Conditions: Pancreatic Tumours Midgut Neuroendocrine Tumours
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 99
Healthy volunteers: no

Brief summary:
This study aims to explore the efficacy and safety of lanreotide Autogel® 120 mg administered every 14 days in subjects with grade 1 or 2, metastatic or locally advanced, unresectable pancreatic or intestinal neuroendocrine tumours (NETs) once they have progressed on the standard dose of lanreotide Autogel® 120 mg every 28 days.

Detailed description:

Arms:
arm 1: One subcutaneous (SC) injection of lanreotide Autogel® 120mg every 14 days until disease progression or death or unacceptable toxicity or tolerability.

Interventions: intervention 1: Lanreotide autogel 120 mg
Intervention descriptions: intervention 1: None

Protocol document:
Prot_001.pdf: 
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EFFICACY AND SAFETY OF LANREOTIDE AUTOGEL® 120 MG ADMINISTERED 
EVERY 14 DAYS IN WELL DIFFERENTIATED, METASTATIC OR LOCALLY 
ADVANCED, UNRESECTABLE PANCREATIC OR MIDGUT NEUROENDOCRINE 
TUMOURS HAVING PROGRESSED RADIOLOGICALLY WHILE PREVIOUSLY 
TREATED WITH LANREOTIDE AUTOGEL® 120 MG ADMINISTERED EVERY 
28 DAYS 
 
STUDY PROTOCOL 
STUDY NUMBER: 8-79-52030-326 (CLARINET FORTE) 
 
LANREOTIDE AUTOGEL® 
EUDRACT NUMBER: 2014-005607-24 
 
Final version (including Amendment 3) dated 09 January 2017 
 
Sponsor’s Medically Responsible Person: 
Study Sponsor: 
 
Ipsen Innovation 
, Endocrinology Franchise 
5 Avenue du Canada 
65 Quai George Gorse 
Zone industrielle de Courtaboeuf 
92100 Boulogne-Billancourt, France 
91940 Les Ulis, France 
 
 
 
 
 
 
Monitoring Office: 
Co-ordinating Investigator: 
Ipsen Pharma 
 
65 Quai Georges Gorse 
 
92100 Boulogne-Billancourt, France 
 
Tel:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacovigilance/Emergency Contact: 
  
 
 
  
 
  
 
For serious adverse events (SAEs) reporting: 
Email: adverse.events@ipsen.com 
 
 
 
 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation. 
PPD
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INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol 8-79-52030-326 entitled “Efficacy and safety of lanreotide 
Autogel® 120 mg administered every 14 days in well differentiated, metastatic or locally 
advanced, unresectable pancreatic or midgut neuroendocrine tumours having progressed 
radiologically while previously treated with lanreotide Autogel® 120 mg administered every 
28 days”. I am aware of my responsibilities as an investigator under the guidelines of Good 
Clinical Practice (GCP), local regulations (as applicable) and the study protocol. I agree to 
conduct the study according to these guidelines and to appropriately direct and assist the staff 
under my control, who will be involved in the study. 
 
NAME: 
 
 
 
TITLE: 
Principal Investigator 
SIGNATURE: 
 
 
DATE: 
 
 
OFFICE: 
 
 
 
Sponsor's Representative Signature: 
NAME: 
 
 
 
 
 
 
SIGNATURE: 
 
 
DATE: 
 
 
OFFICE: 
 
 
 
PPD


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COORDINATING INVESTIGATOR’S AGREEMENT 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol 8-79-52030-326 entitled “Efficacy and safety of lanreotide 
Autogel® 120 mg administered every 14 days in well differentiated, metastatic or locally 
advanced, unresectable pancreatic or midgut neuroendocrine tumours having progressed 
radiologically while previously treated with lanreotide Autogel® 120 mg administered every 
28 days”. I am aware of my responsibilities as a coordinating investigator under the guidelines 
of Good Clinical Practice (GCP), local regulations (as applicable) and the study protocol. I 
agree to conduct the study according to these guidelines and to appropriately direct and assist 
the staff under my control, who will be involved in the study. 
 
NAME: 
 
 
 
TITLE: 
Coordinating Investigator 
SIGNATURE: 
 
 
DATE: 
 
 
OFFICE: 
 
 
 


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SUMMARY OF CHANGES 
The current version of the protocol was released on 09 January 2017 and includes 
Amendments 1, 2 and 3. Amendment forms were prepared and are provided in Appendix 2, 
Appendix 3 and Appendix 4, respectively (Table 1). 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
07 October 2015 
Appendix 2 
2 
16 December 2015 
Appendix 3 
3 
09 January 2017 
Appendix 4 
 


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SYNOPSIS 
Name of sponsor/company: Ipsen Innovation 
Name of finished product: Lanreotide Autogel® 120 mg 
Name of active ingredient(s): Lanreotide acetate 
Title of study: Efficacy and safety of lanreotide Autogel® 120 mg administered every 14 days 
in well differentiated, metastatic or locally advanced, unresectable pancreatic or midgut 
neuroendocrine tumours having progressed radiologically while previously treated with 
lanreotide Autogel® 120 mg administered every 28 days. 
Study number: 8-79-52030-326 (CLARINET FORTE) 
Number of planned centres: 30 to 35 centres in Belgium, France, Germany, Republic of 
Ireland, Italy, Spain, the United Kingdom (UK), the Netherlands, Denmark, and Poland. 
Planned study period: 
First subject screened: Q4 2015 
Last subject, last visit: Q3 2019 
Phase of development: 
Phase II 
Objectives: 
Primary: 
 To assess progression free survival (PFS) when treated with lanreotide Autogel® 
120 mg administered every 14 days based on Response Evaluation Criteria in Solid 
Tumours (RECIST) v1.0, and according to central review. 
Secondary: 
 To evaluate the clinical and biological safety profile. 
 To evaluate time to progression. 
 To evaluate PFS rate every 12 weeks. 
 To evaluate overall survival at Week 48 and at the end of the study period in each 
cohort. 
 To evaluate the objective response rate (ORR) as per RECIST v1.0 every 12 weeks. 
 To evaluate the disease control rate (DCR) as per RECIST v1.0 at Weeks 24 and 
48 and at the end of study period in each cohort. 
 To evaluate the best overall response as per RECIST v1.0. 
 To evaluate the duration of stable disease (SD) as per RECIST v1.0. 
 To detect predictive factors of PFS. 
 To evaluate the effect on symptoms (diarrhoea, flushing). 
 To evaluate quality of life. 
 To evaluate the changes in tumour biomarkers: 
- 
pNET cohort: nonspecific tumour biomarkers (Chromogranin A (CgA), neuron 
specific enolase (NSE) and 5-hydroxyindoleacetic acid (5-HIAA); 5-HIAA only 
in subjects with symptoms of carcinoid syndrome (diarrhoea and/or flushing) or 
if urinary 5-HIAA was elevated (above upper limit of normal (ULN)) at 
Baseline) and pancreatic neuroendocrine tumours (pNET)-specific tumour 
biomarkers (e.g. pancreatic polypeptide, gastrin, glucagon, somatostatin (SST), 
…; only for the tumour biomarkers above normal range at Baseline). 
- 
Midgut cohort: nonspecific tumour biomarkers (CgA, NSE and 5-HIAA).  
 To evaluate the appearance of antilanreotide antibodies. 
 To evaluate the pharmacokinetic (PK) profile of lanreotide and to evaluate, if any, the 
relationship between PK and pharmacodynamics (PD; PFS, tumour response or CgA). 
 To evaluate, if any, the relationships between PK parameters and the safety outcomes. 
 


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Tertiary: 
 
 
  
 
 
 
Methodology:  
This is a phase II, multicentre, prospective, open label, noncomparative, exploratory study. 
Subjects with well differentiated (grade 1 or 2 according to World Health Organisation 
(WHO) 2010 classification), metastatic or locally advanced, unresectable pNET or midgut 
neuroendocrine tumours (NET) with or without hormone related syndromes and who have 
had radiologically documented disease progression (as per RECIST v1.0) at least 24 weeks 
after their first injection of lanreotide Autogel® 120 mg at the standard dosing interval of 
every 28 days will be recruited to this study. Subjects will be recruited into one of two cohorts 
based on type of NET (i.e. pancreatic or midgut). 
Following the Screening visit (Visit 1) and a Screening period of up to 28 days, where 
eligibility tests and assessments will be performed, eligible subjects will be treated with 
lanreotide Autogel® at a reduced dosing interval (i.e. 120 mg every 14 days) beginning at 
Baseline (Visit 2).  
Study visits will be performed at Weeks 2, 4, 8, 12, 24, 36 and 48 (both cohorts), and 
Weeks 60, 72, 84 and 96 (midgut cohort only). An End of Study visit is scheduled 
approximately 2 weeks after the study visit at which progression is confirmed or after 
Weeks 48 (pNET cohort) or 96 (midgut cohort) for nonprogressive subjects, once central 
review of the radiological imaging is available.  
As long as 25 events have not been observed in the respective cohorts, subjects who have not 
progressed at Week 48 (pNET cohort) or Week 96 (midgut cohort) will continue study 
treatment with lanreotide Autogel® 120 mg every 14 days and additional visits will be 
performed every 12 weeks until disease progression, death or unacceptable toxicity or 
tolerability. 
Tumour response will be assessed every 12 weeks by tumour response evaluation according 
to RECIST v1.0, measured using the same imaging technique (CT scan or MRI) for each 
subject throughout the study, and by independent central review. Additional efficacy 
assessments include symptom control (diarrhoea and flushing) and quality of life, as well as 
factors associated with PFS, and nonspecific (both cohorts) and pNET-specific (pNET cohort 
only) tumour biomarker concentrations. Safety evaluations will be performed throughout the 
study and will include the collection of clinical and biological safety data, including adverse 
events (AEs), vital signs, physical examination findings, serum haematology and 
biochemistry panels, urinalysis, and liver and pancreatic enzyme concentrations, as well as 
electrocardiogram (ECG) and gallbladder echography. PK evaluations will consist of 
lanreotide concentrations at selected timepoints throughout the study. 
 
 
 
The overall duration of the study will be approximately 102 weeks assuming at least 
25 subjects progress within 48 and 96 weeks in the 2 cohorts respectively.  
Number of subjects planned:  
It is planned to enrol a total of 100 subjects (50 subjects per cohort). 
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Diagnosis and criteria for inclusion: 
Inclusion criteria:  
1) Male or female subjects aged 18 years old or older. 
2) Histopathologically confirmed well differentiated (grade 1 or grade 2 according to the 
WHO 2010 classification), metastatic or locally advanced, unresectable pNET (pNET 
cohort) or midgut NET (midgut cohort) with or without hormone related syndromes, 
with a proliferation index (Ki67) ≤20%. 
3) Positive somatostatin receptors type 2 (SSTR2) as assessed by imaging (scintigraphy 
or positron emission tomography (PET) scan) in the organs of target lesions. 
4) Progression as assessed by an independent central reviewer according to RECIST v1.0 
from radiological imaging (CT scan or MRI) while receiving first line treatment with 
lanreotide Autogel® at a standard dose of 120 mg every 28 days for at least 24 weeks 
(6 injections). Progression must be radiologically documented using the same 
technique of images (CT scan or MRI) within 24 months prior to enrolment. Inclusion 
into the study must be within 28 days of the radiological imaging that is performed to 
document progression. 
5) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2. 
6) Provision of written informed consent prior to any study related procedures.  
7) Female subjects of childbearing potential (not surgically sterile or 2 years 
postmenopausal) must provide a negative urine pregnancy test at Screening, and use a 
medically accepted method of contraception and must agree to continue use of this 
method for the duration of the study and for 2 months after participation in the study. 
Acceptable methods of contraception include double barrier method, intrauterine 
device (IUD), or steroidal contraceptive (oral, transdermal, implanted and injected). 
8) Subjects must be willing and able to comply with study restrictions and willing to 
return to the clinic for the follow up evaluation as specified in the protocol.  
Exclusion criteria: 
1) Has poorly differentiated grade 3 NET or rapidly progressive NET (within 12 weeks 
of initiation of lanreotide Autogel® 120 mg every 28 days) as per RECIST v1.0.  
2) Has been diagnosed with VIPoma (i.e. Verner Morrison syndrome), insulinoma, 
foregut (except for pNET), hindgut NET, unknown primary NET or multiple 
endocrine neoplasms (MEN). 
3) Has progressed during treatment with somatostatin analogues (SSAs) other than 
lanreotide Autogel® 120 mg. 
4) Has been previously treated with any antitumour agent for NET other than lanreotide 
Autogel® 120 mg every 28 days: chemotherapy, molecular targeted therapy, peptide 
receptor radionuclide therapy (PRRT) or interferon. Exception made of prior treatment 
with Octreotide at standard dose stopped for other reason than disease progression. 
5) Has had major surgery related to the studied disease within 3 months prior to entering 
the study. Previous debulking surgery and liver-directed therapies are acceptable as 
long as tumour burden is measurable (other target lesions). 
6) Has symptomatic gallbladder lithiasis/sludge at Screening or a history of symptomatic 
cholelithiasis with no cholecystectomy since then. 
7) Has had previous cancer (except basocellular carcinoma of the skin and/or in situ 
carcinoma of the cervix/uterus if subjects treated with curative intent and free from 
disease for more than 5 years). 


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8) Was treated with any other investigational medicinal product (IMP) within the last 30 
days before study entry. 
9) Is pregnant or lactating.  
10) Has abnormal findings at Screening, any other medical condition(s) or laboratory 
findings that, in the opinion of the investigator, might jeopardise the subject's safety. 
11) Has any mental condition rendering the subject unable to understand the nature, scope 
and possible consequences of the study, and/or evidence of an uncooperative attitude. 
12) Has been previously screened in this study, exception made of subjects who screen-
failed following central reviewers eligibility assessment (ie non PD). 
13) Has a history of hypersensitivity to lanreotide Autogel® or drugs with a similar 
chemical structure, or any excipient used in the formulation. 
14) Is likely to require treatment during the study with drugs that are not permitted by the 
study protocol.  
15) Has a history of, or known current, problems with substance or alcohol abuse. 
16) Vulnerable subjects (i.e. subjects who are under legal protection, who are interned due 
to a mental disease and who are kept in detention). 
17) Subjects who have a link with the sponsor, the clinical trial site or the investigator 
(medical, pharmacy, dental and nursing students, subordinate hospital and laboratory 
personnel, employees of the sponsor). 
Test product, dose, mode of administration: 
Lanreotide Autogel® will be administered by deep subcutaneous (s.c.) injection at a dose of 
120 mg every 14 days. 
Duration of treatment: 
Up to 48 weeks for the pNET cohort or up to 96 weeks for the midgut NET cohort, or until 
disease progression, death or unacceptable toxicity or tolerability. Subjects in the pNET 
cohort who have not progressed at Week 48 will continue to receive lanreotide Autogel® 
every 14 days until 25 events have been observed. Similarly, subjects in the midgut cohort 
who have not progressed at Week 96 will continue to receive study treatment every 14 days 
until 25 events have been observed. 
Reference therapy, dose and mode of administration:  
Not applicable 
Criteria for evaluation: 
Efficacy: 
Primary endpoint and evaluations: 
 The primary endpoint is median PFS (defined as time from first injection of lanreotide 
Autogel® 120 mg every 14 days to progression or death). Disease progression will be 
assessed by tumour response evaluation according to RECIST v1.0, every 12 weeks, 
measured using the same imaging technique (CT scan or MRI) for each subject 
throughout the study, and by independent central review to ensure intra and intersubject 
consistency and reliability. 
Secondary endpoints and evaluations: 
 Median time to progression (defined as time from first injection of lanreotide Autogel® 
120 mg every 14 days to progression). 
 Proportion of subjects alive and without progression every 12 weeks. 
 Overall survival at Week 48 and at the end of the study for each cohort. 
 ORR every 12 weeks as per RECIST v1.0. ORR is defined as the proportion of subjects 
who achieve either complete response (CR) or partial response (PR). 




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Safety: 
 Clinical (AEs, vital signs, physical examination) and biological (serum haematology 
and biochemistry panels, liver and pancreatic enzymes, urinalysis) safety data collected 
at the timepoints specified in Table 2 (pNET cohort) and Table 3 (midgut cohort).  
 ECG at Screening, Weeks 4, 24 and 48 (pNET cohort) or 96 (midgut cohort) and at End 
of Study.  
 Gallbladder echography at Screening, and at Weeks 24 and 48 (pNET cohort) or 
96 (midgut cohort) and at End of Study, or at any time if symptoms are thought to be 
related to gallbladder lithiasis. 
 Potential relationships (if any) between PK parameters and safety outcomes. 
Pharmacokinetic: 
 Antilanreotide antibodies centrally analysed at Baseline and at the End of Study. 
 Lanreotide serum concentration assessed at:  
- 
Baseline, prior to and 2 to 3 hours after the first injection at reduced dosing 
intervals;  
- 
Week 12, prior to injection 
- 
Week 24, prior to injection in all subjects, except in a subset of 30 subjects from 
selected sites, where a sample will be collected 1 to 3 days after the injection 
instead; 
- 
Week 48, prior to and 2 to 3 hours after injection; 
- 
Week 96, prior to injection (midgut cohort only); 
- 
End of Study, prior to any administration of commercial product (if applicable). 
Statistical methods: 
The sample size in this pilot study is 100 subjects in total (50 subjects per cohort). This should 
be sufficient to explore the efficacy of lanreotide Autogel® 120 mg at a reduced dosing 
interval. For the primary efficacy endpoint, data will be analysed for each cohort separately.  
The primary efficacy analysis on median PFS (measured using RECIST v1.0 and confirmed 
via centralised review) will be performed using the Kaplan Meier estimator. In addition, the 
median PFS, with associated 95% confidence intervals (CIs) will be presented.  
All statistical analyses will be descriptive and p-values will be provided only for exploratory 
purposes. For descriptive analyses, summary statistics will be presented at each scheduled 
visit. Summary statistics will include sample size, number of available observations (N), 
number of missing observations (missing), mean, 95% CI of the mean, standard deviation 
(StD), number of nonmissing observations (n), median and range for continuous variables and 
scores. For categorical or discrete variables, the absolute and relative (percentage) numbers 
based on the nonmissing number of observations for each category will be presented, 
including 95% CIs.  
The full analysis set (FAS) will consist of all subjects who received at least one dose of 
lanreotide Autogel® 120 mg every 14 days during the study. The per protocol (PP) population 
will consist of all subjects in the FAS for whom no major protocol violations/deviations 
occurred. The PK endpoints will be analysed on the PK Valid population (i.e. all subjects who 
received at least one dose and who have at least one serum lanreotide concentration and no 
major protocol deviations affecting PK variables). Population PK (POPPK) modelling will be 
performed and a PK/PD relationship between lanreotide serum concentration and PD (PFS, 
tumour response or CgA) will be assessed, where possible. Exploratory graphs will be 
presented between PK parameters and safety outcomes. If a trend is detected, modelling 
analysis may be performed between PK and safety outcomes.  
 


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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...................................................................................... 2 
COORDINATING INVESTIGATOR’S AGREEMENT..................................................... 3 
SUMMARY OF CHANGES ................................................................................................... 4 
SYNOPSIS ................................................................................................................................ 5 
LIST OF ABBREVIATIONS ................................................................................................ 16 
1 
BACKGROUND INFORMATION ............................................................................ 20 
1.1 
Introduction ................................................................................................................... 20 
1.2 
Name and Description of Investigational Medicinal Product(s) .............................. 21 
1.3 
Findings from Nonclinical and Clinical Studies ......................................................... 21 
1.4 
Known and Potential Risks and Benefits to Human Subjects .................................. 22 
1.4.1 
Potential Benefits ........................................................................................ 22 
1.4.2 
Potential Risks ............................................................................................. 22 
1.4.2.1 
Safety ............................................................................................................ 22 
1.4.2.2 
Efficacy ........................................................................................................ 23 
1.5 
Selection of Investigational Medicinal Products and Dosages .................................. 23 
1.6 
Compliance Statement .................................................................................................. 24 
1.7 
Population to be Studied .............................................................................................. 24 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 25 
2.1 
Purpose of the Study ..................................................................................................... 25 
2.2 
Study Objectives ........................................................................................................... 25 
3 
STUDY DESIGN ........................................................................................................... 27 
3.1 
General Design and Study Schema ............................................................................. 27 
3.2 
Primary, Secondary and Tertiary Endpoints and Evaluations ................................ 30 
3.2.1 
Primary Efficacy Endpoint and Evaluation .............................................. 30 
3.2.2 
Secondary Efficacy Endpoints and Evaluations ........................................ 30 
3.2.3 
Tertiary Efficacy Endpoints and Evaluations ............................................ 31 
3.2.4 
Safety Endpoints and Evaluations ............................................................. 31 
3.2.5 
Pharmacokinetic Endpoints and Evaluations ........................................... 31 
3.3 
Randomisation and Blinding ....................................................................................... 31 
3.4 
Study Treatments and Dosage ..................................................................................... 32 
3.5 
Study Treatment Supply, Packaging and Labelling .................................................. 32 
3.6 
Study Duration .............................................................................................................. 32 
3.7 
Stopping Rules and Discontinuation Criteria ............................................................ 33 
3.8 
Investigational Medicinal Product Preparation Storage and Accountability ......... 34 
3.8.1 
Investigational Medicinal Product Storage and Security .......................... 34 
3.8.2 
Investigational Medicinal Product Preparation ........................................ 34 
3.8.3 
Investigational Medicinal Product Accountability .................................... 34 
3.9 
Maintenance of Randomisation and Blinding ............................................................ 34 


