and is 
defined as follows:
RDI = DI (dosing unit / unit of time) / PDI (dosing unit / unit of time).
Dose intensity (DI) is defined as follows:
DI (dosing unit / unit of time) = Cumulative dose (dosing unit)/Duration of exposure (unit of 
time).
For patients who did not take any drug the DI is by definition equal to zero.
For both Pasireotide LAR and Everolimus the unit of time will be weeks. 
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to 
patients as per protocol in the same dose unit and unit of time as that of the Dose Intensity.
PDI = 10 mg/day = 70 mg/week for Everolimus.
PDI = 60mg per 28 days = 15 mg/week for Pasireotide LAR.
In the combination arm, RDI will be summarized separately for each component, but using 
the duration of the study treatment exposure, not the duration of each of the components. 
Cumulative dose is defined as the total dose taken by the patient during the study treatment 
exposure and will be summarized for each of the study treatment separately. 
For Everolimus total dose = sum of all rows on the dosage administration record of (actual 
dose * (date of end of medication – date of start of medication + 1(only ‘+1’ if end date not 
the same as the start date of the next dose)). If the date of end of medication is missing or after 
the cut-off date then the cut-off date will be used instead. Note that actual dose is the daily 
dose a patient has taken, if a dose is taken every other day instead then the daily dose will be 
halved.
For Pasireotide LAR total dose = sum of all doses recorded on the dosage administration 
record CRF page. 


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Mean and median relative dose intensity will be displayed along with exposure summaries. 
Summary of actual dose intensity, categories of relative dose intensity (<70%, 70 - <90%, 90 -
<100% and >=100%) and cumulative dose received summary will be displayed in a separate
table.
6
Efficacy evaluation
6.1
Implementation of RECIST
Tumor response and disease progression will be evaluated according to the Novartis 
guidelines based on RECIST 1.1 criteria (enclosed in protocol Appendix 1), unless otherwise 
noted.
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below. This 
information will be captured on the CRF.
Table 4 - Evaluation of overall lesion response
Target lesions
Non-target lesions
New Lesions
Overall lesion response
CR
CR
No
CR1
CR
Non-CR/Non PD
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1,2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1 This overall lesion response also applies when there are no non target lesions identified at baseline.
2 Once confirmed PR was achieved, all these assessment are considered PR.
A listing of the tumor assessments and responses will be presented for the full analysis set
after completion of core phase and extension phase analyses. This will include evaluation 
number, type of lesion (target, non-target, new), overall assessment, number, location, 
measurement method, evaluation date, longest diameter (cm), lesion status and an overall 
lesion response as per the investigator. Patients who discontinue study treatment after 12 
months of treatment without evidence of progression or for reasons other than disease 
progression will continue to have tumor evaluation assessments unless consent is withdrawn. 
These will be flagged in this listing.
Another listing of lesion locations and descriptions will also be produced for the full analysis 
set. This will include the evaluation number, the type of lesion (target, non-target, new), the 


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number, the evaluation date, the location, the description, the measurement method and the
measurement method detail.
For each time to event assessment, the assessment date is calculated as follows:

the latest of all measurement dates for assessment with overall lesion response = CR, PR, 
SD or UNK.

the earliest of all measurement dates for assessments with overall lesion response = PD.
6.2
Source for overall lesions response
The tumor endpoints derivation is based on the sequence of overall lesion responses at each 
assessment/time point. Of note, no central review is planned in this study, however all scans 
will be locally stored. If the decision is taken at a later point to perform a central review, then 
the RAP will be amended.
Investigator (local radiology) reported overall lesion response at each assessment will be 
recorded on the eCRF and will be used for the primary endpoint derivation.
6.3
Primary efficacy evaluation
6.3.1
Variable
The primary efficacy endpoint is defined as the proportion of patients who are progression-
free at Month 9 (PFR-9) based on RECIST V. 1.1.
All CT scans and MRI will be assessed and validated at the local sites throughout the trial.
The investigator evaluation of overall lesion response will be used for the assessment of the 
primary efficacy endpoint. 
Patients with CR, PR or SD at Month 9 will be considered as “progression-free”.
Patients with missing tumor assessment, or with overall lesion response “unknown” at Month 
9 will be considered as “non progression-free”, unless any of the following assessments at 
week 48 or week 52 indicate CR, PR or SD, in which case the patient will be considered as 
progression-free at Month 9.
Patients discontinuing the study for any reason prior to the 9 month assessment will be 
considered as “non progression-free”. 
6.3.2
Statistical Hypothesis, model and analysis
Single-stage phase II trials are frequently undertaken to determine whether a new procedure or 
treatment is likely to meet a basic level of efficacy before comparing it with the standard 
technique in a larger randomized phase III trial. This study is of a single stage design, which 
is defined as follows. Let p0 be the highest proportion of patients progression-free at Month 9
which would indicate that the procedure or treatment is clearly ineffective, and p1 be the 
minimum required proportion of patients progression-free to show that the procedure or 
treatment is effective. The trial tests the null hypothesis H0 that the proportion of patients 
progression-free, p, is less than or equal to p0 against the alternative hypothesis H1 that p is 
greater than or equal to p1. It consists of entering a predetermined number of patients and 


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deciding in favor of p0 or p1 based on the success rate observed by using an appropriate cut-off 
between p0 or p1. In a single-stage design, if the number of responses is greater than or equal 
to R+1, the hypothesis that p is less than or equal to p0 is rejected. If the number of responses 
is less than or equal to R, the hypothesis that p is greater than or equal to p1 is rejected.
In this trial, p0 and p1 have been set equal to 0.20 and 0.45, respectively. Forty (40) 
patients are planned to be randomized in each treatment group. If the number of responses 
is 13 or more, the hypothesis that p ≤ p0 = 20% is rejected with a target alpha error rate of 
5% and an actual alpha error rate of 4.3%; if the number of responses is 12 or less, the 
hypothesis that p ≥ p1 = 45% is rejected with an actual beta error rate of 4%.
In the case where more than 40 patients are randomized to one arm, the required number of 
responses to reject the null and alternative hypotheses will be computed using the 
methodology described in Fleming’s paper [Fleming 1982]. R Codes below compute the 
cutoff (RstarPlus1) to reject the null hypothesis for different sample sizes.
For example, with 41 patients, the required number of responses to reject the null hypothesis 
is still 13 responses, and with 42 patients the required number is 14 responses.
fleming <- function(n){
p.0   <- 0.2
Z     <- qnorm(0.95)
N     <- n
s     <- round(N * p.0 + Z * sqrt((N * p.0 * (1 - p.0)))) + 1
thres <- list(N = N , RstarPlus1  = s)
return(thres)  
  
}
n <- 40:45
f <- sapply(n, fleming)
f
##            [,1] [,2] [,3] [,4] [,5] [,6]
## N          40   41   42   43   44   45  
## RstarPlus1 13   13   14   14   14   14
Each arm will be independently evaluated using the above decision rule.
If the null hypothesis is rejected for more than 1 arm the selection of the best arm will be 
based on a risk/benefit evaluation and guided by a Bayesian evaluation described below.
The number and percentage of patients progression-free at Month 9 (PFR-9) will be 
presented for the FAS together with their confidence interval. An exact binomial confidence 
interval (implemented using SAS procedure FREQ with EXACT statement for one-way 
tables) will be calculated [Clopper & Pearson, 1934].
The same computations will be repeated for each stratification factor by stratum.


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6.3.3
Supportive analyses
To further support the decision process, a Bayesian analysis will be performed to estimate the 
proportion of patients who are progression-free at Month 9 for each treatment arm.
Vague prior beliefs about the PFR-9 distribution reflecting the current uncertainty about the 
efficacy of Everolimus and Pasireotide alone or in combination in the study will be 
summarized in prior distributions.  Minimally informative Beta distribution
priors
([Neuenschwander, Branson and Gsponer 2008]) with prior median equal to the clinical 
threshold for futility (20%) will be utilized.
The parameter values of the prior distribution for PFR-9 by arm are summarized in table 5 and 
table 6 summarizes the corresponding prior distribution that PFR-9 falls within the pre-
specified efficacy intervals
Table 5 - Prior parameters for minimally informative Beta distribution of PFR at 9 months
Prior parameters
α
β
0.431
1
Table 6 - Summary of prior distribution of PFR at 9 months  
Efficacy intervals
Prior probabilities (%) that PFR is in interval:
Mean
SD
Quantiles
Unacceptable
Moderate
Substantial
2.5%
50%
97.5%
[0, 20%]
(20%, 45%]
(45%, 100%]
0.500
0.209
0.291
0.301
0.294
<0.001
0.2
0.943
The posterior distribution of the PFR-9 is the update of the prior distribution with all the 
available data from the FAS upon completion of the 9 month follow up. The posterior 
distribution will be used to derive the probability that the true rate lies in the pre-specified 
efficacy intervals. 
In order to guide the selection of the best treatment for further development, for each 
treatment arm selected by the Fleming procedure, the probability that the treatment is the best
will be evaluated based on the posterior distributions of the PFR-9. 
For example, if two treatments A & B are selected using the Fleming single stage method 
with 13 and 14 successes respectively, the posterior probability of being the ‘best’ treatment is
0.4 and 0.60 respectively for treatment A and treatment B, based on a total of 40 patients per 
arm and prior distributions of the rate as defined above. The computations are based on Monte 
Carlo simulations i.e. draws from the posterior Beta distributions of the rates. At each 
iteration of the simulations, the two treatment rates are compared and the frequency of a 
treatment coming up better is computed.