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3.10 Source Data Recorded on the Electronic Case Report Form ................................... 34 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 36 
4.1 
Inclusion Criteria .......................................................................................................... 36 
4.2 
Exclusion Criteria ......................................................................................................... 36 
4.3 
Subject Withdrawal Criteria and Procedures ........................................................... 37 
4.3.1 
 .............................................................................. 38 
5 
STUDY PROCEDURES .............................................................................................. 39 
5.1 
Study Schedule .............................................................................................................. 39 
5.2 
Study Visits .................................................................................................................... 44 
5.2.1 
Procedures for Screening (Visit 1; Day -28) .............................................. 44 
5.2.2 
Procedures for Baseline (Visit 2; Day 1) .................................................... 45 
5.2.3 
Procedures During Study Treatment ......................................................... 45 
5.2.3.1 
Visits 3, 4 and 5 (Weeks 2, 4 (±2 Days) and 8 (±7 Days)): Both Cohorts ... 46 
5.2.3.2 
Visits 6, 7, 8 and 9 (Weeks 12, 24, 36 and 48 (±7 Days)): Both Cohorts .... 46 
5.2.3.3 
Visits 10, 11, 12 and 13 (Weeks 60, 72, 84 and 96 (±7 Days)): Midgut 
Cohort Only ................................................................................................. 47 
5.2.3.4 
Additional Visits Every 12 Weeks (±7 Days) for Subjects Who Have Not 
Progressed ................................................................................................... 47 
5.2.4 
Procedures After Study Treatment ............................................................. 48 
5.2.4.1 
End of Study/Early Withdrawal Visit ........................................................... 48 
6 
TREATMENT OF SUBJECTS ................................................................................... 50 
6.1 
Study Drugs Administered ........................................................................................... 50 
6.1.1 
Investigational Medicinal Product ............................................................. 50 
6.2 
Concomitant Medication/Therapy .............................................................................. 50 
6.3 
Procedures for Monitoring Subject Compliance ....................................................... 51 
7 
ASSESSMENT OF EFFICACY .................................................................................. 52 
7.1 
Primary Efficacy Endpoint and Evaluation ............................................................... 52 
7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 52 
7.3 
Tertiary Efficacy Endpoints and Evaluations ............................................................ 53 
7.4 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 55 
7.4.1 
Time to Disease Progression or Death ....................................................... 55 
7.4.2 
Tumour Response ....................................................................................... 55 
7.4.3 
Factors Associated with PFS ...................................................................... 56 
7.4.4 
Incidence of Stools and Flushing Episodes ............................................... 56 
7.4.5 
Quality of Life ............................................................................................. 56 
7.4.6 
Tumour Biomarkers .................................................................................... 56 
8 
ASSESSMENT OF SAFETY ....................................................................................... 58 
8.1 
Adverse Events .............................................................................................................. 58 
8.1.1 
Definition of an Adverse Event .................................................................. 58 
8.1.2 
Categorisation of Adverse Events ............................................................... 58 
8.1.2.1 
Intensity Classification ................................................................................. 58 
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8.1.2.2 
Causality Classification ............................................................................... 59 
8.1.2.3 
Assessment of Expectedness ......................................................................... 59 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 59 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 59 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 59 
8.1.3 
Recording and Follow Up of Adverse Events ............................................ 59 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 60 
8.1.5 
Pregnancy .................................................................................................... 61 
8.1.6 
Deaths .......................................................................................................... 62 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 62 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 62 
8.2 
Clinical Laboratory Tests ............................................................................................ 62 
8.2.1 
Haematology ................................................................................................ 63 
8.2.2 
Blood Biochemistry ..................................................................................... 63 
8.2.3 
Urinalysis ..................................................................................................... 63 
8.2.4 
Pregnancy Test ............................................................................................ 63 
8.3 
Physical Examination ................................................................................................... 63 
8.4 
Vital Signs ...................................................................................................................... 64 
8.5 
Electrocardiography ..................................................................................................... 64 
8.6 
Gallbladder Echography .............................................................................................. 64 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 65 
9.1 
Pharmacokinetics .......................................................................................................... 65 
9.1.1 
Sample Collection ....................................................................................... 65 
9.1.2 
Analytical Procedures ................................................................................. 65 
9.2 
Putative Antibody Testing ............................................................................................ 65 
9.3 
Pharmacodynamics ....................................................................................................... 65 
10 
STATISTICS ................................................................................................................. 67 
10.1 Analyses Populations .................................................................................................... 67 
10.1.1 
Populations Analysed .................................................................................. 67 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 67 
10.2 Sample Size Determination .......................................................................................... 67 
10.3 Significance Testing and Estimations ......................................................................... 67 
10.4 Statistical/Analytical Methods ..................................................................................... 67 
10.4.1 
Demographic and Other Baseline Characteristics .................................... 68 
10.4.2 
Homogeneity of Treatment Groups ............................................................ 68 
10.4.3 
Subject Disposition and Withdrawals ......................................................... 68 
10.4.4 
Pharmacokinetic Data ................................................................................ 68 
10.4.5 
Efficacy Evaluation ..................................................................................... 68 
10.4.5.1 
Primary Efficacy Variable ........................................................................... 68 
10.4.5.2 
Secondary Efficacy Variables ...................................................................... 69 


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10.4.5.3 
Tertiary Efficacy Variables .......................................................................... 71 
10.4.6 
Adjustment for Country/Centre Effect ....................................................... 71 
10.4.7 
Safety Evaluation ........................................................................................ 71 
10.5 Subgroup Analyses ....................................................................................................... 72 
10.6 Interim Analyses ........................................................................................................... 72 
11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 74 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 75 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................... 75 
12.1.1 
Protocol Amendments ................................................................................. 75 
12.1.2 
Protocol Deviations, Violations, and Exceptions ....................................... 75 
12.2 Information to Study Personnel .................................................................................. 75 
12.3 Study Monitoring .......................................................................................................... 75 
12.4 Audit and Inspection .................................................................................................... 76 
12.5 Data Quality Assurance ................................................................................................ 76 
13 
ETHICS ......................................................................................................................... 77 
13.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 77 
13.2 Informed Consent ......................................................................................................... 77 
13.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 78 
13.4 Confidentiality Regarding Study Subjects ................................................................. 78 
14 
DATA HANDLING AND RECORD KEEPING ....................................................... 79 
14.1 Data Recording of Study Data ..................................................................................... 79 
14.2 Data Management ......................................................................................................... 79 
14.3 Record Archiving and Retention ................................................................................. 80 
15 
FINANCING AND INSURANCE ............................................................................... 81 
15.1 Contractual and Financial Details ............................................................................... 81 
15.2 Insurance, Indemnity and Compensation .................................................................. 81 
16 
REPORTING AND PUBLICATIONS OF RESULTS ............................................. 82 
16.1 Publication Policy ......................................................................................................... 82 
16.2 Clinical Study Report ................................................................................................... 82 
17 
REFERENCES .............................................................................................................. 83 
18 
LIST OF APPENDICES .............................................................................................. 85 
 


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LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Study Procedures and Assessments (pNET Cohort) ........................................ 40 
Table 3 
Study Procedures and Assessments (Midgut Cohort) ...................................... 42 
Table 4 
Primary, Secondary and Tertiary Efficacy Endpoints and Evaluations ....... 53 
Table 5 
Overall Response ................................................................................................. 55 
Table 6 
Censoring Rules for PFS ..................................................................................... 69 
Table 7 
Censoring Rules for Median Time to Progression ........................................... 69 
Table 8 
Censoring Rules for Median Duration of Stable Disease ................................ 70 
 
LIST OF FIGURES 
Figure 1 
Study Schema ....................................................................................................... 29 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
5-HIAA 
5-hydroxyindoleacetic acid 
βHCG 
Beta human chorionic gonadotropin 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
CA(s) 
Competent Authority(ies) 
CFR 
Code of Federal Regulations (United States of America) 
CgA 
Chromogranin A 
CHDR 
Centre for Human Drug Research 
CI 
Confidence interval 
CLARINET 
Controlled Study of Lanreotide Anti-proliferative Response in 
Neuroendocrine Tumours 
Cmax 
Maximum concentration 
CMC-SC 
Chemistry, Manufacturing and Control Supply Chain 
CR 
Complete response 
CRO 
Contract research organisation 
CSR 
Clinical study report 
CT 
Computed tomography 
DCR 
Disease control rate 
 
 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EORTC 
European Organisation into the Research and Treatment of Cancer 
EQ-5D-5L 
EuroQoL 5 dimensions, 5 levels 
EU 
European Union 
FAS 
Full analysis set 
CCI


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LIST OF ABBREVIATIONS (Cont.) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDP 
Good Distribution Practice 
GEP NETs 
Gastroenteropancreatic neuroendocrine tumours 
GH 
Growth hormone 
GI 
Gastrointestinal 
HR 
Hazard ratio 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional review board 
ISF 
Interim Storage Facility  
IUD 
Intrauterine device 
Ki67 
Proliferation index 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN 
Multiple endocrine neoplasms 
MRI 
Magnetic resonance imaging 
N 
Number of available observations 
NCI 
National Cancer Institute  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NE 
Not evaluable  
NET 
Neuroendocrine tumours 
NOS 
Not otherwise specified 
NSE 
Neuron specific enolase 
ORR 
Objective response rate 
PD 
Pharmacodynamic 
PDD 
Protocol deviation document 


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LIST OF ABBREVIATIONS (Cont.) 
PDM 
Pharmacokinetics and Drug Metabolism 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
pNET 
Pancreatic NET 
POPPK 
Population PK 
PP 
Per protocol 
PR 
Partial response 
PRRT 
Peptide receptor radionuclide therapy 
PS 
Performance Status 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QLQ-GI.NET21 
Quality of Life Questionnaire Gastrointestinal Neuroendocrine 
Tumour 21 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumours 
 
 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System® 
s.c. 
Subcutaneous 
SD 
Stable disease 
SOP 
Standard Operating Procedure 
SSA 
Somatostatin analogue 
SST 
Somatostatin 
SSTR 
Somatostatin receptor 
StD 
Standard deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment emergent adverse event 
TFL 
Tables, figures and listings 
 
 
TMF 
Trial master file 
UK 
United Kingdom 
CCI
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LIST OF ABBREVIATIONS (Cont.) 
ULN 
Upper limit of normal 
USA 
United States of America 
WBC 
White blood cell(s) 
WHO 
World Health Organisation 
WHO-DD 
World Health Organisation drug dictionary 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction  
Neuroendocrine tumours (NETs) are a heterogeneous and rare group of malignancies 
originating from neural crest cells, endocrine glands, endocrine islets or in the diffuse 
neuroendocrine system. Although NETs may develop in almost any organ, they predominate 
within the pancreas and the gastrointestinal (GI) tract. Their incidence is increasing, 
approaching 5.25 cases per 100,000 per year [1, 2]. They are usually located in the GI tract 
(53%), but are also seen in the pancreas (7%) and pulmonary bronchii (27%). 
Gastroenteropancreatic neuroendocrine tumours (GEP NETs) constitute a heterogeneous 
group which can be clinically divided into tumours producing hormone related syndromes and 
those not associated with hormonal syndromes. 
Tumours within the GI tract are predominantly of enterochromaffin (Kulchitsky) cell origin. 
Tumours arising at diverse sites demonstrate a similar histological appearance, with numerous 
membrane bound secretory granules within the cell cytoplasm. These granules secrete 
neuroendocrine markers such as chromogranin A (CgA), neuron specific enolase (NSE) and 
synaptophysin. The majority of NETs demonstrate a low proliferation rate and evolve in an 
indolent fashion. Morphologic features suggesting malignancy (cellular pleomorphism, 
hyperchromatic nuclei, necrosis, and high mitotic activity) are not often seen. However, some 
studies have shown that these tumours result in significant morbidity and mortality by local 
disease progression, distant metastatic spread, most particularly to the liver, and the 
development of associated hormonal syndromes. 
Surgery is the mainstay of treatment for resectable disease. However, since many of these 
patients have inoperable disease, medical therapy is often initiated to control disease 
progression. Therapeutic options for patients with advanced or metastatic GEP NETs have 
improved in recent years. 
Somatostatin analogues (SSAs), such as lanreotide and octreotide, are considered the therapy 
of choice in controlling symptoms associated with NETs. With recent antitumour evidence, 
the role of SSAs has expanded from the treatment of the carcinoid syndrome's symptoms to 
control of tumour growth.  
In the Controlled Study of Lanreotide Anti-proliferative Response in Neuroendocrine Tumors 
(CLARINET) [3], the antitumour effect of lanreotide 120 mg every 28 days was investigated 
in more than 200 patients with somatostatin receptor (SSTR) positive enteropancreatic NETs 
(including 45% of patients with pancreatic NET (pNET) and 36% with midgut), without 
hormonal symptoms and with proliferation index (Ki67) values of less than 10% (including 
30% of patients with Ki67 between 3% and 10%). Progression free survival (PFS) was 
significantly prolonged with lanreotide as compared with placebo: median PFS, not reached at 
24 months with lanreotide versus 18.0 months for placebo (95% confidence interval (CI), 12.1 
to 24.0; p<0.001). 
Based on the CLARINET results, lanreotide Autogel® 120 mg every 28 days is approved in 
the European Union (EU) for the treatment of grade 1 and a subset of grade 2 (Ki67 index up 
to 10%) GEP NETs of midgut, pancreatic or unknown origin where hindgut sites of origin 
have been excluded, in adult patients with unresectable locally advanced or metastatic 
disease, as well as the treatment of symptoms associated with neuroendocrine (particularly 
carcinoid) tumours [4]. In the United States of America (USA), lanreotide Autogel® 120 mg 
every 28 days is approved for the treatment of patients with unresectable, well or moderately 
differentiated, locally advanced or metastatic GEP NETs to improve PFS [5]. 


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However, patients treated at this standard dosing regimen may experience disease 
progression. Molecular targeted therapies sunitinib (Sutent®, multiple receptor kinases 
inhibitor) and everolimus (Affinitor®, mTOR inhibitor) have recently demonstrated their 
efficacy in progressive well differentiated pNET, leading to their authorisation in the EU and 
the USA. However, the safety profile of molecular targeted therapies is less favourable than 
the SSAs. In addition, molecular targeted therapies, such as everolimus or sunitinib, are 
currently indicated for pNET only, as they have not demonstrated so far any PFS benefit in GI 
NETs. Dose escalation of SSAs or reduced dosing interval of lanreotide could thus postpone 
the use of more aggressive therapies in progressive pNETs and represent an alternative for 
progressive GI NETs. 
Increasing the dose of SSAs or reducing the interval between injections is a relatively 
common clinical practice in patients with NETs; however, no studies have yet been conducted 
with the primary objective of assessing efficacy and safety of such dose regimen 
modifications of lanreotide. The aim of this study is to explore the efficacy and safety of 
lanreotide Autogel® 120 mg when administered at a reduced dose interval (i.e. every 14 days) 
in subjects who progress while treated with lanreotide Autogel® at the approved dose interval 
of 120 mg every 28 days. A reduction in lanreotide Autogel® dosing interval may achieve 
radiological stabilisation, postpone the use of aggressive and less tolerated targeted and 
systemic therapies, and improve the quality of life of subjects with well differentiated, 
metastatic or locally advanced, unresectable pancreatic or midgut NETs who have progressed 
on a standard dose of lanreotide Autogel® (i.e. 120 mg every 28 days). 
1.2 
Name and Description of Investigational Medicinal Product(s) 
Lanreotide is a synthetic octapeptide analogue of somatostatin (SST) with a longer half life 
than the native molecule. Compared to SST, the biochemical stability, and thereby the half 
life of this synthetic molecule has been increased by the incorporation of modified amino 
acids. In the same way as the native hormone, lanreotide inhibits the secretion of a variety of 
hormones, including growth hormone (GH), and has direct and indirect antiproliferative 
activities (e.g. inhibition of growth factors and growth promoting hormones, antiangiogenic 
and immunomodulatory effects) [6, 7, 8, 9]. Lanreotide has a high affinity for human SST 
receptors 2 and 5. The presence of SST receptors in NETs and the suppressive effect of SST 
on the active substances secreted by these tumours (e.g. serotonin and tachykinins) provide 
the pharmacological rationale for using SSAs, such as lanreotide, to treat the symptoms 
associated with carcinoid syndrome. Furthermore, lanreotide has been shown to stabilise 
tumour size in patients with NETs. 
Lanreotide Autogel® is a prolonged release, pharmaceutical form of lanreotide. The Autogel 
formulation has been developed for two main reasons. Firstly, its characteristics of a smoother 
and more extended release of lanreotide permit an injection interval of 28 days. Secondly, the 
formulation has the advantage of providing a ready to use deep subcutaneous (s.c.) injection. 
The formulation is a supersaturated solution for injection supplied as a prefilled 
polypropylene syringe with a stainless steel needle. Further details can be found in the current 
Investigator’s Brochure (IB). 
1.3 
Findings from Nonclinical and Clinical Studies 
The antiproliferative activity of SSAs has been reported both in vitro and in vivo. Several 
studies have shown a growth inhibiting effect of SSAs on tumour cells: activation of SSTRs, 
SSTR1, SSTR2 and SSTR5 induced antimitotic effects in most cell types [10, 11] whereas 
SSTR3 mediated apoptosis in endocrine cells [12, 13].  
In patients with advanced neuroendocrine GI tumours, induction of apoptosis, determined by 
pre and post-treatment biopsy, was observed in patients who were treated with high doses of 


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lanreotide and who showed a biochemical response [14]. Tumour regression has been 
reported in 5% to 10% of patients with GEP NETs, while stabilisation of tumour size has been 
reported in 36% to 70% of patients [15]. Furthermore, lanreotide Autogel® has also been 
shown to be effective for symptom control, biochemical markers and tumour progression 
associated with NETs [16] (data on file). 
In the phase III, double blind CLARINET study conducted in 204 subjects with 
enteropancreatic NETs not associated with hormonal syndromes, treatment with lanreotide 
Autogel® (120 mg every 28 days for up to 96 weeks) led to statistically significantly longer 
PFS than placebo treatment (not reached at 24 months for lanreotide versus 18 months for 
placebo; p<0.001). Based on Kaplan Meier estimates, 34.9% of subjects had progressed or 
died in the lanreotide Autogel® group compared with 77% of patients in the placebo group. 
Furthermore, treatment with lanreotide Autogel® reduced the risk of progression or death by 
53% (hazard ratio (HR): 0.47; 95% CI: 0.30, 0.73; data on file). 
1.4 
Known and Potential Risks and Benefits to Human Subjects 
1.4.1 
Potential Benefits 
Lanreotide Autogel® (120 mg every 28 days) has shown a positive effect in the relief of 
clinical symptoms associated with carcinoid syndrome and for tumour control of GEP NETs. 
The main potential benefit of lanreotide Autogel® at a reduced dosing interval (120 mg every 
14 days) is that radiological stabilisation may be achieved in participating subjects with 
GEP NETs who have progressed on a standard dose of lanreotide Autogel® 120 mg every 
28 days, thereby postponing the use of aggressive and less tolerated systemic chemotherapy 
or molecular targeted therapies that may negatively impact on quality of life. 
A pharmacokinetic (PK)/pharmacodynamic (PD) model generated from CLARINET data 
revealed a relationship between lanreotide concentrations and change in CgA. In addition, a 
quantitative model showed a relationship between change in CgA and PFS. Predictions from 
this PK/PD model showed that a reduction in the dosing interval of lanreotide may be of 
clinical benefit to the GEP NET population (data on file). 
1.4.2 
Potential Risks 
1.4.2.1 
Safety 
Although reducing the dosing interval would not increase the dose of lanreotide administered 
at each injection, the safety profile of lanreotide Autogel® is not established for this regimen. 
Analyses looking at the relationship between lanreotide PK parameters (maximum 
concentration (Cmax) and area under the curve (AUC)) and probability of occurrence of some 
adverse events (AEs; GI and injection site reactions) in lanreotide studies have been 
conducted. No relationship was observed between occurrence of AEs and exposure to 
lanreotide (data on file). In addition, no new safety signals have been reported in an ongoing 
externally sponsored study (EudraCT Number: 2012-005222-30 17]) assessing the 
antiproliferative effect of lanreotide Autogel® 180 mg administered every 28 days in a similar 
population. To date, 34 subjects with progressive GEP NETs and previously treated with 
octreotide LAR 30 mg every 28 days or lanreotide Autogel® 120 mg every 28 days have been 
enrolled in this ongoing study (EudraCT Number: 2012-005222-30 [17]). 
For information on potential adverse effects of lanreotide on heart rate, injection site, 
gallbladder and pancreas, glycoregulation and thyroid function please refer to the current IB 
(Summary of Data and Guidance for the Investigator, Section 6.4). 


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1.4.2.2 
Efficacy 
Despite patients deriving initial clinical benefit from treatment with lanreotide Autogel® 
120 mg every 28 days, it is not certain that further antitumoural effects will be achieved by 
reducing the dosing interval. The positive antitumour effect observed in the CLARINET study 
may have been maximal at a dose of 120 mg every 28 days and increasing the lanreotide 
exposure by reducing the dosing interval in patients progressing while being treated at the 
standard dose may not bring any further benefit.  
Additionally, tachyphylaxis which may result from desensitisation or downregulation of SST 
receptors on the cell surface, resistance associated with the formation of antibodies to the 
SSA, or SST receptor gene mutations, have previously been reported on SSA treatment [18, 
19, 20]. 
Additional information regarding risks and benefits to human subjects may be found in the 
current IB. 
1.5 
Selection of Investigational Medicinal Products and Dosages 
The dosage to be evaluated in this multicentre, prospective, open label, noncomparative, two 
cohort study (i.e. 120 mg injected every 14 days for up to 48 weeks (pNET) cohort) or 
96 weeks (midgut cohort)) was selected on the basis of data from the CLARINET study, and 
an ongoing externally sponsored study (EudraCT Number: 2012-005222-30 [17]). These 
studies demonstrated that doses of lanreotide Autogel® of 120 to 180 mg every 28 days were 
well tolerated. In addition, increasing the dose of SSAs or reducing the interval between 
injections is relatively common clinical practice in patients with progressive advanced NETs. 
The reduction in dosing interval, and consecutive increase in lanreotide concentration, was 
anticipated to achieve radiological stabilisation in subjects with pNETs or midgut NETs who 
have progressed on the standard dose of lanreotide Autogel®. 
Increasing the exposure to lanreotide Autogel® 120 mg can be obtained either by 
administering two injections every 28 days, or by reducing the dosing interval to every 
21 days or 14 days.  
A simulation of the PK profile of lanreotide Autogel® 120 mg administered every 14 days 
showed a mean exposure (Cmax at steady state) within the range of that observed in subjects 
with NET who received a dose of 120 mg every 28 days (19 ng/mL versus 14 ng/mL, 
respectively), whereas the simulated mean exposure of 240 mg every 28 days was much 
higher. In terms of exposure (i.e. lower Cmax), administration of lanreotide Autogel® 120 mg 
every 14 days is thus preferable to 240 mg every 28 days.  
Furthermore, a study in healthy volunteers evaluated the PK profile of a single administration 
of 240 mg lanreotide in a new Autogel® formulation [21]. Drug related AEs were experience 
by five of 16 subjects in the lanreotide group (including two serious AEs (SAEs)), compared 
with one subject in the placebo group. The type of AEs that occurred during the study was 
broadly consistent with the expected safety profile for lanreotide Autogel®. Some of the 
effects were exaggerated or of a higher incidence (GI disorders such as abdominal pain, 
indurations at site injection), and this is likely to be linked with the higher Cmax observed after 
administration of the new lanreotide Autogel® 240 mg formulation. Five cases of gallbladder 
abnormalities (from sludge to cholelithiasis) were observed (four subjects treated with 
lanreotide Autogel®, one with placebo), including two subjects treated with lanreotide 
Autogel® who experienced cholelithiasis occurring more than 4 months after this single 
injection. These AEs/SAEs did not correlate with the Cmax (mean Cmax was around 25 ng/mL) 
or with the AUC. These safety signals also favoured reducing the dosing interval to 120 mg 
every 14 days rather than increasing the dose to 240 mg every 28 days. 