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If more treatment arms are selected by the Fleming single stage method then 10000 draws will 
be performed from the posterior Beta distributions to decide on the best treatment arm. A 
random seed of 43985 will be used.
The number and percentage of patients progression-free will be presented additionally for the 
PP set, together with the appropriate exact confidence interval (implemented using SAS 
procedure FREQ with EXACT statement for one-way tables) [Clopper & Pearson, 1934].
Results of supportive analyses will be interpreted purely exploratory.
7
Secondary efficacy evaluations
7.1
Progression-free survival (PFS)
The progression-free survival (PFS) is defined as the time from first study drug administration 
to objective tumor progression or death from any cause (including extension phase data, if 
applicable at the time of the extension phase analyses). If a patient has not had an event, PFS
is censored at the date of the last adequate tumor assessment. PFS will be analyzed in the FAS 
and PP set (for both core and extension phases) by presenting the Kaplan-Meier curve and 
estimators.
The Kaplan-Meier estimate of the PFS survival function will be constructed and displayed by 
treatment arm overall and per stratum for the core phase analyses and extension phase 
analyses. The plots will also display the number of patients at risk every 3 months. Median 
PFS for each treatment arm will be obtained along with 95% confidence intervals calculated 
by SAS procedure LIFETEST using method of Brookmeyer and Crowley (1982). 25% and 
75% percentiles will be calculated as well. K-M event-free probability estimates with 95% 
confidence intervals using the Greenwood formula will be summarized as well at the 
following time points: 3, 6, 9, and 12 months. This analysis will be repeated for the FAS set 
after completion of the extension phase and interpreted exploratory. The progression-free 
survival analysis after extension phase will take into consideration evaluations during 
extension phase as well, if a patient has not had an event (discontinued for other reason than 
PD or death or trial was ended), PFS is censored at the date of the patient’s last adequate 
tumor assessment in study.
Time to progression and death will be listed per patient presenting the start and end date of 
treatment, the progression status (Y/N), progression date, last progression-free date, death 
status (Y/N), date of death along with principal cause of death and date of last adequate tumor 
assessment which is used for censoring.
7.2
Disease Control Rate
The endpoint of disease control rate (DCR) is defined as the proportion of patients showing a 
best overall response of CR or PR or SD during the core study (12 months) according to 
RECIST V 1.1. The disease control rate will be calculated for the full analysis set. An exact 
binomial confidence interval (implemented using SAS procedure FREQ with EXACT 
statement for one-way tables) will be calculated [Clopper & Pearson, 1934].


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7.3
Time to Response
Time to response is defined as the time from start of treatment to the first objective tumor 
response (PR or CR) observed up to 12 months (i.e. core phase) according to RECIST V. 1.1 
criteria. Patients who did not achieve a confirmed PR or CR will be censored using one of the 
following options:

At maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case, the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond.

At last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding.
Time to response will be explored by presenting the Kaplan-Meier curve and estimators along 
with associated 95 percent confidence intervals, the number with the event and the number 
censored for the full analysis set.
7.4
Duration of Response
Duration of response is defined as the time from onset of the first objective tumor response 
(CR/PR) to objective tumor progression or death from any cause. The start date is the date of 
first documented response (CR or PR) during core phase and the end date and censoring is 
defined the same as that for time to progression. The duration of response will be summarized 
for the subset of patients who had confirmed response. Duration of response will be explored 
by presenting the Kaplan-Meier curve graphically and presenting the number of patients with 
the event, the number censored, the estimators and associated 95 percent confidence intervals.
The results from this analysis should be interpreted with caution since treatment bias could be 
introduced, as only those patients with a response will be included and the number may vary 
between treatments.
7.5
Objective Response Rate
The objective response rate is defined as the proportion of patients showing a best overall 
response of CR or PR during the core study (i.e. up to 12 months) according to RECIST V.
1.1 criteria. For the assessment of SD as best overall response, there is no specific time 
needed from baseline as the first tumor evaluation takes place after 12 weeks (at Visit 8) from 
randomization thus conforming the required minimum time of 6 weeks from randomization 
based on RECIST 1.1 guidelines. Therefore, the best overall response is interpreted as the best 
response recorded from the start of the treatment until disease progression/recurrence, death 
from any cause or until the patient withdraws consent, whichever is earliest. In order to have a 
best overall response of CR or PR, response must be confirmed by another response assessed 
at least 4 weeks after the initial response. The objective response rate will be calculated at 12 
months and displayed with 95 percent exact binomial confidence intervals (implemented 
using SAS procedure FREQ with EXACT statement for one-way tables) [Clopper & Pearson, 
1934]. Frequencies of each response will also be included. This will be carried out for all 
patients in the full analysis set. 


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7.6
Biochemical Response Rate
The endpoint of BRR is defined as the percentage of patients showing normalization, i.e. 
return to within normal ranges, or a decrease of ≥ 30% from baseline of serum Chromogranin 
A (CgA) concentrations compared to baseline. The parameter of biochemical response will be 
summarized by arm with frequency counts, percentages and 95% exact confidence intervals. 
Additionally, the biochemical response on the basis of urine 5-hydroxyindole acetic acid
(5HIAA) will be assessed, with a response being defined as normalization or a ≥ 50%
reduction of 5HIAA levels from baseline.
Patients who are within normal range at baseline will be excluded from the tables. The 
endpoint of BRR will be analyzed based on core phase data only.
Absolute and relative changes from baseline for each of CgA and 5-HIAA will be 
summarized by arm for the full analysis set up to Visit 4 of extension phase. Any data 
collected after Visit 4 of extension phase will not be summarized or listed in the CSR.
A listing containing the CgA and 5-HIAA results will be presented along with the visit, 
sample date, analyte name (CgA, 5-HIAA) and analyte nature/type (DNA, RNA, Protein).
 