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A more detailed description of administration procedures is given in Section 6.1. 
1.6 
Compliance Statement 
The study will be conducted in compliance with independent ethics committees/institutional 
review boards (IECs/IRBs), informed consent regulations, the Declaration of Helsinki and 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. 
Any episode of noncompliance will be documented. The electronic data capture (EDC) 
system will comply with the Food and Drug Administration (FDA), 21 Code of Federal 
Regulations (CFR) Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance 
for Industry: Computerised Systems Used in Clinical Trials. In addition, the study will adhere 
to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent forms, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided 
to subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
1.7 
Population to be Studied 
The study will enrol adult subjects with histopathologically confirmed well differentiated 
(grade 1 or 2 according to World Health Organisation (WHO) 2010 classification), metastatic 
or locally advanced, unresectable pancreatic or midgut NETs with or without hormone related 
syndromes and who have had radiologically documented (computed tomography (CT) scan or 
magnetic resonance imaging (MRI)) disease progression (as per Response Evaluation Criteria 
in Solid Tumours (RECIST) v1.0) at least 24 weeks after their first injection of lanreotide 
Autogel® (120 mg every 28 days). 


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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
This study (CLARINET FORTE) aims to explore the efficacy and safety of a reduced 
lanreotide Autogel® dosing interval (120 mg every 14 days) in subjects with grade 1 or 2 
(according to WHO 2010 classification), metastatic or locally advanced unresectable 
pancreatic or midgut NETs once they have progressed on the standard dose of lanreotide 
Autogel® (120 mg every 28 days).  
Currently, patients with progressive disease after treatment with lanreotide Autogel® (120 mg 
every 28 days) have limited treatment options and receive aggressive and less tolerated 
systemic chemotherapy or molecular targeted therapies, such as everolimus or sunitinib. As 
lanreotide has a favourable tolerability profile, a reduced dosing interval might delay the need 
for such therapies and could potentially improve a patient's quality of life. 
2.2 
Study Objectives 
The primary objective of the study is to assess PFS when treated with lanreotide Autogel® 
120 mg administered every 14 days based on RECIST v1.0, and according to central review. 
The secondary objectives of the study are as follows: 
• 
To evaluate the clinical and biological safety profile. 
• 
To evaluate time to progression. 
• 
To evaluate PFS rate every 12 weeks. 
• 
To evaluate overall survival at Week 48 and at the end of the study period in each 
cohort. 
• 
To evaluate the objective response rate (ORR) as per RECIST v1.0 every 12 weeks. 
• 
To evaluate the disease control rate (DCR) as per RECIST v1.0 at Weeks 24 and 48 
and at the end of study period in each cohort. 
• 
To evaluate the best overall response as per RECIST v1.0. 
• 
To evaluate the duration of stable disease (SD) as per RECIST v1.0. 
• 
To detect predictive factors of PFS. 
• 
To evaluate the effect on symptoms (diarrhoea, flushing). 
• 
To evaluate quality of life. 
• 
To evaluate the changes in tumour biomarkers: 
- 
pNET 
cohort: 
nonspecific 
tumour 
biomarkers 
(CgA, 
NSE 
and 
5-hydroxyindoleacetic acid (5-HIAA); 5-HIAA only in subjects with symptoms 
of carcinoid syndrome (diarrhoea and/or flushing) or if urinary 5-HIAA was 
elevated (above upper limit of normal (ULN)) at Baseline) and pNET-specific 
tumour biomarkers (e.g. pancreatic polypeptide, gastrin, glucagon, SST, …; only 
for the tumour biomarkers above normal range at Baseline). 
- 
Midgut cohort: nonspecific tumour biomarkers (CgA, NSE and 5-HIAA). 
• 
To evaluate the appearance of antilanreotide antibodies.  
• 
To evaluate the PK profile of lanreotide and to evaluate, if any, the relationship 
between PK and PD (PFS, tumour response or CgA).  
• 
To evaluate, if any, the relationships between PK parameters and the safety outcomes.  


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The tertiary objectives of the study are as follows: 
• 
 
  
 
. 
CCI


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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a phase II, multicentre, prospective, open label, noncomparative, exploratory study to 
evaluate the efficacy and safety of lanreotide Autogel® at a reduced dosing interval of 120 mg 
every 14 days in adults with well differentiated (grade 1 or 2 according to WHO 2010 
classification), metastatic or locally advanced, unresectable pNET or midgut NET with or 
without hormone related syndromes and who have had radiologically documented disease 
progression (as per RECIST v1.0) at least 24 weeks after their first injection of lanreotide 
Autogel® 120 mg at the standard dosing interval of every 28 days. Subjects will be recruited 
into one of two cohorts based on primary location of NET (i.e. pancreatic or midgut). 
The study will consist of a Screening visit (Day -28), where informed consent will be taken, 
followed by a Screening period of up to 28 days, where eligibility tests and assessments will 
be performed. At Baseline (Visit 2), subject eligibility will be verified and Baseline 
assessments will be performed, followed by an open label treatment period. Eligible subjects 
will be treated with lanreotide Autogel® at a reduced dosing interval (i.e. 120 mg every 
14 days) beginning at Visit 2. Subjects in the pNET cohort will be treated for up to 48 weeks 
and subjects in the midgut cohort will be treated for up to 96 weeks. In both cohorts, treatment 
will be discontinued at disease progression or death, or unacceptable toxicity or tolerability.  
Study visits will be performed at Weeks 2, 4, 8, 12, 24, 36 and 48 (both cohorts), and 
Weeks 60, 72, 84 and 96 (midgut cohort only). As long as 25 events have not been observed 
in the respective cohorts, subjects who have not progressed at Week 48 (pNET cohort) or 
Week 96 (midgut cohort) will continue study treatment with lanreotide Autogel® 120 mg 
every 14 days and additional visits will be performed every 12 weeks until disease 
progression or death, or unacceptable toxicity or tolerability.  
An End of Study visit is scheduled approximately 2 weeks after the study visit at which 
progression is confirmed or after Weeks 48 (pNET cohort) or 96 (midgut cohort) for 
nonprogressive subjects, once central review of the radiological imaging is available. Subjects 
still benefiting from treatment at the End of Study visit will have the option to continue on 
commercial product at the discretion of the investigator.  
'Injection only' visits will not be considered as study visits; however, for subjects who will be 
administered the investigational medicinal product (IMP) at home, the date and time of 
injection will be recorded in a subject diary card by the healthcare professional administering 
the injection and will be returned to the investigational site and entered into the electronic 
case report form (eCRF). Any AEs reported at these visits will be transmitted by the 
healthcare professional administering the injection to the responsible investigational site staff 
on the same day to be recorded on the eCRF, reported to the sponsor (if a serious adverse 
event (SAE)), and followed up as appropriate by the responsible investigational site staff. 
A data safety monitoring board (DSMB) covering both cohorts combined will be appointed to 
review data, as determined in the DSMB charter, at the following timepoints: (1) when 
20 subjects from both cohorts have reached the Week 4 evaluation, (2) when 20 subjects from 
both cohorts have reached the Week 12 evaluation, and (3) when 50 subjects from both 
cohorts have reached the Week 12 evaluation. 
Subjects who complete all scheduled visits or who have progressed or died will be considered 
to have completed the study.  
For all subjects, with the exception of those who have died, final evaluations will be 
performed at the End of Study visit approximately 2 weeks (±7 days) after the subject's last 
treatment visit, once central review of radiological imaging data is available. 


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The study schema is provided in Figure 1.


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Figure 1 Study Schema 
 
 


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3.2 
Primary, Secondary and Tertiary Endpoints and Evaluations 
3.2.1 
Primary Efficacy Endpoint and Evaluation 
The primary endpoint is median PFS (defined as time from first injection of lanreotide 
Autogel® 120 mg every 14 days to progression or death). Disease progression will be assessed 
by tumour response evaluation according to RECIST v1.0, every 12 weeks, measured using 
the same imaging technique (CT scan or MRI) for each subject throughout the study, and by 
independent central review to ensure intra and intersubject consistency and reliability. 
3.2.2 
Secondary Efficacy Endpoints and Evaluations 
• 
Median time to progression (defined as time from first injection of lanreotide Autogel® 
120 mg every 14 days to progression). 
• 
Proportion of subjects alive and without progression every 12 weeks. 
• 
Overall survival at Week 48 and at the end of the study for each cohort. 
• 
ORR every 12 weeks as per RECIST v1.0. ORR is defined as the proportion of subjects 
who achieve either complete response (CR) or partial response (PR). 
• 
DCR evaluated according to RECIST v1.0 at Weeks 24 and 48 and at the end of study 
period in each cohort. The DCR is defined as the rate of CR plus PR plus SD. 
• 
Best overall response according to RECIST v1.0 (defined as the best response recorded 
from the initiation of treatment until disease progression). 
• 
Median duration of SD according to RECIST v1.0 (defined as the time from first 
injection of lanreotide Autogel® 120 mg every 14 days until the first occurrence of 
progressive disease by central assessment). 
• 
Factors associated with PFS will include but will not be limited to: hepatic tumour 
volume ≤25% versus >25%, grade 1 versus grade 2, previous surgery of the primary 
tumour (yes/no), Ki67 <10% versus ≥10%, duration of treatment with lanreotide 
Autogel® 120 mg every 28 days. 
• 
Symptom control (diarrhoea, flushing) at Baseline, Weeks 8 and 12 and every 12 weeks 
thereafter, and at the End of Study visit, as measured by the total number of stools and 
flushing episodes during the 7 days prior to the visit reported orally by the subject to 
the investigator. 
• 
Quality of life measured at Baseline, Week 12 and every 12 weeks thereafter, and at the 
End of Study visit, after diagnosis of progression, using European Organisation into the 
Research and Treatment of Cancer (EORTC), Quality of Life Questionnaire Core 
30 (QLQ-C30) v3.0 and Quality of Life Questionnaire Gastrointestinal Neuroendocrine 
Tumour 21 (QLQ-GI.NET21; 2006), and EuroQoL 5 dimensions, 5 levels (EQ-5D-5L) 
v1.0 questionnaires. 
• 
pNET cohort:  
- 
nonspecific tumour biomarkers (CgA, NSE and 5-HIAA) at Baseline, every 
12 weeks thereafter and at the End of Study visit (plasma 5-HIAA at all 
scheduled visits; urinary 5-HIAA at Baseline, Week 12 and at the End of Study 
visit only). Note: at all scheduled visits, except Baseline, plasma/urinary 5-HIAA 
should only be performed in subjects with symptoms of carcinoid syndrome 
(diarrhoea and/or flushing) or if urinary 5-HIAA was elevated (above ULN) at 
Baseline. 




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3.4 
Study Treatments and Dosage 
The test product, lanreotide Autogel® 120 mg, will be administered as deep s.c. injections 
every 14 days starting at Visit 2 for up to 48 weeks (pNET cohort) or up to 96 weeks (midgut 
cohort) or until disease progression, death or unacceptable toxicity or tolerability. 
Subjects in the pNET cohort who have not progressed at Week 48 will continue to receive 
lanreotide Autogel® every 14 days until 25 events in the pNET cohort have been observed. 
Similarly, subjects in the midgut cohort who have not progressed at Week 96 will continue to 
receive study treatment every 14 days until 25 events in the midgut cohort have been 
observed.  
A more detailed description of administration procedures is given in Section 6.1.  
3.5 
Study Treatment Supply, Packaging and Labelling 
Lanreotide Autogel® will be packaged by the Chemistry, Manufacturing and Control Supply 
Chain (CMC-SC; 
) and 
delivered to the investigational sites or deposited in an Interim Storage Facility (ISF). A 
sufficient quantity of lanreotide Autogel® will be supplied as well as an acknowledgement of 
receipt form.  
The sponsor’s representative will receive a Certificate of Analysis for which batch of 
lanreotide Autogel® has been used under their study, Material Data Safety Sheet for lanreotide 
Autogel®, Packaging Order which reflects the product release statement.  
The core label texts for all packaging units will be translated or adjusted, to be in compliance 
with applicable regulatory requirements, national laws in force and in accordance with the 
local languages. 
A description of the core text of the lanreotide Autogel® label is displayed below: 
• 
Sponsor name 
• 
Study Number 
• 
Pharmaceutical dosage form 
• 
Route of administration 
• 
Quantity of dose units 
• 
Batch number 
• 
A treatment number 
• 
A specific blank space to enter the subject ID 
• 
“Keep out of reach of children” 
• 
“For clinical study use only” 
• 
“Caution: new drug limited by Federal Law to investigational use”  
• 
Name, address and telephone number of the sponsor (the main contact for information 
on the product and clinical study) 
• 
Storage conditions 
• 
Expiry date 
The investigator, or designee, will only dispense lanreotide Autogel® to subjects included in 
this study. Each subject will only be given the lanreotide Autogel® carrying his/her subject 
number. The dispensing for each subject will be documented on the eCRF. 
3.6 
Study Duration 
This study will consist of a Screening period of up to 28 days, a Baseline Visit (Visit 2), 
followed by an open label treatment period of up to 48 weeks (pNET cohort) or up to 
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96 weeks (midgut cohort), and a final End of Study visit approximately 2 weeks after the last 
treatment visit.  
Each subject will participate in the study treatment phase for up to 48 weeks (pNET cohort) or 
up to 96 weeks (midgut cohort), or longer (i.e. until 25 events have been observed) for 
subjects who have not progressed within this time. The overall duration of the study will be 
approximately 102 weeks assuming at least 25 subjects progress within 48 and 96 weeks in 
the 2 cohorts respectively.  
The subject’s participation in the study will be considered to have ended at the time of their 
last visit (End of Study) or death. 
The study will be considered to have started when the first subject has provided signed 
informed consent. 
The study will be considered to have ended after the last subject has completed the End of 
Study visit. 
3.7 
Stopping Rules and Discontinuation Criteria 
A DSMB covering both cohorts combined will review data in line with the DSMB charter at 
the following timepoints: (1) when 20 subjects from both cohorts have reached the Week 4 
evaluation, (2) when 20 subjects from both cohorts have reached the Week 12 evaluation, and 
(3) when 50 subjects from both cohorts have reached the Week 12 evaluation. The purpose of 
the DSMB will be to evaluate safety early (Week 4) and at steady state (Week 12) of the 
reduced dosing interval, and to make recommendations to the sponsor as to whether the study 
should continue as planned or whether any changes are recommended to the trial conduct or 
protocol. The Chair of the DSMB will be responsible for communicating the DSMB’s 
recommendations. Full details of the operating model for the DSMB will be provided in a 
DSMB charter.  
A subject may discontinue participation in the study at any time for any reason (for example 
lack of efficacy, withdrawal of consent, AE). The investigator and/or sponsor can withdraw a 
subject from the study at any time for any reason (for example protocol violation or deviation 
as defined in Section 12.1.2, noncompliance with the protocol conditions or AE).  
The investigator should assess the ongoing benefit risk for each subject during their 
participation in the study, in consideration of any adverse events and the potential benefit of 
continued treatment with the study drug or any alternative therapies.  
The study drug should be temporary discontinued in case of: 
• 
Severe unremitting gastrointestinal intolerance: NCI CTCAE grade ≥3 diarrhoea 
(Increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; 
severe increase in ostomy output compared to baseline; limiting self care ADL) or 
vomiting (≥6 episodes (separated by 5 minutes) in 24 hrs; tube feeding, TPN or 
hospitalization indicated) despite optimal antidiarrheal or antiemetic treatment. 
• 
Poorly controlled diabetes mellitus: NCI CTCAE grade ≥4 hyperglycaemia (blood 
glucose >500 mg/dL, >27.8 mmol/L) that does not resolve to CTCAE grade ≤2 (fasting 
glucose ≤250 mg/dL, ≤13.9 mmol/L) within 14 consecutive days after starting optimal 
antidiabetic treatment. 
• 
Pancreatitis: NCI CTCAE grade ≥3 amylase (>2 x ULN) or lipase (>2 x ULN) with 
symptoms, or for >7 consecutive days without symptoms. 
• 
Acute renal injury: NCI CTCAE grade ≥3; Creatinine >3x baseline or >4.0 mg/dL or 
hospitalization indicated. 


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• 
Hepatic impairment: NCI CTCAE grade ≥3 ALT (>5 x ULN) or AST (>5 x ULN) or 
Bilirubin (> 3 x ULN). 
• 
Any other adverse event or lesser severity of the adverse events listed above that, in the 
opinion of the investigator, could jeopardise the subject's safety. 
The Investigator should assess whether permanent discontinuation or reintroduction of study 
drug is appropriate in the event of recovery from any such adverse event, considering the 
assessment of the relationship to the study drug, underlying disease, intercurrent illness or 
concomitant medications, and the overall benefit risk for the subject continuing in the study. 
Subjects recommencing study drug may, if appropriate, re-start with an initial interval of 
28 days between the first and second dose, before returning to the dosing interval of 14 days. 
3.8 
Investigational Medicinal Product Preparation Storage and Accountability 
3.8.1 
Investigational Medicinal Product Storage and Security 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all study 
drug is stored in a secured area, under recommended temperature monitored storage 
conditions (between +2°C and +8°C), in accordance with applicable regulatory requirements. 
Details of storage and distribution of study drug for injections performed at the subject's home 
are provided in Section 6.1. 
3.8.2 
Investigational Medicinal Product Preparation 
Lanreotide Autogel® is supplied as a ready to use syringe, therefore no preparation is 
required. The investigator, or an approved representative (e.g. pharmacist), will ensure that all 
lanreotide Autogel® is dispensed by qualified staff members. 
3.8.3 
Investigational Medicinal Product Accountability 
All study drug is to be accounted for on the accountability log provided by the sponsor. It is 
essential that all used and unused supplies are retained for safety and hygiene reasons and that 
syringes are eliminated in dedicated secure waste boxes, immediately after injection. These 
boxes will be destroyed according to normal practices for this category of injection waste. The 
destruction of unused study drugs and the outer boxes of the used study drugs should be 
performed by the sponsor or its representative. Study drug will be destroyed preferably on site 
or returned to CMC-SC (
). 
3.9 
Maintenance of Randomisation and Blinding 
Not applicable as this is a nonrandomised, single arm, two cohorts study. 
3.10 
Source Data Recorded on the Electronic Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 CFR Part 11. As required by 
GCP, the sponsor assigned monitor will verify, by direct reference to the source documents, 
that the data required by the protocol are accurately reported on the eCRF.  
The source documents must, as a minimum, contain a statement that the subject is included in 
a clinical study, the date that informed consent was obtained prior to participation in the 
study, the identity of the study, diagnosis and eligibility criteria, visit dates (with subject 
status), study drug administration, and any AEs and associated concomitant medication. 
The items recorded directly on the eCRF and considered as source data will be described at 
each site in a site specific document signed by the investigator and filed in the investigator 
site file. 
Definition for source data and source documents are given below: 
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• 
Source Data: All original records and certified copies of original records of clinical 
findings, observations, or other activities necessary for the reconstruction and 
evaluation of the study. Source data are contained in source documents (original 
records or certified copies). 
• 
Source Documents: Original documents, data and records (for example 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 
copies, microfiches, photographic negatives, microfilm or magnetic media, x rays, 
subject files, and records kept at the pharmacy, at the laboratories and at 
medicotechnical departments involved in the clinical study). 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel, and by local, and possibly foreign, Competent Authorities (CAs). This 
information is included in the informed consent. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
All subjects must fulfil all of the following criteria to be included in the study: 
(1) 
Male or female subjects aged 18 years old or older. 
(2) 
Histopathologically confirmed well differentiated (grade 1 or grade 2 according to the 
WHO 2010 classification), metastatic or locally advanced, unresectable pNET (pNET 
cohort) or midgut NET (midgut cohort) with or without hormone related syndromes, 
with a Ki67 ≤20%. 
(3) 
Positive SSTR2 as assessed by imaging (scintigraphy or positron emission tomography 
(PET) scan) in the organs of target lesions. 
(4) 
Progression as assessed by an independent central reviewer according to RECIST v1.0 
from radiological imaging (CT scan or MRI) while receiving first line treatment with 
lanreotide Autogel® at a standard dose of 120 mg every 28 days for at least 24 weeks 
(6 injections). Progression must be radiologically documented using the same technique 
of images (CT scan or MRI) within 24 months prior to enrolment. Inclusion into the 
study must be within 28 days of the radiological imaging that is performed to document 
progression. 
(5) 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2. 
(6) 
Provision of written informed consent prior to any study related procedures.  
(7) 
Female subjects of childbearing potential (not surgically sterile or 2 years 
postmenopausal) must provide a negative urine pregnancy test at Screening, and use a 
medically accepted method of contraception and must agree to continue use of this 
method for the duration of the study and for 2 months after participation in the study. 
Acceptable methods of contraception include double barrier method, intrauterine 
device (IUD), or steroidal contraceptive (oral, transdermal, implanted and injected). 
(8) 
Subjects must be willing and able to comply with study restrictions and willing to 
return to the clinic for the follow up evaluation as specified in the protocol.  
4.2 
Exclusion Criteria 
Subjects will not be included in the study if the subject: 
(1) 
Has poorly differentiated grade 3 NET or rapidly progressive NET (within 12 weeks of 
initiation of lanreotide Autogel® 120 mg every 28 days) as per RECIST v1.0.  
(2) 
Has been diagnosed with VIPoma (i.e. Verner Morrison syndrome), insulinoma, 
foregut (except for pNET), hindgut NET, unknown primary NET or multiple endocrine 
neoplasms (MEN). 
(3) 
Has progressed during treatment with SSAs other than lanreotide Autogel® 120 mg. 
(4) 
Has been previously treated with any antitumour agent for NET other than lanreotide 
Autogel® 120 mg every 28 days: chemotherapy, molecular targeted therapy, peptide 
receptor radionuclide therapy (PRRT) or interferon. Exception made of prior treatment 
with Octreotide at standard dose stopped for other reason than disease progression. 
(5) 
Has had major surgery related to the studied disease within 3 months prior to entering 
the study. Previous debulking surgery and liver-directed therapies are acceptable as 
long as tumour burden is measurable (other target lesions). 
(6) 
Has symptomatic gallbladder lithiasis/sludge at Screening echography or a history of 
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(7) 
Has had previous cancer (except basocellular carcinoma of the skin and/or in situ 
carcinoma of the cervix/uterus if subjects treated with curative intent and free from 
disease for more than 5 years). 
(8) 
Was treated with any other IMP within the last 30 days before study entry.  
(9) 
Is pregnant or lactating.  
(10) Has abnormal findings at Screening, any other medical condition(s) or laboratory 
findings that, in the opinion of the investigator, might jeopardise the subject's safety.  
(11) Has any mental condition rendering the subject unable to understand the nature, scope 
and possible consequences of the study, and/or evidence of an uncooperative attitude. 
(12) Has been previously screened in this study, exception made of subjects who screen-
failed following central reviewers eligibility assessment (ie non PD). 
(13) Has a history of hypersensitivity to lanreotide Autogel® or drugs with a similar 
chemical structure, or any excipient used in the formulation. 
(14) Is likely to require treatment during the study with drugs that are not permitted by the 
study protocol. 
(15) Has a history of, or known current, problems with substance or alcohol abuse. 
(16) Has a history of, or known current, problems with substance or alcohol abuse. 
Vulnerable subjects (i.e. subjects who are under legal protection, who are interned due 
to a mental disease and who are kept in detention). 
(17) Subjects who have a link with the sponsor, the clinical trial site or the investigator 
(medical, pharmacy, dental and nursing students, subordinate hospital and laboratory 
personnel, employees of the sponsor). 
 