7.7
Duration of Biochemical Response
Duration of biochemical response (DBR) is defined as the time from the first documentation
of biochemical response during core phase to the first documentation of biochemical 
progression or death due to any cause, whichever occurs first (including extension phase data, 
if applicable at the time of the extension phase analyses). Biochemical progression is defined 
as an increase of serum CgA levels ≥ 25% compared to baseline. DBR data will be censored 
on the date of the last CgA assessment on study for patients who do not have biochemical 
progression and who do not die due to any cause while on study. DBR will be summarized for 
the subset of patients from the full analysis set who had biochemical response, patients with 
CgA levels within normal range at baseline will also be excluded from the table. This will be 
explored using the Kaplan-Meier method, graphically presenting the Kaplan-Meier curve and 
also tabulating the number with the event, the number censored and the estimators along with 
95 percent confidence intervals. The analysis of this endpoint will be repeated based on 
cumulative study data at the time of extension phase analyses.
7.8
Biochemical Progression-free Survival (BPFS)
Biochemical progression free survival (BPFS) is the time from the first study drug 
administration to the first documentation of biochemical progression or to death due to any 
cause, whichever occurs first (including extension phase data, if applicable at the time of the 
extension phase analyses). Biochemical progression is defined as an increase of serum CgA 
levels ≥ 25% versus baseline. BPFS data will be censored on the date of the last CgA
assessment on study for patients who do not have biochemical progression and who do not die 
due to any cause while on study. BPFS will be analyzed in the FAS set by presenting the 
Kaplan-Meier curve and estimators. The table used will be similar to that described for PFS.


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The analysis of this endpoint will be repeated based on cumulative study data at the time of 
extension phase analyses.


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10
Safety evaluation
For all safety analyses, the safety set will be used. All safety analyses and listings will be 
rerun after completion of the extension phase based on cumulative study data from both core 
and extension phases. The assessment of safety will be based primarily on the frequency of 
AEs and laboratory abnormalities. Other safety data (e.g. gallbladder assessments) will be 
summarized appropriately.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose of 
study medication


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2. On-treatment period: from day of first dose of study medication to 56 days after last dose of 
study medication
3. Post-treatment period: starting at day 56+1 after last dose of study medication.
The listings will all contain a flag to identify which period the event occurred in.
10.1
Adverse Events
Adverse events will be assessed according to the Common Terminology Criteria for Adverse
Events (CTCAE) version 4.0 and recorded on the CRF. If CTCAE grading does not exist for 
an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding 
to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will not be used in this study; rather, 
information about deaths will be collected through both the “Study evaluation completion –
core” form or the “Study evaluation completion – extension phase” form and “Adverse 
Event” form. Table and listing of deaths will be created based on the “Adverse Event” form 
primarily including all reported adverse events with “fatal” outcome indicating end date of 
adverse event as date of death. Fatal adverse events will be flagged appropriately indicating if 
the adverse event ended within the 56-day window after end of study treatment. In case of 
missing adverse event end date, death will be considered as occurring within 56 days from last 
treatment day. A supplementary listing will also be added created based on “Study evaluation 
completion – core” form or the “Study evaluation completion – extension phase” forms 
displaying information related to study discontinuation if death was reported to be the reason 
for discontinuation. Treatment-emergent AEs (TEAEs) are AEs that started or worsened 
during the on-treatment period. Adverse event tables will include only TEAEs. All safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period will be flagged. 
Adverse events will be coded using the most recent version of the medical dictionary for 
regulatory activities (MedDRA) available at the time of each analysis. The incidence of all 
grades of treatment-emergent adverse events and grades 3 or 4 TEAEs will be summarized by 
system organ class only and by system organ class and preferred term for all TEAEs 
regardless of study drug relationship, as well as by system organ class and preferred term for 
serious treatment-emergent AEs regardless of study drug relationship, TEAEs suspected to be 
related to study drug (related to Pasireotide LAR, related to Everolimus, related to both and/or 
undistinguishable), for TEAEs requiring dose adjustment or study drug interruption and for 
TEAEs leading to study drug discontinuation separately. Non-serious TEAEs will be 
tabulated for preferred terms and system organ classes with >5% recorded in any treatment 
group. Incidence of TEAEs will also be summarized by system organ class, preferred term 
and maximum severity (based on CTC grades) for all TEAEs, for those related to study drug 
and for serious TEAEs separately. On treatment deaths will also be tabulated using system 
organ class and preferred term. In all summaries, at each level of summarization (system 
organ class, preferred term) patients will only be counted once regardless of how many times 
it has occurred.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on non-
serious TEAEs with an incidence >=5% and on serious TEAEs, deaths and SAEs suspected to 
be related to study treatment will be provided by system organ class and preferred term.


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If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same system organ class and preferred term:

a single occurrence will be counted if there is <1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is >1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE/ SAE suspected to be related to study 
treatment/ non SAE has to be checked in a block e.g. among AEs in a <=1 day gap block, if at 
least one SAE is occurring then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by system organ class and 
preferred term.
All information pertaining to the AE noted during the study will be listed by treatment group 
and patient, detailing verbatim given by the investigator, the preferred term, the abbreviated 
system organ class, start date, end date, duration, severity (CTCAE grade), relationship to 
study drug (not suspected, suspected to be related to SOM, suspected to be related to RAD, 
suspected to be related to both and/or undistinguishable), action taken (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) and outcome 
(recovered, recovering/resolving, recovered/resolved with sequelae, not recovered/resolved, 
fatal, unknown). The AE onset will also be displayed relative (in number of days) to the day 
of the first dose of study medication. AEs occurring before start of study drug or 57 or more 
days after the discontinuation of study medication will not be considered as treatment-
emergent and will not be included in AE summary tables but will be listed only. This listing 
will be repeated for the subsets of serious TEAEs, TEAEs leading to study drug 
discontinuation and TEAEs requiring dose adjustment or study drug interruption.
All deaths will be listed by treatment group and patient detailing principal cause given by the 
investigator, the preferred term the date of last dose and the date of death. The day of last dose 
and day of death will also be displayed relative to the day of the first dose of study medication. 
The number of days since last dose will also be presented, calculated as death day – day of 
last dose + 1.
Grouping of adverse events of special interest
Specific groupings of adverse events of special interest will be considered and the number of 
patients with at least one event in each grouping will be reported. Such groups consist of 
adverse events for which there is a specific clinical interest in connection with everolimus or 
pasireotide treatment (i.e. where everolimus or pasireotide may influence a common 
mechanism of action responsible for triggering them) or adverse events which are similar in 
nature (although not identical). 
Adverse event groupings can be defined through e.g. the use of Preferred Terms (PT), High 
Level Terms (HLT) or System Organ Classes (SOC) or through a combination of these three 
components. 