4.3 
Subject Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, 
pregnancy (see Section 8.1.5), or other reasons concerning the health or wellbeing of the 
subject, or in the case of lack of cooperation. In addition, a subject may be withdrawn from 
the study as described in Sections 3.7, 6.3, 8.1.7, 8.2.4 and 12.1.2.  
Should a subject decide to withdraw from the study after administration of study drug, or 
should the investigator decide to withdraw the subject, all efforts will be made to complete 
and report the observations up to the time of withdrawal as thoroughly as possible. A 
complete final evaluation at the time of the subject’s withdrawal should be made (see 
Section 5.2.4.1) and an explanation given of why the subject is withdrawing or being 
withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the eCRF. If a 
subject withdraws consent, every attempt will be made to determine the reason. If the reason 
for withdrawal is an AE or a clinically significant laboratory test abnormality, monitoring will 
continue until the event has resolved or stabilised, or until a determination of a cause 
unrelated to the study drug or study procedure is made. The specific AE or test result(s) must 
be recorded on the eCRF. All evaluations should be performed, according to the protocol for 
the End of Study visit.  




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5 
STUDY PROCEDURES  
5.1 
Study Schedule 
The schedule of procedures and assessments during the study for the pNET and midgut 
cohorts is summarised in Table 2 and Table 3, respectively. 
'Injection only' visits will not be considered as study visits; however, for subjects who will be 
administered the IMP at home, the date and time of injection will be recorded in a subject 
diary card by the healthcare professional administering the injection and will be returned to 
the investigational site and entered into the eCRF. Any AEs reported at these visits will be 
transmitted by the healthcare professional administering the injection to the responsible 
investigational site staff on the same day to be recorded on the eCRF, reported to the sponsor 
(if an SAE), and followed up as appropriate by the responsible investigational site staff. 
 


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Table 2 
Study Procedures and Assessments (pNET Cohort) 
Procedures and assessments 
Screening 
period 
Treatment period 
End of 
Study/Early 
withdrawal[a] 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
VX[b] 
EoS/EW 
-28 days 
Baseline 
(Day 1) 
W2 
W4 
W8 
W12 
W24 
W36 
W48 
q12W 
 
Informed consent 
X  
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Significant medical or surgical history 
X 
 
 
 
 
 
 
 
 
 
 
NET history 
X 
 
 
 
 
 
 
 
 
 
 
Prior treatments for study disease 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Imaging assessment of SSTR2 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X  
 
 
 
 
 
 
 
 
 
 
Radiology imaging assessments (CT or MRI)[c] 
X[d] 
 
 
 
 
X 
X 
X 
X 
X 
 
Physical examination (including height (Screening only) 
and weight) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptoms (diarrhoea, flushing)[e] 
 
X 
 
 
X  
X 
X 
X 
X 
X 
X 
Prior and concomitant medication, and concomitant surgery 
and nondrug therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of life questionnaires (QLQ-C30, QLQ-GI.NET21, 
EQ-5D-5L) 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Study drug administration[f] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Gallbladder echography[g] 
X 
 
 
 
 
 
X 
 
X 
 
X 
Clinical laboratory tests (haematology and biochemistry 
panels, liver and pancreatic enzymes) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
X 
Nonspecific tumour biomarkers: 5-HIAA, NSE and CgA[h] 
 
X[i] 
 
 
 
X[i] 
X 
X 
X 
X 
X[i] 
pNET-specific tumour biomarkers (e.g. pancreatic 
polypeptide, gastrin, glucagon, SST, …,)[j] 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
PK samples  
 
X[k] 
 
 
 
X[l] 
X[m] 
 
X[n] 
 
X[o] 


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Procedures and assessments 
Screening 
period 
Treatment period 
End of 
Study/Early 
withdrawal[a] 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
VX[b] 
EoS/EW 
-28 days 
Baseline 
(Day 1) 
W2 
W4 
W8 
W12 
W24 
W36 
W48 
q12W 
 
Antilanreotide antibodies 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
5-HIAA=5-hydroxyindoleacetic acid; CgA=chromogranin A; CT=computed tomography; 
d; ECG=electrocardiogram; EoS=End of Study; EQ-5D-5L=EuroQoL 5 
dimensions, 5 levels; EW=early withdrawal; MRI=magnetic resonance imaging; NET=neuroendocrine tumour; NSE=neuron specific enolase; PK=pharmacokinetic; pNET=pancreatic NET; 
q12w=every 12 weeks; QLQ-C30=Quality of Life Questionnaire Core 30; QLQ-GI.NET21=Quality of Life Questionnaire Gastrointestinal Neuroendocrine Tumour 21; 
; 
SST=somatostatin; SSTR2=somatostatin receptor 2; ULN=upper limit of normal; V=Visit; W=Week. 
Note: for study visits up to and including Week 4, visit windows are ±2 days and for visits after Week 4, visit windows are ±7 days. 
a 
to be scheduled approximately 2 weeks after last treatment visit, once central review of radiological imaging is available. 
b 
additional visits every 12 weeks: only for subjects not progressing within 48 weeks until 25 events have been observed in the pNET cohort. 
c 
CT or MRI of the abdomen; additional scan of the pelvis and/or chest as deemed necessary or clinically indicated, or as per the centre's standard of care. 
d 
radiology imaging assessments (CT or MRI) performed prior to signature of the informed consent form but within 28 days of the Baseline Visit (Visit 2; Day 1) do not need to be repeated as 
a screening procedure provided that the radiology imaging was performed at the centre's radiology facility or that the radiology imaging was deemed by the centre's radiologist to be of 
sufficient quality to be used as the reference screening assessment for the evaluation of response during the study. 
e 
subjects will report the total number of stools and flushing episodes during the 7 days prior to the visit orally to the investigator. 
f 
study drug will be administered every 14 days (±1day). 
g 
may be performed at any time if symptoms are thought to be related to gallbladder lithiasis. 
h 
at all scheduled visits, except Baseline, plasma/urinary 5-HIAA should only be performed in subjects with symptoms of carcinoid syndrome (diarrhoea and/or flushing) or if urinary 5-HIAA 
was elevated (above ULN) at Baseline. 
i 
in addition to plasma 5-HIAA, urinary 5-HIAA will be assessed at Baseline, Week 12 and at the End of Study visit only. 
j 
only for the tumour biomarkers above normal range at Baseline. 
k 
collected prior to and 2 to 3 hours after the first injection (exact time to be recorded) at reduced dosing intervals. 
l 
collected prior to injection. 
m collected prior to injection in all subjects, except in a subset of 30 subjects from selected sites who provide additional informed consent, where a sample will be collected 1 to 3 days after the 
injection instead. 
n 
collected prior to and 2 to 3 hours after the injection (exact time to be recorded). 
o 
at End of Study only: prior to any administration of commercial product (if applicable). 
p 
 
. 
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Table 3 
Study Procedures and Assessments (Midgut Cohort) 
Procedures and assessments 
Screening 
period 
Treatment period 
End of 
Study/Early 
withdrawal[a] 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
VX[b] 
EoS/EW 
-28 days 
Baseline 
(Day 1) 
W2 
W4 
W8 
W12 W24 W36 W48 W60 W72 W84 W96 q12W 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Significant medical or surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NET history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior treatments for study disease 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging assessment of SSTR2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiology imaging assessments (CT or 
MRI)[c] 
X[d] 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination (including height 
(Screening only) and weight) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptoms (diarrhoea, flushing)[e] 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medication, and 
concomitant surgery and nondrug therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of life questionnaires (QLQ-C30, 
QLQ-GI.NET21, EQ-5D-5L) 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration[f] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
Gallbladder echography[g] 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Clinical laboratory tests (haematology and 
biochemistry panels, liver and pancreatic 
enzymes) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 


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Procedures and assessments 
Screening 
period 
Treatment period 
End of 
Study/Early 
withdrawal[a] 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
VX[b] 
EoS/EW 
-28 days 
Baseline 
(Day 1) 
W2 
W4 
W8 
W12 W24 W36 W48 W60 W72 W84 W96 q12W 
 
Nonspecific tumour biomarkers: 5-HIAA, 
NSE and CgA 
 
X[h] 
 
 
 
X[h] 
X 
X 
X 
X 
X 
X 
X 
X 
X[h] 
PK samples  
 
X[i] 
 
 
 
X[j] X[k] 
 
X[l] 
 
 
 
X[j] 
 
X[m] 
Antilanreotide antibodies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
] 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
5-HIAA=5-hydroxyindoleacetic acid; CgA=chromogranin A; CT=computed tomography; 
; ECG=electrocardiogram; EoS=End of Study; EQ-5D-5L=EuroQoL 5 
dimensions, 5 levels; EW=early withdrawal; MRI=magnetic resonance imaging; NET=neuroendocrine tumour; NSE=neuron specific enolase; PK=pharmacokinetic; pNET=pancreatic NET; 
q12w=every 12 weeks; QLQ-C30=Quality of Life Questionnaire Core 30; QLQ-GI.NET21=Quality of Life Questionnaire Gastrointestinal Neuroendocrine Tumour 21; 
 
SST=somatostatin; SSTR2=somatostatin receptor 2; V=Visit; W=Week. 
Note: for study visits up to and including Week 4, visit windows are ±2 days and for visits after Week 4, visit windows are ±7 days. 
a 
to be scheduled approximately 2 weeks after last treatment visit, once central review of radiological imaging is available. 
b 
additional visits every 12 weeks: only for subjects not progressing within 96 weeks until 25 events have been observed in the midgut cohort. 
c 
CT or MRI of the abdomen; additional scan of the pelvis and/or chest as deemed necessary or clinically indicated, or as per the centre's standard of care. 
d 
radiology imaging assessments (CT or MRI) performed prior to signature of the informed consent form but within 28 days of the Baseline Visit (Visit 2; Day 1) do not need to be repeated as 
a screening procedure provided that the radiology imaging was performed at the centre's radiology facility or that the radiology imaging was deemed by the centre's radiologist to be of 
sufficient quality to be used as the reference screening assessment for the evaluation of response during the study. 
e 
subjects will report the total number of stools and flushing episodes during the 7 days prior to the visit orally to the investigator. 
f 
study drug will be administered every 14 days (±1day). 
g 
may be performed at any time if symptoms are thought to be related to gallbladder lithiasis. 
h 
in addition to plasma 5-HIAA, urinary 5-HIAA will be assessed at Baseline, Week 12 and at the End of Study visit only. 
i 
collected prior to and 2 to 3 hours after the first injection (exact time to be recorded) at reduced dosing intervals. 
j 
collected prior to injection. 
k 
collected prior to injection in all subjects, except in a subset of 30 subjects from selected sites who provide additional informed consent, where a sample will be collected 1 to 3 days after the 
injection instead. 
l 
collected prior to and 2 to 3 hours after the injection (exact time to be recorded). 
m at End of Study only: prior to any administration of commercial product (if applicable). 
n 
 
 
 
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The maximum volume of blood drawn for each subject who continues up to Week 48 (pNET 
cohort) or Week 96 (midgut cohort), including the End of Study/Early Withdrawal Visit, is 
267 mL and 295 mL, respectively. For subjects who continue after 48 or 96 weeks until the 
25 events have been observed, 15 mL of blood will be taken for clinical laboratory tests 
(blood sampling for haematology and biochemistry panels, liver and pancreatic enzymes), 
6 mL of blood will be taken for nonspecific tumour biomarkers and between 4 mL and 10 mL 
of blood will be taken for pNET-specific tumour biomarkers (depending on type) at each 
additional visit (where applicable). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
5.2 
Study Visits 
5.2.1 
Procedures for Screening (Visit 1; Day -28) 
The study will consist of a Screening visit (Day -28) followed by a Screening period of up to 
28 days. 
Signed and dated informed consent forms will be obtained at Screening (Day -28; Visit 1) 
before any study related procedures. 
 
 
 
  
After informed consent is obtained, subjects who are screened will be allocated a subject 
number. All screened subjects must be identifiable throughout the study. The investigator will 
maintain a list of subject numbers and names to enable records to be found at a later date if 
required. 
The following assessments will be performed in both cohorts during the Screening period of 
up to 28 days, prior to administration of study treatment at Baseline (Visit 2; Day 1): 
• 
Demographic data (date of birth, sex and race will be collected according to individual 
country requirements) 
• 
Significant medical or surgical history  
• 
NET history 
• 
Prior treatments for the study disease 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
Imaging assessment of SSTR2 (previous assessment within 24 months is acceptable) 
• 
Urine pregnancy test 
• 
Radiology imaging assessments (CT or MRI of the abdomen; additional scan of the 
pelvis and/or chest as deemed necessary or clinically indicated, or as per the centre's 
standard of care). Note: radiology imaging assessments (CT or MRI) performed prior to 
signature of the informed consent form but within 28 days of the Baseline Visit 
(Visit 2; Day 1) do not need to be repeated as a screening procedure provided that the 
radiology imaging was performed at the centre's radiology facility or that the radiology 
imaging was deemed by the centre's radiologist to be of sufficient quality to be used as 
the reference screening assessment for the evaluation of response during the study. 
• 
Physical examination (including weight and height) 
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• 
Vital signs (body temperature, supine and standing blood pressure and heart rate) 
• 
Prior and concomitant medications, and concomitant surgery and nondrug therapies 
• 
Start of collection of AEs 
• 
ECG 
• 
Gallbladder echography 
• 
Clinical laboratory tests (blood sampling for haematology and biochemistry panels, 
liver and pancreatic enzymes) 
• 
Urinalysis 
Only subjects who screen-failed solely due to non-eligibility according to central review (ie 
non PD) can be screened more than once. 
Each investigator will maintain a record of all subjects screened into the study (i.e. who 
signed the informed consent forms). Records up to the time of premature termination should 
be completed. In the event that the subject does not receive study drug the primary reason will 
be recorded on the eCRF. 
5.2.2 
Procedures for Baseline (Visit 2; Day 1) 
The following Baseline assessments will be performed: 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
Symptoms of diarrhoea and flushing (total number of stools/flushing episodes during 
previous 7 days) 
• 
Concomitant medication, surgery and nondrug therapies 
• 
Quality of life questionnaires 
• 
Review of AEs since Screening  
• 
Clinical laboratory tests (blood sampling for haematology and biochemistry panels, 
liver and pancreatic enzymes) 
• 
Urinalysis 
• 
Nonspecific biomarkers: plasma and urinary 5-HIAA, NSE and CgA; both cohorts 
• 
pNET-specific tumour biomarkers (e.g. pancreatic polypeptide, gastrin, glucagon, 
SST,…,) for subjects in the pNET cohort only 
• 
Blood sampling for PK and antilanreotide antibodies 
• 
 
Study drug administration at the reduced dosing interval of every 14 days will commence at 
Visit 2 (Baseline) following completion of the Baseline assessments. Following the first 
injection of lanreotide Autogel® 120 mg at the reduced dosing interval, blood samples for PK 
analysis will be taken 2 to 3 hours post dose (exact time to be recorded). 
5.2.3 
Procedures During Study Treatment 
Following the first dose at the reduced dosing interval at Visit 2 (Baseline), lanreotide 
Autogel® will be administered every 14 days (± 1 day) thereafter for up to 48 weeks (pNET 
cohort) and up to 96 weeks (midgut cohort), or until disease progression, death, or 
unacceptable toxicity or tolerability. For subjects who have not progressed at 48 weeks 
(pNET cohort) or 96 weeks (midgut cohort), study drug administration will continue and 
additional visits will be performed every 12 weeks after this time until 25 events have been 
observed in the respective cohort. 
'Injection only' visits will not be considered as study visits; however, for subjects who will be 
administered the IMP at home, the date and time of injection will be recorded in a subject 
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diary card by the healthcare professional administering the injection and will be returned to 
the investigational site and entered into the eCRF. Any AEs reported at these visits will be 
transmitted by the healthcare professional administering the injection to the responsible 
investigational site staff on the same day to be recorded on the eCRF, reported to the sponsor 
(if an SAE), and followed up as appropriate by the responsible investigational site staff. At 
some sites and for some subjects, the injections at 'injection only' visits may be carried out by 
a "nurse service" at the subject's home rather than the subject attending the investigational site 
or a member of the investigational site personnel visiting the subject's home. In such cases, 
the subject will give their consent and the nurses will be qualified, trained in the study 
protocol and fully aware of the AE reporting procedure. In addition, they will be under the 
sponsor's responsibility and in contact with the investigational site.  
5.2.3.1 
Visits 3, 4 and 5 (Weeks 2, 4 (±2 Days) and 8 (±7 Days)): Both Cohorts 
The following procedures will be performed in both cohorts prior to administration of 
lanreotide Autogel®: 
• 
Physical examination (including weight) 
• 
Vital signs (body temperature, supine and standing blood pressure and heart rate) 
• 
Symptoms of diarrhoea and flushing (total number of stools/flushing episodes during 
previous 7 days; Visit 5 (Week 8) only) 
• 
Concomitant medication, surgery and nondrug therapies 
• 
Review of AEs 
• 
ECG (Visit 4 (Week 4) only) 
• 
Clinical laboratory tests (blood sampling for haematology and biochemistry panels, 
liver and pancreatic enzymes; except Visit 3 (Week 2)) 
5.2.3.2 
Visits 6, 7, 8 and 9 (Weeks 12, 24, 36 and 48 (±7 Days)): Both Cohorts  
The following procedures will be performed in both cohorts prior to administration of 
lanreotide Autogel®: 
• 
Radiology imaging assessments (CT or MRI of the abdomen; additional scan of the 
pelvis and/or chest as deemed necessary or clinically indicated, or as per the centre's 
standard of care; same technique as performed at Screening) 
• 
Physical examination (including weight) 
• 
Vital signs (body temperature, supine and standing blood pressure and heart rate) 
• 
Symptoms of diarrhoea and flushing (total number of stools/flushing episodes during 
previous 7 days) 
• 
Concomitant medication, surgery and nondrug therapies 
• 
Quality of life questionnaires 
• 
Review of AEs 
• 
ECG and gallbladder echography (Visit 7 (Week 24) only both cohorts; Visit 9 
(Week 48) only pNET cohort) 
• 
Clinical laboratory tests (blood sampling for haematology and biochemistry panels, 
liver and pancreatic enzymes) 
• 
Urinalysis (Visit 9 (Week 48) only) 
• 
Nonspecific biomarkers: plasma 5-HIAA, NSE and CgA; urinary 5-HIAA at 
Visit 6 (Week 12) only; both cohorts. Note: in the pNET cohort, plasma/urinary 


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5-HIAA should only be performed in subjects with symptoms of carcinoid syndrome 
(diarrhoea and/or flushing) or if urinary 5-HIAA was elevated (above ULN) at Baseline 
• 
pNET-specific tumour biomarkers (e.g. pancreatic polypeptide, gastrin, glucagon, 
SST,…,) for subjects in the pNET cohort only and only for the tumour biomarkers 
above normal range at Baseline 
• 
Blood sampling for PK at: 
- 
Visit 6 (Week 12): prior to injection 
- 
Visit 7 (Week 24): prior to injection in all subjects, except in a subset of 
30 subjects from selected sites who provide additional informed consent, where a 
sample will be collected 1 to 3 days after the injection instead 
- 
Visit 9 (Week 48): prior to injection and 2 to 3 hours after injection (exact time 
to be recorded) 
• 
 
 
5.2.3.3 
Visits 10, 11, 12 and 13 (Weeks 60, 72, 84 and 96 (±7 Days)): Midgut Cohort Only 
The following procedures will be performed in the midgut cohort only prior to administration 
of lanreotide Autogel®: 
• 
Radiology imaging assessments (CT or MRI of the abdomen; additional scan of the 
pelvis and/or chest as deemed necessary or clinically indicated, or as per the centre's 
standard of care; same technique as performed at Screening) 
• 
Physical examination (including weight) 
• 
Vital signs (body temperature, supine and standing blood pressure and heart rate) 
• 
Symptoms of diarrhoea and flushing (total number of stools/flushing episodes during 
previous 7 days) 
• 
Concomitant medication, surgery and nondrug therapies 
• 
Quality of life questionnaires 
• 
Review of AEs 
• 
ECG and gallbladder echography (Visit 13 (Week 96) only) 
• 
Clinical laboratory tests (blood sampling for haematology and biochemistry panels, 
liver and pancreatic enzymes) 
• 
Urinalysis (Visit 13 (Week 96) only) 
• 
Nonspecific biomarkers: plasma 5-HIAA, NSE and CgA 
• 
Blood sampling for PK at: 
- 
Visit 13 (Week 96): prior to injection  
• 
 
5.2.3.4 
Additional Visits Every 12 Weeks (±7 Days) for Subjects Who Have Not Progressed 
Subjects in the pNET cohort who have not progressed at Week 48 will continue to receive 
lanreotide Autogel® every 14 days and be followed up every 12 weeks until progression, 
death, or unacceptable toxicity or tolerability or until 25 events have been observed in the 
pNET cohort. Similarly, subjects in the midgut cohort who have not progressed at Week 96 
will continue to receive study treatment every 14 days after Week 96 and will also be 
followed up every 12 weeks until progression, death, unacceptable toxicity or tolerability or 
until 25 events have been observed in the midgut cohort.  
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The following procedures will be performed in both cohorts prior to administration of 
lanreotide Autogel®: 
• 
Radiology imaging assessments (CT or MRI of the abdomen; additional scan of the 
pelvis and/or chest as deemed necessary or clinically indicated, or as per the centre's 
standard of care; same technique as performed at Screening) 
• 
Physical examination (including weight) 
• 
Vital signs (body temperature, supine and standing blood pressure and heart rate) 
• 
Symptoms of diarrhoea and flushing (total number of stools/flushing episodes during 
previous 7 days) 
• 
Concomitant medication, surgery and nondrug therapies 
• 
Quality of life questionnaires 
• 
Review of AEs 
• 
Clinical laboratory tests (blood sampling for haematology and biochemistry panels, 
liver and pancreatic enzymes) 
• 
Nonspecific biomarkers: plasma 5-HIAA, NSE and CgA; both cohorts. Note: in the 
pNET cohort, plasma/urinary 5-HIAA should only be performed in subjects with 
symptoms of carcinoid syndrome (diarrhoea and/or flushing) or if urinary 5-HIAA was 
elevated (above ULN) at Baseline 
• 
pNET-specific tumour biomarkers (e.g. pancreatic polypeptide, gastrin, glucagon, 
SST,…,) for subjects in the pNET cohort only and only for the tumour biomarkers 
above normal range at Baseline 
5.2.4 
Procedures After Study Treatment 
5.2.4.1 
End of Study/Early Withdrawal Visit 
Subjects who complete all scheduled visits or who have progressed or died will be considered 
to have completed the study.  
For all subjects, with the exception of those who have died, final evaluations will be 
performed at the End of Study visit approximately 2 weeks (±7 days) after the subject's last 
treatment visit, once central review of radiological imaging data is available. Subjects with 
ongoing AEs or clinically significant laboratory test abnormalities (as determined by the 
investigator) will be monitored as described in Section 8.1.3 and Section 8.2, respectively. 
The following procedures will be performed in both cohorts at the End of Study visit: 
• 
Physical examination (including weight) 
• 
Vital signs (body temperature, supine and standing blood pressure and heart rate) 
• 
Symptoms of diarrhoea and flushing (total number of stools/flushing episodes during 
previous 7 days) 
• 
Concomitant medication, surgery and nondrug therapies 
• 
Quality of life questionnaires 
• 
Review of AEs 
• 
ECG and gallbladder echography 
• 
Clinical laboratory tests (blood sampling for haematology and biochemistry panels, 
liver and pancreatic enzymes) 
• 
Urinalysis 
• 
Nonspecific biomarkers: plasma and urinary 5-HIAA, NSE and CgA; both cohorts. 
Note: in the pNET cohort, plasma/urinary 5-HIAA should only be performed in 


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subjects with symptoms of carcinoid syndrome (diarrhoea and/or flushing) or if urinary 
5-HIAA was elevated (above ULN) at Baseline 
• 
pNET-specific tumour biomarkers (e.g. pancreatic polypeptide, gastrin, glucagon, 
SST,…,) for subjects in the pNET cohort only and only for the tumour biomarkers 
above normal range at Baseline 
• 
Blood sampling for PK and antilanreotide antibodies 
Subjects still benefiting from treatment at the End of Study visit will have the option to 
continue on commercial product at the discretion of the investigator once all study 
assessments have been performed. 


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6 
TREATMENT OF SUBJECTS 
6.1 
Study Drugs Administered 
All subjects will receive deep s.c. injections of lanreotide Autogel® 120 mg every 14 days for 
up to 48 weeks (pNET cohort) or up to 96 weeks (midgut cohort), or until disease 
progression, death, or unacceptable toxicity or tolerability. Subjects in the pNET cohort who 
have not progressed at Week 48 will continue to receive lanreotide Autogel® every 14 days 
until 25 events have been observed in the pNET cohort. Similarly, subjects in the midgut 
cohort who have not progressed at Week 96 will continue to receive study treatment every 
14 days until 25 events have been observed in the midgut cohort. At some sites and for some 
subjects, the injections at 'injection only' visits may be carried out by a "nurse service" at the 
subject's home rather than the subject attending the investigational site or a member of the 
investigational site personnel visiting the subject's home (see Section 5.2.3). 
Where administrations are to be performed at a subject's home, in order to comply with the 
storage requirements, study drug will be delivered directly to subject in due time, from the 
investigational sites, through a specific courier. This courier will act upon request of the 
investigators, according to applicable Good Distribution Practice (GDP). Traceability will be 
maintained throughout the product flows. Full logistics, including responsibilities of the 
courier, sponsor and investigators, will be detailed in a separate document agreed between 
sponsor and the courier. 
6.1.1 
Investigational Medicinal Product 
Lanreotide Autogel® is a prolonged release, pharmaceutical form of lanreotide. It is a mixture 
of lanreotide acetate (0.246 mg/mg of product) and water (0.754 mg/mg of product) and is 
provided in a 0.5 mL prefilled syringe fitted with a 2 cm needle of 1.2 mm external diameter 
and an automatic safety system, sealed in a laminated bag. 
Lanreotide Autogel® will be administered by deep s.c. injection in the superior, external 
quadrant of the buttock at a dose of 120 mg, every 14 days. 
6.2 
Concomitant Medication/Therapy  
All prior treatments for the study disease will be recorded on the eCRF. Any prior or 
concomitant therapy or medication given to a subject for another indication within 28 days 
before study drug administration or during study drug administration will be indicated on the 
eCRF. Dose and generic name or tradename will be indicated.  
The following concomitant medications, therapy or procedures are not permitted prior to and 
during this study: 
• 
chemotherapy, molecular targeted therapy, PRRT and interferon 
• 
any SSAs other than lanreotide Autogel® 120 mg, 
• 
GH antagonists, 
• 
Cyclosporin 
• 
tumour resection. 
Previous debulking surgery and liver-directed therapies are acceptable as long as tumour 
burden is measurable (other target lesions). 
All other concomitant treatments taken by the subject during the course of the study will be 
recorded on the eCRF. For information regarding the effects on blood glucose and the need 
for monitoring and adjustment of antidiabetic agents, as well as information about the 
possible effects on bioavailability of drugs mainly metabolised by CYP3A4 and which have a 
low therapeutic index (e.g. quinidine, terfenadine) and bradycardia inducing drugs (e.g. beta 


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blockers) please refer to the current IB (Section 6 Summary of Data and Guidance for the 
Investigator). 
6.3 
Procedures for Monitoring Subject Compliance 
Study drug will be administered by a healthcare professional at each visit. 'Injection only' 
visits will not be considered as study visits; however, the date and time of injection will be 
recorded in a subject diary card by the healthcare professional administering the injection and 
will be returned to the investigational site and entered into the eCRF. At some sites and for 
some subjects, the 'injection only' visits may be carried out by a "nurse service" at the 
subject's home rather than the subject attending the investigational site or a member of the 
investigational site personnel visiting the subject's home. In such cases, the subject will give 
their consent and the nurses will be qualified, trained in the study protocol and fully aware of 
the AE reporting procedure. In addition, they will be under the sponsor's responsibility and in 
contact with the investigational site. 
The investigator will be responsible for monitoring subject compliance. Subjects can be 
withdrawn from the study at any time if the investigator or the sponsor determines that the 
subject is not in compliance with the study protocol. 
Please refer to Section 4.3 for the criteria for discontinuing the subject from study drug. 


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7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedule in Table 2 (pNET cohort) 
and Table 3 (midgut cohort). 
7.1 
Primary Efficacy Endpoint and Evaluation 
The primary endpoint is median PFS (defined as time from first injection of lanreotide 
Autogel® 120 mg every 14 days to progression or death). Disease progression will be assessed 
by tumour response evaluation according to RECIST v1.0, every 12 weeks, measured using 
the same imaging technique (CT scan or MRI) for each subject throughout the study, and by 
independent central review to ensure intra and intersubject consistency and reliability. 
7.2 
Secondary Efficacy Endpoints and Evaluations 
• 
Median time to progression (defined as time from first injection of lanreotide Autogel® 
120 mg every 14 days to progression). 
• 
Proportion of subjects alive and without progression every 12 weeks. 
• 
Overall survival at Week 48 and at the end of the study for each cohort. 
• 
ORR every 12 weeks as per RECIST v1.0. ORR is defined as the proportion of subjects 
who achieve either CR or PR. 
• 
DCR evaluated according to RECIST v1.0 at Weeks 24 and 48 and at the end of study 
period in each cohort. The DCR is defined as the rate of CR plus PR plus SD. 
• 
Best overall response according to RECIST v1.0 (defined as the best response recorded 
from the initiation of treatment until disease progression). 
• 
Median duration of SD according to RECIST v1.0 (defined as the time from first 
injection of lanreotide Autogel® 120 mg every 14 days until the first occurrence of 
progressive disease by central assessment).  
• 
Factors associated with PFS will include but will not be limited to: hepatic tumour 
volume ≤25% versus >25%, grade 1 versus grade 2, previous surgery of the primary 
tumour (yes/no), Ki67 <10% versus ≥10%, duration of treatment with lanreotide 
Autogel® 120 mg every 28 days. 
• 
Symptom control (diarrhoea, flushing) at Baseline, Weeks 8 and 12 and every 12 weeks 
thereafter, and at the End of Study visit, as measured by the total number of stools and 
flushing episodes during the 7 days prior to the visit reported orally by the subject to 
the investigator. 
• 
Quality of life measured at Baseline, Week 12 and every 12 weeks thereafter, and at the 
End of Study visit, after diagnosis of progression, using EORTC QLQ-C30 v3.0 and 
QLQ-GI.NET21 (2006), and EQ-5D-5L v1.0 questionnaires. 
• 
pNET cohort:  
- 
nonspecific tumour biomarkers (CgA, NSE and 5-HIAA) at Baseline, every 
12 weeks thereafter and at the End of Study visit (plasma 5-HIAA at all 
scheduled visits; urinary 5-HIAA at Baseline, Week 12 and at the End of Study 
visit only). Note: at all scheduled visits, except Baseline, plasma/urinary 5-HIAA 
should only be performed in subjects with symptoms of carcinoid syndrome 
(diarrhoea and/or flushing) or if urinary 5-HIAA was elevated (above ULN) at 
Baseline. 
- 
pNET-specific tumour biomarkers (e.g. pancreatic polypeptide, 
gastrin, 
glucagon, SST, …) at Baseline, every 12 weeks thereafter and at the End of 
Study visit: only for the tumour biomarkers above normal range at Baseline.  




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Measure 
Timepoint 
Variable 
Endpoint 
Symptom 
control 
Baseline, 
Weeks 8 and 12, 
every 12 weeks 
thereafter, 
and 
at EoS 
Total number of stools, 
total number of flushing 
episodes 
in 
previous 
7 days 
(reported 
by 
subject) 
Symptom control (diarrhoea and flushing) at 
Baseline, Weeks 8 and 12 and every 12 weeks 
thereafter, and at the End of Study visit, as 
measured by total number of stools and 
flushing episodes during the 7 days prior to the 
visit reported orally by the subject to the 
investigator. 
Quality of life 
Baseline, 
Week 12, every 
12 weeks 
thereafter and at 
EoS 
EORTC QLQ-C30 v3.0 
and 
QLQ-GI.NET21 
(2006), and EQ-5D-5L 
v1.0 questionnaires 
Quality of life measured at Baseline, Week 12 
and every 12 weeks thereafter, and at the EoS 
visit, after diagnosis of progression, using 
EORTC QLQ-C30 v3.0 and QLQ-GI.NET21 
(2006), and EQ-5D-5L v1.0 questionnaires. 
Tumour 
biomarkers 
(pNET 
cohort) 
Baseline 
and 
every 12 weeks 
thereafter, 
and 
at EoS[a] 
Concentrations 
of 
nonspecific 
and 
pNET-specific 
tumour 
biomarkers 
• 
Nonspecific tumour biomarkers (CgA, 
NSE and 5-HIAA) at Baseline, every 
12 weeks thereafter and at the End of 
Study visit (plasma 5-HIAA at all 
scheduled visits; urinary 5-HIAA at 
Baseline, Week 12 and at the End of 
Study visit only).[a] 
• 
pNET-specific 
tumour 
biomarkers 
(e.g. pancreatic polypeptide, gastrin, 
glucagon, SST, …) at Baseline, every 
12 weeks thereafter and at the End of 
Study visit: only for the tumour 
biomarkers above normal range at 
Baseline. 
Tumour 
biomarkers 
(midgut 
cohort) 
Baseline 
and 
every 12 weeks 
thereafter, 
and 
at EoS 
Concentrations 
of 
nonspecific 
tumour 
biomarkers 
Nonspecific tumour biomarkers (CgA, NSE and 
5-HIAA) at Baseline, every 12 weeks thereafter 
and at the End of Study visit (plasma 5-HIAA 
at all scheduled visits; urinary 5-HIAA at 
Baseline, Week 12 and at the End of Study visit 
only). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
. 
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Measure 
Timepoint 
Variable 
Endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
5-HIAA=5-hydroxyindoleacetic acid; CgA=chromogranin A; CT=computed tomography; DCR=disease control rate; 
EORTC=European Organisation into the Research and Treatment of Cancer; EoS=End of Study; EQ-5D-5L=EuroQoL 5 
dimensions, 5 levels; Ki67=proliferation index; MRI=magnetic resonance imaging; NSE=neuron specific enolase; 
ORR=objective response rate; PFS=progression free survival; pNET=pancreatic neuroendocrine tumour; QLQ-C30=Quality 
of Life Questionnaire-Core 30; QLQ-GI.NET21=Quality of Life Questionnaire Gastrointestinal Neuroendocrine Tumour 21; 
RECIST=Response Evaluation Criteria in Solid Tumours; SD=stable disease; SST=somatostatin; StD=standard deviation; 
; ULN=upper limit of normal. 
. 
a 
at all scheduled visits, except Baseline, plasma/urinary 5-HIAA should only be performed in subjects with symptoms of 
carcinoid syndrome (diarrhoea and/or flushing) or if urinary 5-HIAA was elevated (above ULN) at Baseline. 
7.4 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data 
Methods for assessing efficacy data are described below. Timing of efficacy assessments are 
discussed in Section 5. Procedures for recording efficacy data are discussed in Section 14.1, 
and methods of analyses are discussed in Section 10.4.5. 
7.4.1 
Time to Disease Progression or Death 
Median PFS (defined as time from first injection of lanreotide Autogel® 120 mg every 
14 days to progression or death) will be presented for each cohort. In addition, the proportion 
of subjects alive and without progression every 12 weeks will be estimated. 
7.4.2 
Tumour Response 
Tumour assessments will be performed using the RECIST v1.0 criteria every 12 weeks 
throughout the study. The same imaging technique (CT scan or MRI) will be used for each 
subject throughout the study and assessments will be made by independent central review to 
ensure intra and intersubject consistency and reliability. In addition, at Screening, the Central 
Reading contract research organisation (CRO) will measure the hepatic tumour load. From the 
imaging data, median PFS and PFS rate (see Section 7.4.1), median time to progression, 
ORR, best overall response, DCR and median duration of SD will be estimated, along with 
 CT or MRI. 
Table 5 
Overall Response 
Target lesion 
Nontarget lesion 
New lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non progressive disease 
No 
PR 
SD 
Non progressive disease 
No 
SD 
Progressive disease 
Any 
Yes or no 
Progressive disease 
Any 
Progressive disease 
Yes or no 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
CR=complete response; PR=Partial response; SD=stable disease [23]. 
Median time to progression is defined as time from first injection of lanreotide Autogel® 
120 mg every 14 days to progression. The ORR, defined as the proportion of subjects who 
achieve either CR or a PR, will be assessed every 12 weeks. The best overall response is 
defined as the best response recorded from initiation of treatment until disease progression 
(Table 5). The DCR is defined as the rate of CR plus PR plus SD and will be presented at 
Weeks 24 and 48 and at the End of Study. Median duration of SD is defined as the time from 
first injection of lanreotide Autogel® 120 mg every 14 days until the first occurrence of 
progressive disease by central assessment.  
CCI
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7.4.3 
Factors Associated with PFS 
Factors associated with PFS will include but will not be limited to: hepatic tumour volume 
≤25% versus >25%, grade 1 versus grade 2, previous surgery of the primary tumour (yes/no), 
Ki67 <10% versus ≥10%, duration of treatment with lanreotide Autogel® 120 mg every 
28 days). These factors are recorded at Screening, prior to dosing with lanreotide Autogel® at 
the reduced dosing interval. 
7.4.4 
Incidence of Stools and Flushing Episodes 
The total number of stools and flushing events in the 7 days prior to each visit will be 
collected at each visit (except Screening, and Visits 3 and 4) based on information reported 
orally by the subject to the investigator. 
7.4.5 
Quality of Life 
Quality of life will be assessed using the EORTC QLQ-C30 v3.0 and QLQ-GI.NET21 (2006), 
and EQ-5D-5L v1.0 questionnaires. The questionnaires will be completed at each visit (except 
Screening, and Visits 3, 4 and 5). The investigator or delegated personnel will explain the 
questions to the subject if necessary. The subject will complete the questionnaires in the same 
conditions throughout the study (i.e. prior to study medication administration). 
7.4.6 
Tumour Biomarkers 
Blood samples will be taken for tumour biomarker analyses as follows: 
• 
pNET cohort:  
- 
nonspecific tumour biomarkers (CgA, NSE and 5-HIAA) at Baseline, every 
12 weeks thereafter and at the End of Study visit. At all scheduled visits, except 
Baseline, plasma 5-HIAA should only be performed in subjects with symptoms 
of carcinoid syndrome (diarrhoea and/or flushing) or if urinary 5-HIAA was 
elevated (above ULN) at Baseline. 
- 
pNET-specific tumour biomarkers (e.g. pancreatic polypeptide, 
gastrin, 
glucagon, SST, …) at Baseline, every 12 weeks thereafter and at the End of 
Study visit: only for the tumour biomarkers above normal range at Baseline.  
• 
Midgut cohort:  
- 
nonspecific tumour biomarkers (CgA, NSE and 5-HIAA) at Baseline, every 
12 weeks thereafter and at the End of Study visit. 
Samples will be taken, prepared and shipped as specified in the Central Laboratory Services 
Manual. 
A 24-hour urine sample for 5-HIAA will also be taken at Baseline, Week 12, and at the End 
of Study visit for all subjects in the midgut cohort. For subjects in the pNET cohort, a 24-hour 
urine sample for 5-HIAA will be taken at Baseline for all subjects, and at Week 12 and the 
End of Study visit for subjects with symptoms of carcinoid syndrome (diarrhoea and/or 
flushing) or for those with elevated (above ULN) urinary 5-HIAA at Baseline. Each 
assessment of urinary 5-HIAA will require subjects to collect their urine for the 24-hour 
period prior to the study visit. Subjects will be provided with a receptacle for this purpose and 
will be asked to come with it to the next treatment period visit.  
The collection period will begin once the subject has emptied his/her bladder (not into the 
collection receptacle) after waking up on the morning of the day prior to the study visit. This 
time should be recorded on the receptacle. 
The subject will be instructed to collect all their urine in the receptacle for a period of 
24 hours. Due to the potential interference with the assay for 5-HIAA, subjects will be 


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instructed not to eat bananas, pineapple, plums, walnuts, eggplant, tomatoes, chocolate or 
avocado during the urine collection period and the 72 hours prior to the collection. At the 
study visits the investigator will question the subject about his/her diet over the collection 
period. At the end of the collection period the subject should empty his/her bladder as fully as 
possible into the collection receptacle, and record the time. 
The collected urine will be given to the investigator (or designee), who will measure the 
volume of urine collected and record this, along with the start and stop times of the collection 
period, on the appropriate section of the eCRF. Any prohibited food will also be recorded on 
the eCRF. 
The sample of the collected urine should be prepared and shipped as specified in the Central 
Laboratory Services Manual. 
In addition, urinary creatinine will be analysed in order to assess compliance with the 24-hour 
collection period. 


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8 
ASSESSMENT OF SAFETY 
For the timing of assessments in this study, refer to the schedule in Table 2 (pNET cohort) 
and Table 3 (midgut cohort). 
8.1 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study (see Section 3.6 for a definition of the study duration) and will be 
elicited by direct, nonleading questioning or if spontaneously reported by the subject. Further 
details for AE reporting can be found in Section 8.1.3. 
Any AEs reported at 'injection only' visits will be transmitted by the healthcare professional 
administering the injection to the responsible investigational site staff on the same day to be 
recorded on the eCRF, reported to the sponsor (if an SAE), and followed up as appropriate by 
the responsible investigational site staff. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g. laboratory findings, ECG). In clinical studies an AE 
can include an undesirable medical condition occurring at any time, including run in or 
washout periods, even if no lanreotide Autogel® has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until the end of the study (as defined in Section 3.6). 
Natural progression or deterioration of the disease under study will be recorded as part of the 
efficacy evaluation and should not be recorded as an AE/serious adverse event (SAE). 
Death due to disease progression will be recorded as part of the efficacy evaluation and will 
not be regarded as an AE/SAE. 
Signs and symptoms should not be reported as AEs/SAEs if they are clearly related to a 
relapse or an expected change or progression of the disease under study. 
These signs and symptoms should only be reported as AEs/SAEs (depending on the 
investigator’s judgement) if they are: 
• 
Judged by the investigator to be unusually severe or accelerated disease, or 
• 
If the investigator considers the deterioration of disease signs and symptoms to be 
caused directly by study drug. 
If there is any uncertainty about an AE being due solely to the disease under study, it should 
be reported as an AE/SAE as appropriate. 
Symptoms of diarrhoea and flushing will be collected as AEs and recorded on the eCRF.  
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
AEs will be recorded and graded according to the National Cancer Institute Common 
Terminology Criteria for AEs (NCI CTCAE) (Version 4.03, Dated 14 June 2010). 
In view of meta-analyses, and for conversion purposes, the following conversion mapping 
will apply if the NCI CTCAE scale is not available for a given AE: 
• 
NCI CTCAE grade 1 corresponds to mild, 
• 
NCI CTCAE grade 2 corresponds to moderate, 


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• 
NCI CTCAE grade 3 corresponds to severe, 
• 
NCI CTCAE grade 4 corresponds to life threatening/disabling, 
• 
NCI CTCAE grade 5 corresponds to death (related to AE). 
Where:  
• 
Mild: symptoms do not alter the subject’s normal functioning. 
• 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject. 
• 
Severe: symptoms definitely hazardous to wellbeing, significant impairment of 
function or incapacitation. 
• 
Life threatening: any event that places the subject at immediate risk of death from the 
event as it occurred, i.e. it does not include a reaction that, had it occurred in a more 
severe form, might have caused death (also see Section 8.1.4). 
8.1.2.2 
Causality Classification 
The relationship of an AE to study drug administration will be classified according to the 
following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with study drug administration in the sense 
that it is plausible, conceivable or likely. 
• 
Not 
related: 
reports 
including 
good 
reasons 
and 
sufficient 
information 
(e.g. implausible time sequence and/or attributable to concurrent disease or other drugs) 
to rule out a causal relationship with study drug administration. 
8.1.2.3 
Assessment of Expectedness 
The reference document for assessing expectedness of AEs in this study will be the current 
IB. 
8.1.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They result in a change in study drug schedule of administration (change in dosage, 
delay in administration, study drug discontinuation), 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject, 
• 
They are considered as clinically significant by the investigator. 
8.1.2.5 
Abnormal Physical Examination Findings 
Clinically significant changes, in the judgement of the investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the investigator as clinically significant (e.g. ECG 
changes) that result in a change in study drug dosage or administration schedule, or in 
discontinuation of study drug, or require intervention or diagnostic evaluation to assess the 
risk to the subject, should be recorded as AEs. 
8.1.3 
Recording and Follow Up of Adverse Events 
At each study visit, the subject should be asked a nonleading question such as: “How have 
you felt since starting treatment at the reduced dosing interval?”  