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Adverse event groupings will be performed by Novartis and the created adverse event risk 
analysis dataset will be forwarded 
 to generate summary tables. Summaries of the 
adverse events of special interest by specific grouping term and preferred term will be 
produced. These summaries will be repeated for adverse event groupings related to 
everolimus and pasireotide treatment separately. These will be produced for all adverse events
of special interest regardless of study drug relationship as well as for adverse events of special 
interest suspected to be related to study drug including summaries for all CTC grades and 
CTC grades 3 or 4.
10.2
Laboratory values
All laboratory values will be converted into SI units; for laboratory tests covered by the
CTCAE version 4.0 (see National Cancer Institute (NCI) 2009), the study’s biostatistical and 
reporting team will grade laboratory data accordingly. For laboratory tests covered by 
CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests where grades are not defined by CTCAE, results 
will be graded by the low/normal/high classifications based on laboratory normal ranges.
All summaries will be produced separately for each lab category (hematology, biochemistry 
and urinalysis). Hematology includes hemoglobin, hematocrit, platelets and total white blood 
cell count (WBC, absolute & differential including neutrophils, lymphocytes, monocytes, 
eosinophils and basophils). Biochemistry includes sodium, potassium, chloride, bicarbonate, 
creatinine, total protein, uric acid, blood urea nitrogen (BUN), calcium, magnesium and 
phosphate. Urinalysis includes pH, protein, glucose, blood, ketones and leukocytes. They will 
be tested using a dipstick. In some cases urea results will be collected rather than BUN. In 
these cases urea will be converted to BUN using the following conversions:
BUN (mg/dL) = Urea (mg/dL) / 2.14
BUN (mmol/L) = Urea (mmol/L) / 2
Shift tables using CTCAE grades will be produced for hematology and biochemistry 
separately to compare baseline and the worst on-treatment value with each laboratory 
parameter on a new page. Percentages will be calculated using the number of available 
patients at baseline with corresponding grade and at least one non-missing post baseline value 
as the denominator.
For laboratory tests where CTCAE grades are not defined, shift tables using the
low/normal/high/(low and high) classification will be produced to compare baseline to the 
worst on-treatment value with each laboratory parameter on a new page. Percentages will be 
calculated using the number of available patients at baseline with corresponding level and at 
least one non-missing post baseline value as the denominator. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available (this is mainly important for neutrophils and lymphocytes, as the 
CTC grading is based on the absolute counts).
The method to convert the value is as follows: for each patient, the original laboratory value 
(%) is divided by 100 and multiplied by the WBC count, e.g. for neutrophils (NEU): 


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NEU count = (WBC count) * (NEU %value / 100)
In order to derive the corresponding absolute normal range, the rule to be applied depends on 
the availability of the % range and the absolute range for the differential:
•
If the % range is missing and the absolute range is missing, then the pre-defined 
normal range as reported in the Merck manual (FRM-0015557 Laboratory value 
references) will be used.
•
If the absolute range is NOT missing (% range is or isn’t missing), then the absolute 
range provided by the site will be used. 
•
If the % range is NOT missing and the absolute range is missing, then the % normal 
limits (i.e. lower limit normal (LLN) and upper limit normal (ULN)) are divided by 
100 and multiplied by the corresponding normal limits of WBC count, e.g. for NEU:
LLN for NEU count = (LLN for WBC count) * (LLN for NEU % value/ 100)
ULN for NEU count = (ULN for WBC count) * (ULN for NEU % value / 100)
A listing will be presented for all hematology, biochemistry and urinalysis laboratory data, 
with values flagged to show the corresponding CTCAE grades and the classifications relative 
to the laboratory normal ranges. A separate listing will be created presenting the laboratory 
normal ranges for the collected parameters by laboratory identification number and laboratory 
group.
10.3
Hepatitis screening and evaluation
In certain instances, patients must be tested for Hepatitis B viral load and serologic markers, 
that is, HBV-DNA, HBsAg, HBsAb, and HBcAb as well as Hepatitis C. These instances are 
described in the protocol.
For the parameter of HBV-DNA where the result is recorded as negative, positive or not done 
at multiple visits, frequencies of these results will be produced for baseline and each post-
baseline visit. Percentages will be calculated using the number of available patients at that 
visit, for the particular treatment group. A similar table will be produced for the HCV RNA-
PCR parameter. 
For the parameters of HBsAg, HBsAb and HBcAb where the result is recorded as negative, 
positive or not done at baseline only, the frequencies of these results will be produced by 
treatment. 
A listing will be presented by treatment showing the visit, sample date, laboratory number, 
laboratory name, HBV-DNA (negative, positive, not done), HBsAg (negative, positive, not 
done), HBsAb (negative, positive, not done), HBcAb (negative, positive, not done) and HCV 
RNA-PCR (negative, positive, not done). HBV-DNA and HCV RNA-PCR are the only tests 
carried out post-baseline and only in certain circumstances.
10.4
Liver function tests
The liver function tests carried out will be albumin, serum glutamic oxaloacetic transaminase 
(aspartate aminotransferase) (SGOT (AST)), serum glutamic pyruvic transaminase SSC 


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(alanine aminotransferase) (SGPT (ALT)), total bilirubin (fractionate to direct/indirect 
bilirubin if total bilirubin is > 2.0 x ULN), alkaline phosphatase and gamma-glutamyl 
transpeptidase (GGT). For patients treated with pasireotide LAR: the Day 21 and Day 49 liver 
function tests should be available and assessed prior to dosing on Day 29 (2nd LAR injection) 
and Day 57 (3rd LAR injection). The coagulation parameters of international normalized ratio 
(INR) will be determined at baseline, at Visits 2, 5, 7, 8, then every 8 weeks in the core study 
and every 3 months in the extension phase. It will be determined also at Visits 4 and 6 for 
patients treated with pasireotide LAR. The partial thromboplastin time (PTT) will be 
determined only at baseline.
A shift table using CTCAE grades will be produced for these parameters, with the exception 
of PTT as it is captured as baseline only, to compare baseline and the worst on-treatment 
value with each laboratory parameter on a new page. Percentages will be calculated using the 
number of available patients at baseline with corresponding grade and at least one non-
missing post baseline value as the denominator.
For laboratory tests where CTCAE grades are not defined, a shift table using the 
low/normal/high/(low and high) classification will be produced to compare baseline to the 
worst on-treatment value with each laboratory parameter on a new page. Percentages will be 
calculated using the number of available patients at baseline with corresponding level and at 
least one non-missing post baseline value as the denominator. 
A frequency table will be created presenting number of patients with elevated liver chemistry 
tests based on worst post-baseline values for aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, and alkaline phosphatase parameters. Categories of 
elevated tests will be defined with regards to the upper or lower normal ranges, whichever is 
applicable. Percentages will be calculated using the number of patients in the safety analysis 
set.
A listing will be presented showing the visit sample date, laboratory number, laboratory name, 
albumin, SGOT (AST), SGPT (ALT), alkaline phosphatase, GGT, total bilirubin, direct 
bilirubin, indirect bilirubin, INR and PTT split by treatment.
10.5
Glucose, insulin & HbA1c
A shift table using CTCAE grades will be produced for these parameters to compare baseline 
and the worst on-treatment value with each laboratory parameter on a new page. Percentages 
will be calculated using the number of available patients at baseline with corresponding grade 
and at least one non-missing post baseline value as the denominator.
For laboratory tests where CTCAE grades are not defined, a shift table using the 
low/normal/high/(low and high) classification will be produced to compare baseline to the 
worst on-treatment value with each laboratory parameter on a new page. Percentages will be 
calculated using the number of available patients at baseline with corresponding level and at 
least one non-missing post baseline value as the denominator. 
Tables created as part of the extension phase analyses will be repeated excluding patients
missing glucose, insulin and HbA1c assessment during Extension study phase.


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A listing will be provided split by treatment arm summarizing this information and will 
include visit, sample date, laboratory number, laboratory name, glucose, insulin, HbA1c and a 
flag to indicate whether it was taken whilst fasting.
10.6
Serum lipid profile
A shift table using CTCAE grades will be produced for these parameters to compare baseline 
and the worst on-treatment value with each laboratory parameter on a new page. Percentages 
will be calculated using the number of available patients at baseline with corresponding grade 
and at least one non-missing post baseline value as the denominator.
For tests where CTCAE grades are not defined, a shift table using the low/normal/high/(low 
and high) classification will be produced to compare baseline to the worst on-treatment value
with each laboratory parameter on a new page. Percentages will be calculated using the 
number of available patients at baseline with corresponding level and at least one non-missing 
post baseline value as the denominator.
A listing will be provided split by treatment displaying the visit, sample date, laboratory 
number, laboratory name, cholesterol, triglycerides, LDL and HDL.
10.7
Thyroid function
Thyroid function tests of thyroid stimulating hormone (TSH), free T3 (tri-iodothyronine) and 
T4 (levothyroxine) along with B12 vitamin will be collected at baseline, week 12, week 24 
and at the end of the core study. Plasma ACTH will be taken at baseline and only those 
patients with hypersecretion will be tested again.
A shift table using CTCAE grades will be produced for these parameters to compare baseline 
and the worst on-treatment value with each laboratory parameter on a new page. Percentages 
will be calculated using the number of available patients at baseline with corresponding grade 
and at least one non-missing post baseline value as the denominator.
For laboratory tests where CTCAE grades are not defined, a shift table using the 
low/normal/high/(low and high) classification will be produced to compare baseline to the 
worst on-treatment value with each laboratory parameter on a new page. Percentages will be 
calculated using the number of available patients at baseline with corresponding level and at 
least one non-missing post baseline value as the denominator. 
This information will also be presented in a listing along with the visit, sample date, 
laboratory number and laboratory name split by treatment.
10.8
Electrocardiograms (ECGs)
Overall ECG interpretation and details of abnormalities are collected at Screening and 
selected visits. The ECG QTcF result at each visit will be categorized. A shift table displaying 
the baseline categorized ECG QTcF result compared with the worst post-baseline categorized 
result will be produced. Percentages will be calculated using the number of patients with that 
categorized result at baseline as the denominator.