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'Injection only' visits will not be considered as study visits; however, any AEs reported at 
these visits will be transmitted by the healthcare professional administering the injection to 
the responsible investigational site staff on the same day to be recorded on the eCRF, reported 
to the sponsor (if an SAE), and followed up as appropriate by the responsible investigational 
site staff. 
All observed or volunteered AEs, regardless of suspected causal relationship to study drug, 
will be recorded on the AE page(s) of the eCRF. Events involving drug reactions, accidents, 
illnesses with onset during the treatment phase of the study, or exacerbation’s of pre-existing 
illnesses should be recorded according to the National Cancer Institute (NCI) terminology if 
applicable.  
Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to the sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the investigator to make an assessment of the 
causality of the AE (i.e. study drug or other illness). The investigator is required to assess 
causality and record that assessment on the eCRF. Follow up of the AE, after the date of study 
drug discontinuation, is required if the AE or its sequelae persist. Follow up is required until 
the event or its sequelae resolve or stabilise at a value acceptable to the investigator and the 
sponsor’s clinical monitor or his/her designated representative. 
8.1.4 
Reporting of Serious Adverse Events 
All SAEs (as defined below) regardless of suspected relationship to study drug must be 
reported immediately (within 24 hours of the investigator’s knowledge of the event) to the 
pharmacovigilance contact specified at the beginning of this protocol. If the immediate report 
is submitted by telephone, this must be followed by detailed written reports using the SAE 
report form. 
An SAE is any AE that: 
(1) 
Results in death, 
(2) 
Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a 
more severe form, might have caused death, 
(3) 
Results in inpatient hospitalisation or prolongation of existing hospitalisation, 
excluding admission for social or administrative reasons (see further), 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a 
substantial disruption of a person's ability to conduct normal life functions, 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who received 
study drug, 
(6) 
Is an important medical event that may not result in death, be life threatening, or 
require hospitalisation when, based upon appropriate medical judgement, may 
jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalisation, or the 
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In addition to the above criteria, any additional AE that the sponsor or an investigator 
considers serious should be immediately reported to the sponsor and included in the corporate 
SAEs database system. 
• 
Hospitalisation is defined as any inpatient admission (even if less than 24 hours). 
For chronic or long term inpatients, inpatient admission also includes transfer 
within the hospital to an acute/intensive care inpatient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an inpatient 
hospitalisation beyond the stay anticipated/required in relation to the original 
reason for the initial admission, as determined by the investigator or treating 
physician. For protocol specified hospitalisation in clinical studies, prolongation 
is defined as any extension beyond the length of stay described in the protocol. 
Prolongation in the absence of a precipitating, treatment emergent, clinical AE 
(i.e. not associated with the development of a new AE or worsening of a 
pre-existing condition) may meet criteria for "seriousness" but is not an adverse 
experience and thus is not subject to immediate reporting to the sponsor.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the 
subject’s screening documentation. Hospitalisation for a preplanned or elective 
treatment/surgical procedure should not be reported as an SAE unless there are 
complications or sequelae which meet the criteria for seriousness described 
above. 
Any SAE must be reported immediately (within 24 hours), independent of the circumstances 
or suspected cause, if it occurs or comes to the attention of the investigator at any time during 
the study period. 
Any AE/SAE with a suspected causal relationship to study drug administration occurring at 
any other time after completion of the study must be promptly reported. 
The following information is the minimum that must be provided to the sponsor 
pharmacovigilance contact within 24 hours for each SAE: 
• 
Study number 
• 
Centre number 
• 
Subject number 
• 
AE 
• 
Investigator's name and contact details 
The additional information included in the SAE form must be provided to the sponsor or 
representative as soon as it is available. The investigator should always provide an assessment 
of causality for each event reported to the sponsor. Upon receipt of the initial report, the 
sponsor will ask for the investigator's causality assessment if it was not provided with the 
initial report. 
The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to separate a primary AE considered as the 
foremost untoward medical occurrence from secondary AEs which occurred as complications. 
8.1.5 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that study drug has 
interfered with a contraceptive method. If pregnancy occurs during the study, the outcome of 
the pregnancy will then need to be collected (poststudy if necessary) and it may be necessary 
to discontinue administration of study drug.  


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Information regarding pregnancies must be collected on the AE page of the eCRF and 
reported to the sponsor as an SAE. The sponsor will request further information from the 
investigator as to the course and outcome of the pregnancy using the Standard Pregnancy 
Outcome Report Form.  
The investigator must instruct all female subjects to inform them immediately should they 
become pregnant during the study. The investigator should counsel the subject, discuss the 
risks of continuing with the pregnancy and the possible effects on the foetus. Monitoring of 
the subject should continue until conclusion of the pregnancy, which may involve follow up 
after the subject’s involvement in the study has ended. 
Pregnancies with a conception date within 90 days after subject’s last dose of study drug or 
completion of the study must also be reported to the investigator for onward reporting to the 
sponsor. 
If the investigator becomes aware of a pregnancy occurring in the partner of a subject 
participating in the study, this should be reported to the sponsor. After the partner has given 
written consent, she should be counselled and followed as described above. Monitoring of the 
partner should continue until conclusion of the pregnancy. 
8.1.6 
Deaths 
All AEs resulting in death during the study period or within 28 days after the last dose of 
lanreotide Autogel® must be reported as an SAE within 24 hours of the investigator’s 
knowledge of the event, apart from death due to disease progression, which will not be 
regarded as an AE/SAE (see Section 8.1.1).  
For AEs leading to death, NCI CTCAE grade 5 is the only appropriate grade (see 
Section 8.1.2.1). Deaths that cannot be attributed to an NCI CTCAE term associated with 
grade 5 or that cannot be reported within an NCI CTCAE category as ‘Other’ have to be 
reported as one of these four AE options: 
• 
Death not otherwise specified (NOS), 
• 
Disease progression NOS, 
• 
Multi-organ failure, 
• 
Sudden death. 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to study drug. 
If the study drug is discontinued due to an AE/SAE, it must be reported immediately to the 
sponsor’s designated representative (see Section 8.1.4). In all cases, the investigator must 
ensure the subject receives appropriate medical follow up (see Section 8.1.3). 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring during the study to the CA, IECs 
and other investigators concerned by study drug. Reporting will be done in accordance with 
the applicable regulatory requirements. 
8.2 
Clinical Laboratory Tests 
Blood and urine samples will be collected according to the study schedule in Table 2 (pNET 
cohort) and Table 3 (midgut cohort) for the evaluation of haematology and biochemistry 
panels, liver and pancreatic enzymes, and urinalysis.  


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The investigator will review the safety laboratory test results, document the review, and 
record any clinically relevant changes occurring or observed during the study in the AE 
section of the eCRF (see Section 8.1.2.4 for abnormal laboratory tests that should be recorded 
as AEs). 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to Baseline or to a value deemed acceptable by the 
investigator and the sponsor’s clinical monitor (or his/her designated representative) or until 
the abnormality is explained by an appropriate diagnosis. 
8.2.1 
Haematology 
The following parameters will be assessed: red blood cell (RBC) count, haemoglobin, 
haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean 
corpuscular haemoglobin concentration (MCHC), white blood cell (WBC) count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils, and others) and 
platelet count. 
8.2.2 
Blood Biochemistry 
The following parameters will be assessed: 
• 
urea, creatinine, total bilirubin, conjugated bilirubin 
• 
chloride, bicarbonate, sodium, potassium, calcium, phosphate 
• 
alkaline 
phosphatase, 
aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase (ALT), gamma glutamyl transferase 
• 
albumin, total protein, total cholesterol, triglycerides, fasting glucose (blood 
sample to be taken after at least 6 hours of fasting), amylase and lipase 
Blood samples will be collected to assess HbA1c. 
Any unscheduled test (indication and results) will be recorded on the dedicated page in the 
eCRF. 
8.2.3 
Urinalysis 
Fresh urine samples (at least 10 mL) will be collected to assess the following parameters: pH, 
protein, ketones, bilirubin, blood, urobilinogen, nitrites, leukocytes, glucose and specific 
gravity. 
Microscopy will be performed, if indicated, but results will not be collected in the eCRF. If in 
the opinion of the investigator there are any clinically significant abnormalities in microscopy, 
they will be recorded as an AE in the eCRF. 
8.2.4 
Pregnancy Test  
A urine pregnancy test will be performed for all female subjects of childbearing potential at 
Screening (Visit 1) and if clinically indicated thereafter. If this is found to be positive, it will 
be followed up with a beta human chorionic gonadotropin (βHCG) serum test. Any subject 
becoming pregnant during the study will be withdrawn. All pregnancies that occur during the 
study are to be reported as described in Section 8.1.5. 
8.3 
Physical Examination 
Physical examinations, including body weight, will be conducted according to the study 
schedule in Table 2 (pNET cohort) and Table 3 (midgut cohort), and height will be measured 
at Screening (Visit 1). 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 


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the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.4 
Vital Signs 
Vital signs will be recorded according to the study schedule in Table 2 (pNET cohort) and 
Table 3 (midgut cohort). Blood pressure and heart rate will be recorded after 5 minutes rest in 
the supine position and after 1 minute standing. 
Body temperature will also be recorded.  
Any clinically significant abnormalities will be recorded as AEs. 
8.5 
Electrocardiography 
An ECG analysis will be included as a safety evaluation/endpoint in this study. 
The ECGs will be recorded according to the study schedule in Table 2 (pNET cohort) and 
Table 3 (midgut cohort). Computerised standard 12 lead ECGs will be used so that the 
different ECG parameters (sinus rhythm, heart rate, RR interval, PR interval, QRS interval, 
QT and QTc) can be measured automatically. QTc will be calculated using Fridericia 
methodology. The ECG will be recorded with the subject in a supine position after 5 minutes 
of rest until four regular consecutive complexes are available. Automated ECG interval 
estimates taken from the ECG recorder will be used in this study.  
Any clinically significant abnormalities will be recorded as AEs. A copy of the ECG trace and 
report will be retained.  
8.6 
Gallbladder Echography 
Gallbladder echography will be conducted according to the study schedule in Table 2 (pNET 
cohort) and Table 3 (midgut cohort), or at any time if symptoms are thought to be related to 
gallbladder lithiasis, as per study site procedures. The results will be recorded in the eCRF. 
The presence of lithiasis or sludge will be assessed and recorded (yes/no) on the eCRF. Any 
clinically significant abnormalities will be recorded as AEs. 


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9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
9.1 
Pharmacokinetics 
9.1.1 
Sample Collection 
Blood samples (3 mL each) for determination of serum lanreotide concentrations will be 
collected according to the study schedule in Table 2 (pNET cohort) and Table 3 (midgut 
cohort). 
Lanreotide serum concentrations will be assessed in both cohorts at Baseline, prior to and 2 to 
3 hours after the first injection at the reduced dosing interval; Week 12, prior to injection; 
Week 24, prior to injection in all subjects, except in a subset of 30 subjects from selected 
sites, where a sample will be collected 1 to 3 days after the injection instead; Week 48, prior 
to and 2 to 3 hours after the injection; and at the End of Study (prior to any administration of 
commercial product (if applicable)). In addition, in the midgut cohort, a blood sample will be 
collected at Week 96, prior to injection. During the study, the nominal sample collection times 
may be changed, but the total number of samples will not increase. The exact dates and times 
of blood sample collection, and lanreotide Autogel® administration must be recorded on the 
eCRF. 
The tubes will be left to stand for 30 minutes and will then be centrifuged at 1000 g to 1300 g 
for 10 minutes at 4ºC. For each analyte, the resulting serum will be stored as two 500 μL 
aliquots at 20°C in polypropylene tubes prior to shipment to the analysis laboratory. Each 
tube should be labelled in accordance with the sponsor’s requirements. Aliquots will be 
shipped on dry ice and with a temperature tracker. 
Details of the sample handling methodology will be provided in the Study Manual and 
archived in the TMF. Additionally, details will be included in the Pharmacokinetics and Drug 
Metabolism (PDM) Sample Management Plan. 
9.1.2 
Analytical Procedures 
The determination of lanreotide serum concentrations will be performed using a validated 
assay by a bioanalytical CRO under Ipsen's PDM department supervision. 
9.2 
Putative Antibody Testing 
Blood samples (3 mL) will be collected according to the study schedule in Table 2 (pNET 
cohort) and Table 3 (midgut cohort) for the assay of putative antibodies to lanreotide. The 
tubes should be left to stand for 30 minutes and then centrifuged at 1000 g to 1300 g for 
10 minutes at 4°C. The resulting serum will be stored as two 500 μL aliquots at -20°C in 
polypropylene tubes prior to shipment to the analysis laboratory. Each tube should be labelled 
with the sample identification, study number, site number, subject number and initials, visit 
number (when applicable) and the planned time of collection. 
Full details regarding the requirements for processing, labelling and shipment of these 
samples are provided in the Study Manual and archived in the trial master file (TMF). 
Additionally, details will be included in the PDM Sample Management Plan. 
The determination of putative antibodies against lanreotide will be performed using a 
validated assay by a bioanalytical CRO under Ipsen's PDM department supervision. 
9.3 
Pharmacodynamics 
 
 
 
 
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10 
STATISTICS  
10.1 
Analyses Populations 
The following populations will be used during statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent). 
• 
Full analysis set (FAS): All subjects who received at least one dose of lanreotide 
Autogel® 120 mg every 14 days during the study 
• 
Per protocol (PP) population: All subjects in the FAS for whom no major protocol 
violations/deviations occurred. 
• 
Pharmacokinetics Valid (PK Valid) population: All subjects who received at least 
one dose and who have at least one serum lanreotide concentration and no major 
protocol deviations affecting PK variables. 
10.1.1 
Populations Analysed 
The primary analysis based on the primary efficacy endpoint(s) will be performed on the 
FAS. All secondary and tertiary endpoints will be evaluated based on the FAS population. In 
addition, a PP population analysis will be performed on the primary and secondary endpoints 
of PFS, median time to progression, ORR, DCR, best overall response and median duration of 
SD. 
The analyses of safety data will be performed on the FAS. 
PK endpoints will be analysed and population PK (POPPK) modelling will be performed on 
the PK Valid population. 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses 
Any major protocol deviation will be described in the Protocol Deviation Document (PDD) 
and its impact on inclusion in each analysis population (FAS, PP, and PK Valid) for any 
subject will be specified. The final list of protocol deviations, including determination of 
those which are major, impacting the PP population will be reviewed during the data review 
meeting held prior to database lock. 
10.2 
Sample Size Determination 
The sample size in this pilot study is 100 subjects in total (50 subjects per cohort). This should 
be sufficient to explore the efficacy of lanreotide Autogel® 120 mg at a reduced dosing 
interval.  
10.3 
Significance Testing and Estimations 
Analyses will be descriptive and p-values will be provided only for descriptive exploratory 
purposes. All statistical tests will be two sided at the α 0.05 level. 
10.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s 
Speciality Franchise Clinical Operations Department. 
A Statistical Analysis plan (SAP) describing the planned statistical analysis in detail with 
tables, figures and listings (TFLs) templates will be developed as a separate document. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® (version 9). 
For descriptive analyses, summary statistics will be presented at each scheduled visit. 
Summary statistics will include sample size, number of available observations (N), number of 
missing observations (missing), mean, 95% CI of the mean, standard deviation (StD), number 
of nonmissing observations (n), median and range for continuous variables and scores. For 


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categorical or discrete variables, the absolute and relative (percentage) numbers based on the 
nonmissing number of observations for each category will be presented, including 95% CIs. 
10.4.1 
Demographic and Other Baseline Characteristics 
In order to characterise the pNET and midgut cohorts, descriptive summary statistics (n, 
mean, StD, median, minimum, maximum) or frequency counts of demographic and baseline 
data (significant medical history, concomitant disease (predosing AEs and ongoing medical 
history, prior medications and therapies, baseline symptoms, etc.) will be presented by cohort 
and both cohorts combined for the FAS population. 
10.4.2 
Homogeneity of Treatment Groups 
In this nonrandomised exploratory study, all efficacy endpoints will be analysed by cohort 
and overall, with the exception of endpoints pertaining to disease progression and median 
duration of SD which will only be analysed by cohort. In addition, for the factors associated 
with the PFS endpoint, a model will be used for each cohort. Safety endpoints will be 
presented by cohort and overall, and PK endpoints will be evaluated for the overall 
population. It is not intended to compare the baseline characteristics of the cohorts. 
10.4.3 
Subject Disposition and Withdrawals 
The number and percentage of subjects included in the FAS will be tabulated by cohort, 
country and centre. The reasons for subject exclusions from each of the populations will also 
be tabulated. In addition, the number of subjects who were treated, and who discontinued and 
completed the study will be tabulated by cohort. Primary reasons for discontinuation of study 
treatment will be tabulated. 
10.4.4 
Pharmacokinetic Data 
The analysis of PK data will be performed by a CRO under the supervision of Ipsen’s PDM 
department. 
Individual serum concentrations for lanreotide will be listed and summarised by timepoint 
using descriptive statistics for continuous variables (N, mean, median, StD, minimum, 
maximum, geometric mean, and geometric coefficient of variation assuming log normally 
distributed data). 
Population PK modelling will be performed for the PK Valid population, both cohorts 
combined, and a PK/PD relationship between lanreotide serum concentrations and PD (PFS, 
tumour response or CgA) will be assessed, where possible. Exploratory graphs will be 
presented between PK parameters and safety outcomes. If a trend is detected, modelling 
analysis may be performed between PK and safety outcomes. 
The appearance of antilanreotide antibodies will be listed by cohort and overall, subject and 
visit and the percentage of subjects developing putative antidrug antibodies will be computed 
at Baseline and End of Study visits. 
10.4.5 
Efficacy Evaluation 
10.4.5.1 Primary Efficacy Variable 
The primary efficacy variable is median PFS (defined as time from first injection of lanreotide 
Autogel® 120 mg every 14 days to progression or death). Disease progression will be assessed 
by tumour response evaluation according to RECIST v1.0, every 12 weeks, measured using 
the same imaging technique (CT scan or MRI) for each subject throughout the study, and by 
independent central review to ensure intra and intersubject consistency and reliability. Data 
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PFS of subjects who are lost to follow up and those who are alive and without disease 
progression at the End of Study will be censored at the date of the last disease assessment 
subject to the rules summarised in Table 6. 
Table 6 
Censoring Rules for PFS 
Reason for censoring 
Rule 
No Screening evaluable assessment 
Date of first treatment administration 
Two or more not evaluable (NE) assessments before 
progressive disease or death 
Date of last evaluable disease assessment before the 
second NE assessment 
No progressive disease 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented 
progression 
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or other reason 
Date of last evaluable disease assessment 
The distribution of PFS times will be estimated using the Kaplan Meier method for each 
cohort. The median PFS time will be presented with its associated 95% CI. The results will 
also be presented graphically in Kaplan Meier plots. 
10.4.5.2 Secondary Efficacy Variables 
Median time to progression 
A similar analysis to the primary analysis will be performed. Time to progression is defined 
as time from first injection of lanreotide Autogel® 120 mg every 14 days to progression. Data 
will be analysed by cohort only. 
Subjects who are lost to follow up or who die during the study will be censored at the date of 
the last disease assessment subject to the rules summarised Table 7. 
Table 7 
Censoring Rules for Median Time to Progression 
Reason for censoring 
Rule 
No Screening evaluable assessment 
Date of first treatment administration 
Two or more NE assessments before progressive 
disease 
Date of last evaluable disease assessment before the 
second NE assessment 
No progressive disease 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented 
progression 
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or other reason 
Date of last evaluable disease assessment 
Death 
Date of last evaluable disease assessment 
The distribution of time to progression will be estimated using the Kaplan Meier method for 
each cohort. The median time to progression will be presented with its associated 95% CI. 
The results will also be presented graphically in Kaplan Meier plots. 
Proportion of subjects alive and without progression every 12 weeks 
The proportion of subjects alive and without progression will be presented by cohort every 
12 weeks with the corresponding 95% CIs. Data will be analysed by cohort only. 
Overall survival at Week 48 and at the end of the study for each cohort 
The overall survival rate will be presented at Visit 9 (Week 48) and at End of Study for both 
cohorts separately and overall, with the corresponding 95% CI. 
Objective response rate (ORR) 
The ORR is defined as the proportion of subjects who achieve either CR or PR according to 
centralised RECIST v1.0 criteria. The ORR will be computed every 12 weeks and presented 
by cohort and overall, with the corresponding 95% CI. 


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Disease control rate (DCR) 
The DCR is defined as the rate of CR plus PR plus SD, evaluated according to RECIST v1.0. 
The DCR will be presented at Weeks 24 and 48 and End of Study by cohort and overall, with 
the corresponding 95% CI. 
Best overall response 
Best overall response is defined as the best response recorded from the initiation of treatment 
until disease progression, according to RECIST v1.0 evaluation. These data will be 
summarised descriptively by cohort and overall, using a frequency table. 
Median duration of stable disease (SD) 
Median duration of SD is the time from first injection of lanreotide Autogel® 120 mg every 
14 days until the first occurrence of progressive disease by central assessment. Data will be 
analysed by cohort only.  
A similar analysis to the primary analysis will be performed. Subjects who are lost to follow 
up or who die during the study will be censored at the date of the last disease assessment 
subject to the rules summarised Table 8. 
Table 8 
Censoring Rules for Median Duration of Stable Disease 
Reason for censoring 
Rule 
No Screening evaluable assessment 
Date of first treatment administration 
Two or more NE assessments before progressive 
disease 
Date of last evaluable disease assessment before the 
second NE assessment 
No progressive disease 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented 
progression  
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or other reason 
Date of last evaluable disease assessment 
Death 
Date of last evaluable disease assessment 
The distribution of duration of SD will be estimated using the Kaplan Meier method for each 
cohort. The median duration of SD will be presented with its associated 95% CI. The results 
will also be presented graphically in Kaplan Meier plots. 
Factors associated with PFS 
A Cox proportional hazards model for each cohort will be used to estimate the stratified HR 
and its 2 sided 95% CI. The factors included in this analysis will include but will not be 
limited to: hepatic tumour volume ≤25% versus >25%, grade 1 versus grade 2, previous 
surgery of the primary tumour (yes/no), Ki67 <10% versus ≥10%, duration of treatment with 
lanreotide Autogel® 120 mg every 28 days. Each factor will be assessed for its importance in 
the model and further exploratory analyses may be carried out assessing interaction effects, 
where stratum sizes are sufficiently large. 
Symptom control (diarrhoea, flushing) at each visit 
Symptom control will be assessed by the total number of stools and flushing episodes during 
the 7 days prior to the visit reported orally by the subject to the investigator. The total number 
of stools and flushing episodes will be summarised by cohort and overall using summary 
statistics, including 95% CIs of the mean number of stools and flushing episodes, by visit. 
Quality of life 
Quality of life questionnaire overall and subscale scores will be derived according to the 
standard algorithms recommended for their derivation; full details of which will be provided 
in the SAP. Data will be summarised by cohort and overall every 12 weeks through summary 
statistics and 95% CIs of the mean values. Individual questionnaire responses will be listed 
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Incidence of all reported treatment emergent AEs (TEAEs) and SAEs will be tabulated by 
cohort and overall, by associated NCI CTCAE worst grade and by drug relationship. In the 
event of multiple occurrences of the same AEs being reported by the same subject, the 
maximum intensity (grade 5 >grade 4 >grade 3 >grade 2 >grade 1 >missing >not applicable) 
will be chosen. Haematological and biochemistry toxicities will be recorded and graded 
according to the NCI CTCAE criteria. The NCI CTCAE grade 3 and 4 haematology and 
biochemistry parameters will be listed by cohort, subject and visit. AEs resulting in dose 
delays, dose interruption and withdrawal will be listed and presented in summary tables.  
A TEAE is defined as any AE that occurs during the study if:  
• 
it was not present prior to receiving the first dose of lanreotide Autogel® 120 mg at a 
reduced dosing interval , or  
• 
it was present prior to receiving the first dose of lanreotide Autogel® 120 mg at a 
reduced dosing interval but the intensity increased during the study, or  
• 
it was present prior to receiving the first dose of lanreotide Autogel® 120 mg at a 
reduced dosing interval, the intensity is the same but the drug relationship became 
related during the study.  
All TEAEs will be flagged in the AEs listings. 
Prior and concomitant medication will be coded by using WHO drug dictionary (WHO-DD) 
and will be summarised by cohort and overall with the number and percentage of subjects 
receiving prior and concomitant medication by drug class and preferred drug name. 
Summary statistics (mean, median, StD and range as appropriate) by cohort and overall will 
be presented for physical examination and vital signs (weight and height, body temperature, 
supine and standing blood pressure) and heart rate, ECG parameters, and clinical laboratory 
tests at each assessment (absolute values and change from Baseline). For gallbladder 
echography, the presence and/or absence of lithiasis and sludge will be presented at each visit. 
For laboratory data, abnormal values will be flagged in the data listings and a list of clinically 
significant abnormal values will be presented. Shift tables will be presented of the number and 
percentage of subjects with low, normal or high values and normal or abnormal physical 
examinations. 
10.5 
Subgroup Analyses 
Descriptive statistics for the following efficacy endpoints will be presented by cohort (pNET 
and midgut) and overall: ORR, DCR, OS, best overall response, tumour biomarkers, 
symptoms (diarrhoea and flushing) and quality of life. In addition, safety analyses will be 
performed on the cohorts separately and on the overall population.  
Survival rates, ORR and DCR will also be presented for hepatic tumour volume ≤25% versus 
>25%, grade 1 versus grade 2, previous surgery of the primary tumour (yes/no) and Ki67 
<10% versus ≥10. 
10.6 
Interim Analyses 
No interim analysis will be performed. One final analysis will be performed at the end of the 
study, after database lock. 
A DSMB covering both cohorts combined will be appointed to review data, as determined in 
a DSMB charter, at the following timepoints:  
(1) 
when 20 subjects from both cohorts have reached the Week 4 evaluation,  
(2) 
when 20 subjects from both cohorts have reached the Week 12 evaluation, and  
(3) 
when 50 subjects from both cohorts have reached the Week 12 evaluation.  


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The DSMB will be composed of independent experts. The purpose of the DSMB will be to 
evaluate safety early (Week 4) and at steady state (Week 12) of the reduced dosing interval, 
and to make recommendations to the sponsor as to whether the study should continue as 
planned or whether any changes are recommended to the trial conduct or protocol. The Chair 
of the DSMB will be responsible for communicating the DSMB’s recommendations. Full 
details of the operating model for the DSMB will be provided in a DSMB charter. 


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11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
Authorised personnel from external CAs and sponsor authorised Quality Assurance personnel 
may carry out inspections and audits. The purpose of an audit is to ensure that ethical, 
regulatory and quality requirements are fulfilled in all studies performed by the sponsor. 
Auditors and inspectors must have direct access to study documents and site facilities as 
specified in Section 12.4, and to any other locations used for the purpose of the study in 
question (e.g. laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Protocol Amendments and Protocol Deviations and Violations 
12.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior 
written approval or favourable opinion of a written amendment by the IEC/IRB, except when 
necessary to eliminate immediate safety concerns to the subjects or when the change involves 
only logistics or administration. The principal investigator and the sponsor will sign the 
protocol amendment. 
12.1.2 
Protocol Deviations, Violations, and Exceptions 
A protocol deviation is nonadherence to protocol specific study procedures or schedules that 
does not involve inclusion/exclusion criteria, primary objective evaluation criteria, and/or 
GCP guidelines. Deviations are considered minor and do not impact the study. 
A protocol violation is any clinically significant divergence from the protocol, 
i.e. nonadherence on the part of the subject, the investigator, or the sponsor to protocol 
specific inclusion/exclusion criteria, primary objective evaluation criteria, and/or GCP 
guidelines. Protocol violations will be identified and recorded, by study centre personnel, on 
the eCRF. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific entry criteria 
to allow subjects to enter a study. If under extraordinary circumstances such action is 
considered ethically, medically, and scientifically justified for a particular subject, prior 
approval from the sponsor and the responsible IRB/IEC, in accordance with the Standard 
Operating Procedure (SOP), is required before the subject will be allowed to enter the study. 
If investigative centre personnel learn that a subject who did not meet protocol eligibility 
criteria was entered in a study (a protocol violation), they must immediately inform the 
sponsor. Such subjects will be discontinued from the study, except in an exceptional instance 
following review and written approval by the sponsor and the responsible IRB/IEC, according 
to the applicable SOP. 
12.2 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of subject management, both before starting any study 
procedures and during the course of the study (e.g. when new staff become involved). The 
investigator must assure that all study staff members are qualified by education, experience, 
and training to perform their specific responsibilities. These study staff members must be 
listed on the study centre authorisation form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
12.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring this data to verify that the rights and wellbeing of 
subjects are protected, that study data are accurate (complete and verifiable to source data) 
and that the study is conducted in compliance with the protocol, GCP and regulatory 
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Sponsor assigned monitors will conduct regular site visits. The investigator will allow direct 
access to all relevant files (for all subjects) and clinical study supplies (dispensing and storage 
areas) for the purpose of verifying entries made in the eCRF, and assist with the monitor’s 
activities, if requested. Adequate time and space for monitoring visits should be made 
available by the investigator. 
The site must complete the eCRFs according to the sponsor monitoring manual, of the 
subject’s visit and on an ongoing basis (in a maximum 5 days) to allow regular review by the 
study monitor, both remotely by the internet and during site visits. The study monitors will 
use functions of the EDC system to address any queries raised while reviewing the data 
entered by the study site personnel in a timely manner. 
Whenever a subject name is revealed on a document required by the sponsor (e.g. laboratory 
print outs) the name must be blacked out permanently by the site personnel, leaving the 
initials visible, and annotated with the subject number as identification. 
12.4 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 11). 
12.5 
Data Quality Assurance 
Monitored eCRFs transferred from the investigational site to the assigned Data Management 
group will be reviewed (secondary monitoring) for completeness, consistency, legibility and 
protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the investigator by the monitor for 
clarification/correction. The investigator must ensure that queries are dealt with promptly. All 
data changes and clarifications can be viewed in the audit trail function of the eCRF. 


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13 
ETHICS 
13.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, 
the Declaration of Helsinki and ICH GCP Guidelines (Section 1.6). 
The EDC system will comply with FDA, 21 CFR Part 11, Electronic Records, Electronic 
Signatures, and FDA, Guidance for Industry: Computerised Systems Used in Clinical Trials. 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent forms, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided 
to subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has 
started, amendments should be made only in exceptional circumstances. Changes that do not 
affect subject safety or data integrity are classified as administrative changes and generally do 
not require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
13.2 
Informed Consent 
Prior to study entry, the investigator, or a person designated by the investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject, subject’s 
legally acceptable representative or impartial witness. Written informed consent must be 
obtained prior to the subject entering the study (before initiation of any study related 
procedure and administration of lanreotide Autogel®). Sufficient time will be allowed to 
discuss any questions raised by the subject. 
 
 
. 
The sponsor will provide sample informed consent forms. The final version controlled forms 
must be agreed to by the sponsor and the IEC/IRB, and must contain all elements included in 
the sample forms, in language readily understood by the subject. Each subject’s original 
consent form, personally signed and dated by the subject or by the subject’s legally acceptable 
representative, and by the person who conducted the informed consent discussion, will be 
retained by the investigator. The investigator will supply subjects with a copy of their signed 
informed consent. 
The consent form(s) may need to be revised during the study should important new 
information become available that may be relevant to the safety of the subject or as a result of 
protocol amendments. In this instance approval should always be given by the IEC/IRB. It is 
the investigator’s responsibility to ensure that all subjects subsequently entered into the study 
and those currently in the study sign the amended form. This is documented in the same way 
as previously described. Subjects who have completed the study should be informed of any 
new information that may impact on their welfare/wellbeing. 
The investigator should, with the consent of the subject, inform the subject’s primary 
physician about their participation in the clinical study. 
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13.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s Regulatory Affairs group will ensure all legal 
regulatory aspects are covered, and obtain approval of the appropriate regulatory bodies, prior 
to study initiation in regions where an approval is required. 
13.4 
Confidentiality Regarding Study Subjects 
The investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In eCRFs and other 
documents or image material submitted to the sponsor, subjects will be identified not by their 
names, but by an identification code (e.g. initials and identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the eCRF. This review may be conducted by the study monitor, properly authorised persons 
on behalf of the sponsor, the quality assurance unit, or regulatory authorities. Personal 
medical information will always be treated as confidential. 


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14 
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Recording of Study Data 
In compliance with GCP, the medical records/medical notes, etc., should be clearly marked 
and permit easy identification of a subject’s participation in the specified clinical study. 
The investigator must record all data relating to protocol procedures, lanreotide Autogel® 
administration, laboratory data, safety data and efficacy ratings on the eCRFs provided for the 
study. The investigator, by completing the signature log, may formally designate authority to 
complete eCRFs to appropriately qualified staff having certified user access to the eCRF. 
Subject completed questionnaires will be printed. 
The investigator must, as a minimum, provide an electronic signature (e-signature) to each 
case report book to attest to the accuracy and completeness of all the data. If any changes are 
made to the eCRF, after a form has been locked and electronically signed, the investigator 
will be required to perform an additional e-signature authorising agreement with any new 
information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on 
each item entered. 
14.2 
Data Management 
Electronic Data Capture will be utilised for collecting subject data. Each site is required to 
have a computer and internet connection available for site entry of clinical data. All entries in 
the eCRF will be done under the electronic signature of the person performing the action. This 
electronic signature consists of an individual and confidential username and password 
combination. It is declared to be the legally binding equivalent of the handwritten signature. 
Only sponsor authorised users will have access to the eCRF as appropriate to their study 
responsibilities. Users must have successfully undergone software application training prior to 
entering data into the eCRF. 
Data management will be conducted by a CRO, directed by the Specialty Franchise Clinical 
Operation Department. All data management procedures will be completed in accordance with 
the sponsor and the contracted CRO SOPs. Prior to data being received inhouse at the assigned 
CRO, it will be monitored at the investigator site, (for further details please see Section 12.3 
Monitoring Procedures). The eCRF and other data documentation removed from the investigator 
site(s) will be tracked by the CRO and the monitor. 
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately, 
and suitable queries are raised to resolve any missing or inconsistent data. The investigator will 
receive their data, from the clinical study, in an electronic format (PDF files) which will be an 
exact copy of the eCRF, and will include the full audit trail, for archiving purposes and future 
reference. 
Any queries generated during the data management process will also be tracked by the 
contracted data management CRO/will be raised within the EDC system. It is the central study 
monitor’s responsibility to ensure that all queries are resolved by the relevant parties. 
The sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  
The coding of AEs, medical history procedures, and therapies/medications will be performed by 
Medical Dictionaries and Coding specialist upon Sponsor supervision. Therapies/medications 
will be coded using WHO-DD and AEs/medical history procedure terms will be coded using 
MedDRA. 


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14.3 
Record Archiving and Retention 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed 
by the monitor when closing out the site. The sponsor will inform the investigator, in writing, 
as to when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 


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15 
FINANCING AND INSURANCE 
15.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
sponsor and investigator responsibilities in relation to the study. Financial remuneration will 
cover the cost per included subject, based on the calculated costs of performing the study 
assessments in accordance with the protocol, and the specified terms of payment will be 
described in the contract. The contract should describe whether costs for pharmacy, laboratory 
and other protocol required services are being paid directly or indirectly. 
Financial Disclosure Statements will need to be completed, as requested by FDA 21 CFR 
Part 54. 
15.2 
Insurance, Indemnity and Compensation 
The sponsor will provide Product Liability insurance for all subjects included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 


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16 
REPORTING AND PUBLICATIONS OF RESULTS 
16.1 
Publication Policy 
The sponsor encourages acknowledgement of all individuals/organisations involved in the 
funding or conduct of the study, including medical writers or statisticians subject to the 
consent of each individual and entity concerned, including acknowledgement of the sponsor. 
The results of this study may be published or communicated to scientific meetings by the 
investigators involved in the study. For multicentre studies, a plan for scientific publication 
and presentation of the results may be agreed and implemented by the study investigators or a 
Steering Committee. The sponsor requires that reasonable opportunity be given to review the 
content and conclusions of any abstract, presentation, or paper before the material is 
submitted for publication or communicated. This condition also applies to any amendments 
that are subsequently requested by referees or journal editors. The sponsor will undertake to 
comment on the draft documents within the time period agreed in the contractual 
arrangements, including clinical trial agreements, governing the relationship between the 
sponsor and authors (or the author’s institution). Requested amendments will be incorporated 
by the author, provided they do not alter the scientific value of the material. 
If patentability would be adversely affected by publication, this will be delayed until (i) a 
patent application is filed for the content of the publication in accordance with applicable 
provisions of the clinical trial agreement concerned, (ii) the sponsor consents to the 
publication, or (iii) the time period as may be agreed in the contractual arrangements, 
including clinical trial agreements, governing the relationship between the sponsor and 
authors (or authors’ institution) after receipt of the proposed publication by the sponsor, 
whichever of (i), (ii) or (iii) occurs first. 
The author undertakes to reasonably consider the sponsor's request for delay to the proposed 
publication should the sponsor reasonably deem premature to publish the results obtained at 
the then stage of the study. 
16.2 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH guideline on 
structure and contents of CSRs. A final CSR will be prepared where any subject has signed 
informed consent, regardless of whether the study is completed or prematurely terminated. 
Where appropriate an abbreviated report may be prepared. The CSR will be in compliance 
with any applicable regulatory requirements, national laws in force and will be in English. 
Analysis of the data and preparation of the final study report will be performed once all 
subjects have reached their End of Study Visit. 
 
 
CCI


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17 
REFERENCES 
1. 
Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of 
and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J 
Clin Oncol. 2008;26:3063-3072. 
2. 
Öberg KE. Gastrointestinal neuroendocrine tumors. Ann Oncol. 2010;21 Suppl 
7:vii72-80. 
3. 
Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic 
neuroendocrine tumors. N Engl J Med 2014;371:224-233.  
4. 
Lanreotide Autogel 60, 90 and 120 mg Summary of Product Characteristics, dated 
27 February 2015. Ipsen Limited. Available at https://www.medicines.org.uk 
(Accessed 09 April 2015) 
5. 
Somatuline® Depot (lanreotide) Injection Prescribing Information, dated December 
2014. 
Ipsen 
Pharma. 
Available 
at 
http://www.accessdata.fda.gov/drugsatfda_ 
docs/label/2014/022074s011lbl.pdf (Accessed 09 April 2015) 
6. 
Danila DC, Haidar JN, Zhang X, et al. Somatostatin receptor-specific analogs: effects 
on cell proliferation and growth hormone secretion in human somatotroph tumors. J 
Clin Endocrinol Metab 2001;86:2976-2981. 
7. 
Florio T, Thellung S, Arena S, et al. Somatostatin and its analog lanreotide inhibit the 
proliferation of dispersed human non-functioning pituitary adenoma cells in vitro. Eur J 
Endocrinol 1999;141:396-408. 
8. 
Florio T, Thellung S, Corsaro A, et al. Characterization of the intracellular mechanisms 
mediating somatostatin and lanreotide inhibition of DNA synthesis and growth 
hormone release from dispersed human GH-secreting pituitary adenoma cells in vitro. 
Clin Endocrinol (Oxf) 2003;59:115-128.  
9. 
Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. 
Ann Oncol. 2006;17:1733-1742. 
10. 
Buscail L, Delesque N, Estève JP, et al. Stimulation of tyrosine phosphatase and 
inhibition of cell proliferation by somatostatin analogues: mediation by human 
somatostatin receptor subtypes SSTR1 and SSTR2. Proc Natl Acad Sci USA 
1994;91:2315-2319. 
11. 
Buscail L, Estève JP, Saint-Laurent N, et al. Inhibition of cell proliferation by the 
somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 
and 
SSTR5 
through 
different 
mechanism. 
Proc 
Natl 
Acad 
Sci 
USA 
1995;92:1580-1584. 
12. 
Sharma K, Patel YC, Srikant CB. Subtype-selective induction of wild-type p53 and 
apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. Mol Endocrinol 
1996;10:1688-1696. 
13. 
Imam H, Eriksson B, Lukinius A, et al. Induction of apoptosis in neuroendocrine 
tumors of the digestive system during treatment with somatostatin analogs. Acta Oncol 
1997;36:607-614. 
14. 
Eriksson B, Renstrup J, Imam H, Öberg K. High-dose treatment with lanreotide of 
patients with advanced neuroendocrine gastrointestinal tumours: clinical and biological 
effects. Ann Oncol 1997;8:1041-1044. 
15. 
Öberg K, Astrup L, Eriksson B, et al. Guidelines for the management of 
gastroenteropancreatic neuroendocrine tumours (including bronchopulmonary and 
thymic neoplasms). Part I-general overview. Acta Oncol 2004;43:617-625. 


IPSEN GROUP 
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CONFIDENTIAL 
PROTOCOL: FINAL (INCLUDING AMENDMENT #3): 09 JANUARY 2017 
PAGE 84/111 
 
 
16. 
Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: Somatostatin analogues 
in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment 
Pharmacol Ther. 2010;31:169-188. 
17. 
Universita' Di Genova. EudraCT Number: 2012-005222-30. Feasibility study to assess 
safety of high dose of lanreotide in NET patients poorly controlled by standard doses of 
SSA. EU Clinical Trials Register. https://www.clinicaltrialsregister.eu [Accessed 24 
March 2015] 
18. 
Hofland LJ, Lamberts SW. The pathophysiological consequences of somatostatin 
receptor internalization and resistance. Endocr Rev 2003;24:28-47. 
19. 
Janson ET, Öberg K. Long-term management of the carcinoid syndrome. Treatment 
with octreotide alone and in combination with alpha-interferon. Acta Oncol 
1993;32(2):225-229. 
20. 
Toumpanakis C, Caplin ME. Update on the role of somatostatin analogs for the 
treatment of patients with gastroenteropancreatic neuroendocrine tumors. Semin Oncol 
2013;40:56-68. 
21. 
Study 2-55-52030-724. Phase I Randomised Double Blind Placebo Controlled Parallel 
Group Study to Assess the Pharmacokinetic Profile, Safety and Tolerability of 
Lanreotide Immediate Release Formulation Administered by Intravenous Infusion at 
7 µg/kg and Lanreotide Autogel 240 mg Administered as a Single Deep Subcutaneous 
Injection in Healthy volunteers.  
22. 
Ferté C, Fernandez M, Hollebecque A et al. Tumor growth rate is an early indicator of 
antitumor drug activity in phase I clinical trials. Clin Cancer Res. 2014;20:246-252. 
23. 
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response 
to treatment in solid tumors. European Organization for Research and Treatment of 
Cancer, National Cancer Institute of the United States, National Cancer Institute of 
Canada. J Natl Cancer Inst. 2000;92:205-216. 