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The number of patients recording notable ECG QTcF increases from baseline at least once 
will also be presented. Percentages will be calculated using the number of patients with both 
baseline and post baseline evaluations.
A listing of ECG evaluations will be presented for all patients with at least one treatment 
emergent abnormality i.e. where no clinically significant abnormality was present at baseline 
and a clinically significant abnormality was present on-treatment. This listing will include the 
date of ECG, clinically significant abnormality (yes, no) and abnormality descriptions.
10.9
ECHO or MUGA scan
All patients will have an echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan 
at screening and when it is indicated clinically during the study. A summary table of LVEF 
will be produced to display baseline result. This information will also be listed along with any 
optional post-baseline records and includes the method (ECHO, MUGA scan), the LVEF (%), 
the result (normal, clinically insignificant abnormality, clinically significant abnormality) and 
the abnormality descriptions.
10.10
Gallbladder assessment
The gallbladder evaluation, either magnetic resonance imaging (MRI) or a computer 
tomography (CT) scan, will be performed together with the radiological tumor assessment at 
baseline for all patients, on treatment only for patients treated with pasireotide LAR.
If the patient discontinues treatment, an end of core study visit MRI/CT scan has to be 
performed only if the end of core study visit occurred 3 months or more after the previous 
MRI/CT scan.
A table will be presented showing the frequencies at baseline of image performed? (yes, no),
were any gallstones detected? (yes, no), was any sludge detected? (yes, no), is there any 
dilatation of the intra- or extrahepatic ductal system (yes, no) and if yes was it the intrahepatic 
ductal system or the extrahepatic dutal system, gallbladder imaging technique (CT scan, MRI) 
and was there any gallbladder thickening (yes, no). Percentages will be calculated based on 
the number of patients with available data for each of these questions.
A shift table will also be produced for gallstones detection, sludge detection, dilatation and 
thickening comparing the baseline result with the most extreme post-baseline result (defined 
as ‘yes’ if it occurs post-baseline). This will only include the treatments of Pasireotide LAR 
and both Pasireotide LAR and Everolimus since this data is not collected for patients in the 
Everolimus group. 
A listing will be presented showing the visit, image performed? (yes, no), date, were any 
gallstones detected? (yes, no) and if yes, the location, was any sludge detected? (yes, no) and
if yes, the location, is there any dilatation of the intra- or extrahepatic ductal system (yes, no) 
and if yes was it the intrahepatic ductal system or the extrahepatic dutal system, gallbladder 
imaging technique (CT scan, MRI) and was there any gallbladder thickening (yes, no).


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10.11
Pulmonary function test
At baseline, prior to administration of study drug, pulmonary function tests (PFT) can be 
performed, if clinically indicated. During study treatment, all PFTs including spirometry, 
diffusion capacity for carbon monoxide (DLCO) and room air oxygen saturation at rest must 
be performed if the patient develops non-infectious pneumonitis. A listing split by treatment 
will be provided showing the spirometry date, total lung capacity, forced vital capacity (FVC), 
forced expiratory volume in one second (FEV1), functional residual capacity, residual 
capacity, was DLCO done? (yes, no) and if yes, the date and capacity, pulse oximetry done? 
(yes, no) and if yes the date, percent inspired oxygen and percent oxygen saturation.
10.12
Bronchoscopy
A bronchoscopy with biopsy and/or bronchoalveolar lavage (BAL) will be performed only
when medically necessary for ensuring patient care. When non-infectious pneumonitis is
diagnosed, consultation with a pulmonologist should be considered. 
A listing showing the assessment date, was infectious agent identified? (yes, no), was BAL 
done? (yes, no), was BAL cell count done? (yes, no), was alveolar hemorrhage seen? (yes, no) 
and if yes, the predominance (lymphocyte, eosinophil, neutrophil, dysplastic type II, 
malignant, other), was a transbronchial biopsy done? (yes, no) and if yes, the findings.
10.13
Chest X-ray or chest CT-scan
If the baseline scan shows signs suggestive of interstitial lung disease (ILD)/non-infectious 
pneumonitis, it is at the discretion of the investigator to follow the patient with appropriate 
chest imaging. For all other patients chest X-rays or chest CT-scans are to be performed 
during the study if clinically indicated e.g. if there is suspicion of non-infectious pneumonitis, 
in the investigator’s discretion. A shift table displaying the baseline result (normal, 
insignificant abnormality, clinically significant abnormality) compared with the worst post-
baseline categorized result will be produced. Percentages will be calculated using the number 
of patients with that categorized result at baseline as the denominator.
A listing split by treatment will be provided showing the X-ray/CT-scan date, the examination 
of the chest in the P-A and/or lateral view (normal, clinically insignificant abnormality, 
clinically significant abnormality) and if clinically significant, details of the abnormality.
10.14
Hepatic assessment
If certain criteria occur then one of the tests that must be carried out within 72 hours of 
awareness of the abnormality is a hepatitis screen. This consists of anti-HAV (positive, 
negative, not done), IgM (positive, negative, not done) to confirm acute Hepatitis A, HbsAg  
(positive, negative, not done), Anti-HBc (positive, negative, not done), anti-HCV (positive, 
negative, not done) and if positive, PCR viral load, Anti-HEV ANA antibodies (positive, 
negative, not done), anti-smooth muscle anti-bodies (positive, negative, not done), CMV 
(positive, negative, not done) and EBV (positive, negative, not done). All these will be listed 
split by treatment arm along with the sample date, laboratory number and laboratory name.


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10.15
Vital signs
Vital signs data includes weight, body temperature, respiratory rate, sitting pulse as well as 
sitting blood pressure (systolic and diastolic). Shift tables using the low/normal/high/(low and 
high) classification (as shown below.) will be produced to compare baseline to the worst on-
treatment value with each vital sign parameter on a new page. Percentages will be calculated 
using the number of available patients at baseline with corresponding level and at least one 
non-missing post baseline value as the denominator. For baseline value classification 
(low/normal/high) the normal ranges per parameter will be taken into account (except for 
weight displaying only Total and Missing rows as there is no normal range defined). For post-
baseline classification change from baseline will also be considered (except for respiratory 
rate). Only assessments obtained after start of study drug and up to 56 days after the 
discontinuation of study medication will be considered “on-treatment”.
Table 11 - Notable abnormalities
Notable abnormalities
Vital signs
Low
High
Pulse (beats/min)
50 + decrease 15* 
120 + increase 15* 
Blood pressure 
(mmHg)
Systolic
90 + decrease 20* 
180 + increase 20* 
Diastolic
50 + decrease 15* 
105 + increase 15* 
Weight (kg)
decrease of > 10% during 
the study*
increase of > 10% during 
the study*
Respiratory rate 
(per min)
12
25
* Refers to post-baseline value as compared to baseline value
The notable abnormality of ‘> 120 + increase > 15’ is interpreted as that the value at that visit
is > 120 and the increase from baseline is > 15. 
The vital signs variables of weight, body temperature, respiratory rate, sitting pulse and sitting 
blood pressure (systolic and diastolic) will also be listed and clinically notable values/changes 
from baseline will be flagged. A separate listing containing all records for patients with 
clinically notable abnormal vital signs will also be generated.
10.16
Eastern Cooperative Oncology Group (ECOG) performance 
status (WHO)
The ECOG performance status is captured throughout the study. A shift table displaying the 
baseline category compared with the worst post-baseline category will be produced. 
Percentages will be calculated using the number of patients with that category at baseline as 
the denominator. A listing of all ECOG records will also be produced. In addition, bar charts 
will be created separately for each treatment group, displaying the percentage distribution of 
each ECOG performance score at each scheduled visit.


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11
Interim analyses
An external and independent Data Monitoring Committee (DMC) was instituted before study 
start. The DMC
will review safety-related issues and will be entitled to make 
recommendations for changes in study conduct, if needed during core phase of the study. 
Details on the function of the DMC are reported in a separate DMC Charter. A separate 
Module 3, Module 7.1 and Module 8.1 have been produced with details of what will be 
produced for each DMC.
12
Other topics
No other topics will be studied.
13
Determination of sample size
The trial tests the null hypothesis H0 that the observed proportion of patients progression free, 
p, is less than or equal to p0 against the alternative hypothesis H1 that p is greater than or 
equal to p1. It consists of entering a predetermined number of patients and deciding in favor of 
p0 or p1 based on the success rate observed by using an appropriate cut-off between p0 and p1. 
If the number of responses is greater than or equal to R+1, p0 is rejected in favor of p1. If the 
number of responses less than or equal to R, p1 is rejected in favor of p0.
For this study let p0 be the highest proportion of patients progression-free at Month 9 which 
would indicate that the treatment is clearly ineffective, and p1 be the minimum required 
proportion of patients progression-free for the procedure or treatment to be effective.
Table 12 – Design features for single arm trials
p0
p1
Target
Cut-Off
R + 1
N
Actual
alpha
beta
alpha
beta
20%
45%
5%
10%
13
40
4.3%
4%
A study requires 40 patients per treatment to decide whether the proportion responding, p, is 
less than or equal to p0=20% or greater than or equal to p1=45%. If the number of responses is 
13 or more, the hypothesis that p ≤ p0 = 20% is rejected with a target alpha error rate of 5% 
and an actual alpha error rate of 4.3%. This indicates that the treatment is not ineffective i.e. it 
is likely be effective and so it is worth proceeding with a phase III trial. If the number of 
responses is 12 or less, the hypothesis that p ≥ p1 = 45% is rejected with a target beta error 
rate of 10% and an actual beta error rate of 4%. This indicates that the treatment is not 
effective i.e. is likely to be ineffective and so it is not worth pursuing any further. 
14
References
Clopper CJ, Pearson ES (1934).  The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413.


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Fleming T (1982). One-sample multiple testing procedure for phase II clinical trials, 
Biometrics 38, 143-151.
Neuenschwander B, Branson M, Gsponer T (2008). Critical aspects of the Bayesian approach 
to phase I cancer trials. Statist. Med. 2008; Vol. 27; pages 2420–2439