SAP_000.pdf: 
Document Name: Clarinet Forte Study_SAP_Final Version 2.0_13Jan2020
Approved
Clinical
12:53 GMT+0000
Clinical
 20:45:54 GMT+0000
Clinical
:51:56 GMT+0000
Clinical
00
PPD
PPD
PPD
PPD


IPSEN GROUP 
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SAP Final Version 2.0: 13 January 2020 
Page 1 of 69 
CONFIDENTIAL 
STATISTICAL AND ANALYSIS PLAN 
PROTOCOL TITLE EFFICACY AND SAFETY OF LANREOTIDE AUTOGEL® 120 
MG ADMINISTERED EVERY 14 DAYS IN WELL DIFFERENTIATED, METASTATIC 
OR LOCALLY ADVANCED, UNRESECTABLE PANCREATIC OR MIDGUT 
NEUROENDOCRINE TUMOURS HAVING PROGRESSED RADIOLOGICALLY 
WHILE PREVIOUSLY TREATED WITH LANREOTIDE AUTOGEL® 120 MG 
ADMINISTERED EVERY 28 DAYS 
PROTOCOL VERSION AND DATE: 2.0 – 15 DECEMBER 2015 
PROTOCOL AMENDEMENT 1: 07 OCTOBER 2015 
PROTOCOL AMENDEMENT 2: 15 DECEMBER 2015 
PROTOCOL AMENDEMENT 3: 09 JANUARY 2017 
SAP Version 
Date 
Final Version 1.0 
 22 January 2019 
Final Version 2.0 
13 January 2020 


IPSEN GROUP 
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SAP Final Version 2.0: 13 January 2020 
Page 2 of 69 
 
 
 
CONFIDENTIAL 
 
 
STUDY NUMBER: 
8 79 52030 326 (CLARINET FORTE) 
EUDRACT NUMBER 
2014 005607 24 
PROTOCOL TITLE: 
EFFICACY 
AND 
SAFETY 
OF 
LANREOTIDE 
AUTOGEL® 120 MG ADMINISTERED EVERY 14 
DAYS IN WELL DIFFERENTIATED, METASTATIC 
OR 
LOCALLY 
ADVANCED, 
UNRESECTABLE 
PANCREATIC OR MIDGUT NEUROENDOCRINE 
TUMOURS 
HAVING 
PROGRESSED 
RADIOLOGICALLY 
WHILE 
PREVIOUSLY 
TREATED WITH LANREOTIDE AUTOGEL® 120 MG 
ADMINISTERED EVERY 28 DAYS 
SAP VERSION: 
Final Version 2.0 
SAP DATE: 
13 January 2020 
 
Further to your review and agreement to the Statistical and Analysis Plan version 
indicated above, please sign to indicate approval for your area of responsibility: 
 
RESPONSIBILITY 
NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Clinical 
Statistics 
Manager or designee 
  
 
Boulogne Billancourt 
 
 
Medical Development 
Director 
 
 
 
 
Rare Diseases 
 
 
 
RESPONSIBILITY 
NAME, TITLE & OFFICE 
SIGNATURE 
DATE 
Statistician 
 
 
Covance Clinical Development 
SARL 
 
 
Manager Statistician 
 
  
Covance Clinical Development 
SARL 
 
 
 
PPD
PPD
PPD
PPD


IPSEN GROUP 
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SAP Final Version 2.0: 13 January 2020 
Page 3 of 69 
 
 
 
CONFIDENTIAL 
 
IMPORTANT: This completed record (with additional sheets, where required), confirms the 
above-mentioned Statistical and Analysis Plan version became the Final Statistical and 
Analysis Plan 




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CONFIDENTIAL 
 
TABLE OF CONTENTS 
1 
INFORMATION TAKEN FROM THE PROTOCOL ............................................. 11 
1.1 
Study objectives ............................................................................................................. 11 
1.1.1 
Primary objective ......................................................................................... 11 
1.1.2 
Secondary objectives ................................................................................... 11 
1.1.3 
Tertiary objectives ....................................................................................... 11 
1.2 
Study design ................................................................................................................... 12 
1.2.1 
Study population ......................................................................................... 14 
1.2.2 
Study exposure ............................................................................................ 14 
1.3 
Methods and procedures .............................................................................................. 14 
1.3.1 
Subject identification and allocation to study treatment ........................... 14 
1.3.2 
Subjects assessments ................................................................................... 15 
1.3.2.1 
Efficacy assessments .................................................................................... 15 
1.3.2.2 
Safety assessments ....................................................................................... 16 
1.3.2.3 
Other assessments ........................................................................................ 18 
1.3.2.4 
Withdrawal/discontinuation ......................................................................... 18 
1.3.3 
Schedule of assessments ............................................................................. 18 
1.3.4 
Planned sample size .................................................................................... 24 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................... 24 
2.1 
Efficacy .......................................................................................................................... 24 
2.1.1 
Full analysis set (FAS) ............................................................................... 24 
2.1.2 
Per Protocol population (PP) ..................................................................... 24 
2.2 
Safety .............................................................................................................................. 24 
2.3 
Pharmacokinetics .......................................................................................................... 24 
2.3.1 
Pharmacokinetics Valid (PK Valid) population ........................................ 24 
2.4 
Primary population ....................................................................................................... 25 
3 
STATISTICAL METHODS ........................................................................................ 25 
3.1 
Statistical analysis strategy .......................................................................................... 25 
3.1.1 
Primary efficacy endpoint(s) ...................................................................... 25 
3.1.2 
Secondary efficacy endpoint(s) ................................................................... 25 
3.1.3 
Safety endpoint(s) ........................................................................................ 32 
3.1.4 
Multiplicity .................................................................................................. 33 
3.1.5 
Significance testing and estimation ............................................................ 33 
3.2 
Analysis methods ........................................................................................................... 33 
3.2.1 
Efficacy ........................................................................................................ 33 
3.2.1.1 
Primary efficacy analysis ............................................................................. 33 
3.2.1.2 
Secondary efficacy analysis ......................................................................... 35 
3.2.2 
Safety ........................................................................................................... 42 


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3.2.2.1 
Adverse events .............................................................................................. 42 
3.2.2.2 
Laboratory data ........................................................................................... 43 
3.2.2.3 
Vital signs ..................................................................................................... 44 
3.2.2.4 
Physical examination ................................................................................... 44 
3.2.2.5 
ECG .............................................................................................................. 44 
3.2.2.6 
Gallbladder Echography ............................................................................. 45 
3.2.2.7 
Specific analysis of cholecystectomy, gallbladder surgery, lithiasis or 
sludge during the study ................................................................................ 45 
3.2.3 
Missing data and outliers ............................................................................ 45 
3.2.3.1 
Missing data ................................................................................................. 45 
3.2.3.2 
Missing or incomplete dates ........................................................................ 46 
3.2.3.3 
Outliers ........................................................................................................ 46 
3.2.4 
Subject disposition ....................................................................................... 47 
3.2.5 
Withdrawals ................................................................................................. 47 
3.2.6 
Demographic and baseline characteristics ................................................ 48 
3.2.7 
Medical and surgical history ...................................................................... 48 
3.2.8 
Prior Surgical Procedures for Pancreatic/Midgut NETs .......................... 48 
3.2.9 
Specific analysis of prior cholecystectomy, gallbladder surgery, lithiasis 
or sludge ...................................................................................................... 49 
3.2.10 
Radiotherapy for Pancreatic/Midgut NETs ............................................... 49 
3.2.11 
Subject compliance ..................................................................................... 49 
3.2.12 
Prior and concomitant therapies ................................................................ 49 
3.2.12.1 
Prior and concomitant medication .............................................................. 49 
3.2.12.2 
Prior and concomitant non-drug therapies ................................................. 50 
3.2.12.3 
Prior 
and 
concomitant 
medications 
for 
Pancreatic/Midgut 
Neuroendocrine Tumours ............................................................................ 50 
3.2.12.4 
Concomitant surgical procedures ................................................................ 51 
3.2.13 
Pharmacokinetics ........................................................................................ 51 
3.2.14 
Derived data ................................................................................................. 51 
3.2.15 
Visit windows ............................................................................................... 51 
3.2.16 
Rules and data formats ............................................................................... 53 
3.2.17 
Pooling of Centres ....................................................................................... 53 
3.2.18 
Interim analysis ........................................................................................... 54 
3.2.19 
Role of the Data Safety Monitoring Board (DSMB) ................................. 54 
3.2.20 
Covariates and analysis of subgroups ........................................................ 55 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 55 
4.1 
Hardware ....................................................................................................................... 55 
4.2 
Software ......................................................................................................................... 55 
4.3 
Validation programs ..................................................................................................... 55 
4.4 
Restitution of the programs ......................................................................................... 55 


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5 
CHANGES FROM PROTOCOL ................................................................................ 56 
6 
APPENDICES TO THE SAP TEMPLATE ............................................................... 57 
6.1 
List of TFLs ................................................................................................................... 57 
6.1.1 
Listings index .............................................................................................. 57 
6.1.2 
Tables and Figures index ........................................................................... 61 
7 
REFERENCES .............................................................................................................. 69 
 


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CONFIDENTIAL 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
5-HIAA: 
AE: 
5 Hydroxyindoleacetic Acid 
Adverse Event 
ALP: 
Alkaline phosphatase 
ALT (SGPT): 
Alanine aminotransferase 
ANCOVA:  
Analysis of Covariance 
AST (SGOT): 
Aspartate aminotransferase 
ATC: 
Anatomic Therapeutic Chemical 
AUC: 
Area Under the Curve 
BMI: 
Body Mass Index 
CgA: 
CI: 
CLARINET: 
 
Chromogranin A 
Confidence interval 
Controlled Study of Lanreotide Anti proliferative Response in 
Neuroendocrine Tumours 
CR: 
CRF: 
Complete response 
Case Report Form 
CRO: 
Contract Research Organisation 
CSR: 
CT: 
DCR:  
Clinical Study Report 
Computed Tomography 
Disease Control Rate 
DSMB: 
Data Safety Monitoring Board 
e: 
Electronic 
ECG: 
Electrocardiogram 
ECOG: 
EORTC: 
 
EQ-5D-5L: 
FAS: 
FDA: 
GGT: 
GI: 
Eastern Cooperative Oncology Group 
European Organisation for Research and Treatment of Cancer 
EuroQoL 5 dimensions, 5 levels 
Full analysis set 
Food and Drug Administration 
Gamma-Glutamyl Transferase 
Gastrointestinal 
HbA1c 
Haemoglobin A1C 
HR: 
ICH: 
Hazard Ratio 
International Conference on Harmonisation  


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IMP: 
Investigational Medicinal Product 
Ki67: 
Proliferation index 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCI-CTC: 
NCI-CTCAE: 
National Cancer Institute - Common Toxicity Criteria 
National Cancer Institute - Common Terminology Criteria for 
Aes 
NET: 
NSE: 
ORR: 
OS: 
Neuroendocrine Tumours 
Neuron Specific Enolase 
Objective Response Rate 
Overall Survival 
PD: 
Progressive Disease 
PDD: 
Protocol Deviation Document 
PH: 
Proportional Hazards 
PhD: 
Pharmacodynamics 
PK: 
Pharmacokinetic 
PFS: 
pNET: 
POPPK: 
PP: 
PR:  
Progression Free Survival 
Pancreatic Neuroendocrine Tumours 
Population PK 
Per Protocol 
Partial response 
PV: 
Pharmacovigilance 
QLQ C30: 
QLQ GI.NET21: 
 
QRS: 
Quality of Life Questionnaire Core 30 
Quality of Life Questionnaire Gastrointestinal 
Neuroendocrine Tumour 21 
QRS interval duration 
QT: 
Time interval for ventricular depolarisation and repolarisation 
QTc: 
Corrected QT interval 
SAP: 
Statistical and Analysis Plan  
SD: 
Se: 
SoD: 
Sp: 
Stable Disease 
Sensitivity 
Sum of Diameter 
Specificity 


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RBC: 
RECIST: 
Red blood cell 
Response Evaluation Criteria in Solid Tumours 
ROC: 
SAE: 
Receiver Operating Characteristics 
Serious Adverse Event/Experience 
SAS®: 
s.c.: 
Statistical Analysis System® 
Subcutaneous 
SI: 
Standard International 
SOP: 
SSTR 
Standard Operating Procedure 
Somatostatin receptor 
StD: 
TEAE: 
Standard Deviation 
Treatment Emergent Adverse Event 
TFLs: 
Tables, Figures and Listings 
 
 
 
UK 
United Kingdom 
ULN 
Upper Limit of Normal 
WBC: 
White blood cell 
WHO- DD: 
World Health Organization – Drug dictionary 
 
 
 
 
 
CCI
CCI


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CONFIDENTIAL 
 
1 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1 
Study objectives 
1.1.1 
Primary objective 
The primary objective of the study is to assess progression free survival (PFS) when treated 
with lanreotide Autogel® 120 mg administered every 14 days based on Response Evaluation 
Criteria in Solid Tumours (RECIST) v1.0 [1], and according to central review. 
1.1.2 
Secondary objectives 
The secondary objectives of the study are as follows: 
• 
To evaluate the clinical and biological safety profile. 
• 
To evaluate time to progression. 
• 
To evaluate PFS rate every 12 weeks. 
• 
To evaluate overall survival (OS) at Week 48 and at the end of the study period in each 
cohort. 
• 
To evaluate the objective response rate (ORR) as per RECIST v1.0 every 12 weeks. 
• 
To evaluate the disease control rate (DCR) as per RECIST v1.0 at Weeks 24 and 48 and 
at the end of study period in each cohort. 
• 
To evaluate the best overall response as per RECIST v1.0. 
• 
To evaluate the duration of stable disease (SD) as per RECIST v1.0. 
• 
To detect predictive factors of PFS. 
• 
To evaluate the effect on symptoms (diarrhoea, flushing). 
• 
To evaluate quality of life. 
• 
To evaluate the changes in tumour biomarkers: 
- 
pNET cohort: nonspecific tumour biomarkers (Chromogranin A (CgA), neuron 
specific enolase (NSE) and 5-hydroxyindoleacetic acid (5-HIAA); 5-HIAA only 
in subjects with symptoms of carcinoid syndrome (diarrhoea and/or flushing) or if 
urinary 5-HIAA was elevated (above upper limit of normal (ULN)) at Baseline) 
and pancreatic neuroendocrine tumours (pNET)-specific tumour biomarkers 
(e.g. pancreatic polypeptide, gastrin, glucagon, somatostatin (SST), …; only for 
the tumour biomarkers above normal range at Baseline). 
- 
Midgut cohort: nonspecific tumour biomarkers (CgA, NSE and 5-HIAA).  
• 
To evaluate the appearance of antilanreotide antibodies.  
• 
To evaluate the pharmacokinetic (PK) profile of lanreotide and to evaluate, if any, the 
relationship between PK and pharmacodynamics (PhD) (PFS, tumour response or CgA).  
• 
To evaluate, if any, the relationships between PK parameters and the safety outcomes. 
1.1.3 
Tertiary objectives 
• 
 
  
 
 
 
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1.2 
Study design 
This is a phase II, multicentre, prospective, open label, noncomparative, exploratory study to 
evaluate the efficacy and safety of lanreotide Autogel® at a reduced dosing interval of 120 mg 
every 14 days in well differentiated, metastatic or locally advanced, unresectable pancreatic or 
midgut neuroendocrine tumours having progressed radiologically while previously treated with 
lanreotide autogel® 120 mg administered every 28 days. 
Subjects will be recruited into one of two cohorts based on their primary location of NET (i.e. 
pNET cohort and midgut cohort). 
 
The study consists of a Screening visit (Visit 1, Day -28 / Day -1), where informed consent is 
taken, followed by a Screening period of up to 28 days, where eligibility tests and assessments 
are performed.  
At Baseline (Visit 2), subject eligibility is verified and Baseline assessments are performed, 
followed by an open label treatment period. Eligible subjects are treated with lanreotide 
Autogel® at a reduced dosing interval (i.e. 120 mg every 14 days) beginning at Visit 2. Subjects 
in the pNET cohort are treated for up to 48 weeks and subjects in the midgut cohort are treated 
for up to 96 weeks. In both cohorts, treatment will be discontinued at disease progression or 
death, or unacceptable toxicity or tolerability.  
Study visits are performed at Weeks 2, 4, 8, 12, 24, 36 and 48 (both cohorts), and Weeks 60, 
72, 84 and 96 (midgut cohort only). As long as 25 events, i.e. either progressions (assessed 
centrally) or deaths, have not been observed in the respective cohorts, subjects who have not 
progressed at Week 48 (pNET cohort) or Week 96 (midgut cohort) will continue study 
treatment with lanreotide Autogel® 120 mg every 14 days and additional visits will be 
performed every 12 weeks until disease progression or death, or unacceptable toxicity or 
tolerability. 
For all subjects, with the exception of those who have died, final evaluations will be performed 
at the End of Study visit approximately 2 weeks (±7 days) after the subject's last treatment visit, 
once central review of radiological imaging data is available. 
The study schema is provided in Figure 1. 
Figure 1 Study Schema 


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Figure 1 Study Schema 


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1.2.1 
Study population 
It is planned to enrol a total of 100 subjects (50 subjects per cohort), in 30 to 35 centres in 
Belgium, France, Germany, Republic of Ireland, Italy, Spain, the United Kingdom (UK), the 
Netherlands, Denmark and Poland.  
Adults with well differentiated (grade 1 or 2 according to WHO 2010 classification), metastatic 
or locally advanced, unresectable pancreatic neuroendocrine tumours (pNET) or midgut 
neuroendocrine tumours (NET) with or without hormone related syndromes and who have had 
radiologically documented disease progression (as per RECIST v1.0) at least 24 weeks after 
their first injection of lanreotide Autogel® 120 mg at the standard dosing interval of every 28 
days will be recruited in this study. 
1.2.2 
Study exposure 
This study will consist of a Screening period of up to 28 days, a Baseline Visit (Visit 2), 
followed by an open label treatment period of up to 48 weeks (pNET cohort) or up to 96 weeks 
(midgut cohort), and a final End of Study visit approximately 2 weeks after the last treatment 
visit.  
Each subject will participate in the study treatment phase for up to 48 weeks (pNET cohort) or 
up to 96 weeks (midgut cohort), or longer (i.e. until 25 events i.e. either progressions assessed 
centrally or deaths, have been observed) for subjects who have not progressed within this time. 
The overall duration of the study will be approximately 102 weeks assuming at least 25 subjects 
progress within 48 and 96 weeks in the 2 cohorts respectively.  
Subjects who complete all scheduled visits or who have progressed or died will be considered 
to have completed the study.  
For all subjects, with the exception of those who have died, final evaluations will be performed 
at the End of Study visit approximately 2 weeks (±7 days) after the subject's last treatment visit, 
once central review of radiological imaging data is available. 
The subject’s participation in the study will be considered to have ended at the time of their last 
visit (End of Study) or death. 
The study will be considered to have started when the first subject has provided signed informed 
consent. 
The study will be considered to have ended after the last subject has completed the End of Study 
visit. 
 
1.3 
Methods and procedures 
1.3.1 
Subject identification and allocation to study treatment 
After informed consent is obtained, subjects who are screened will be allocated a subject 
number. All screened subjects must be identifiable throughout the study. The investigator will 
maintain a list of subject numbers and names to enable records to be found at a later date if 
required. 


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1.3.2 
Subjects assessments 
1.3.2.1 
Efficacy assessments 
 
• 
Tumour assessments  
Tumour assessments will be performed using the RECIST v1.0 criteria every 12 weeks 
throughout the study: 
- at screening (Visit 1),  
- Visit 6 (Week 12), Visit 7 (Week 24), Visit 8 (Week 36), Visit 9 (Week 48) for both cohorts,  
- Visit 10 (Week 60), Visit 11 (Week 72), Visit 12 (Week 84), Visit 13 (Week 96) for midgut 
cohort only, and, 
- additionally every 12 weeks for subjects who have not progressed. Subjects in the pNET 
cohort who have not progressed at Week 48 will continue to receive lanreotide Autogel® every 
14 days and be followed up every 12 weeks until progression, death, or unacceptable toxicity 
or tolerability until 25 events have been observed in the pNET cohort. Similarly, subjects in the 
midgut cohort who have not progressed at Week 96 will continue to receive study treatment 
every 14 days after Week 96 and will also be followed up every 12 weeks until progression, 
death, or unacceptable toxicity or tolerability until 25 events have been observed in the midgut 
cohort. 
The same imaging technique (CT scan or MRI) will be used for each subject throughout the 
study and assessments will be made by independent central review to ensure intra and 
intersubject consistency and reliability. 
From the imaging data, median PFS and PFS rate, median time to progression, objective 
response rate, best overall response, disease control rate and median duration of stable disease 
will be estimated,
 on 
CT or MRI. 
In addition, at Screening, the Central Reading Contract Research Organisation (CRO) will 
measure the hepatic tumour load. 
 
• 
Symptoms of diarrhoea and flushing 
Symptom control (diarrhoea, flushing) at Baseline, Visit 5 (Weeks 8), Visit 6 (Week 12) and 
every 12 weeks thereafter, and at the End of Study visit, as measured by the total number of 
stools and flushing episodes during the 7 days prior to the visit reported orally by the subject to 
the investigator. 
 
• 
Quality of life questionnaires (QLQ-C30, QLQ-GI.NET21, EQ-5D-5L) 
The questionnaires will be completed at Baseline, Visit 6 (Week 12), Visit 7 (week 24), Visit 8 
(Week 36), Visit 9 (Week 48) for both cohorts, Visit 10 (Week 60), Visit 11 (Week 72), Visit 
12 (Week 84), Visit 13 (Week 96) for midgut cohort only, and then every 12 weeks until 
progression, death, or unacceptable toxicity or tolerability until 25 events have been observed 
in each cohort. 
 
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• 
Tumour biomarkers concentration Blood samples will be taken for tumour biomarker 
analyses as follows: 
• 
pNET cohort:  
- 
nonspecific tumour biomarkers (CgA, NSE and 5-HIAA) at Baseline, every 
12 weeks thereafter and at the End of Study visit (plasma 5-HIAA at all 
scheduled visits; urinary 5-HIAA at Baseline, Week 12 and at the End of 
Study visit only). Note: at all scheduled visits, except Baseline, 
plasma/urinary 5-HIAA should only be performed in subjects with 
symptoms of carcinoid syndrome (diarrhoea and/or flushing) or if urinary 
5-HIAA was elevated (above ULN) at Baseline.  
 
- 
pNET-specific tumour biomarkers (e.g. pancreatic polypeptide, gastrin, 
glucagon, SST, …) at Baseline, every 12 weeks thereafter and at the End of 
Study visit: only for the tumour biomarkers above normal range at Baseline.  
• 
Midgut cohort:  
- 
nonspecific tumour biomarkers (CgA, NSE and 5-HIAA) at Baseline, every 
12 weeks thereafter and at the End of Study visit (plasma 5-HIAA at all 
scheduled visits; urinary 5-HIAA at Baseline, Week 12 and at the End of 
Study visit only). 
 
1.3.2.2 
Safety assessments 
 
• 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study. AEs will be elicited by direct, nonleading questioning or by spontaneous 
reports. 
AEs will be recorded and graded according to the National Cancer Institute Common 
Terminology Criteria for AEs (NCI-CTCAE) (Version 4.03, Dated 14 June 2010). 
 
• 
Vital signs 
Blood pressure and heart rate will be collected at each visit (except baseline). 
Blood pressure and heart rate will be recorded after 5 minutes rest in the supine position and 
after 1 minute standing. 
Body temperature will also be recorded.  
Any clinically significant abnormalities will be recorded as AEs. 
 
• 
Physical Examination 
Physical examinations, including body weight and height (screening only) will be conducted at 
each visit (except baseline). 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 
the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 


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• 
Electrocardiography 
The Electrocardiograms (ECGs) will be recorded at Screening (Visit 1), Visit 4 (Week 4), 
Visit 7 (Week 24), for both cohorts, at Visit 9 (Week 48) for pNET cohort, and Visit 13 (Week 
96) for midgut cohort, and at the end of study/early withdrawal visit for both cohorts. 
Computerised standard 12 lead ECGs will be used so that the different ECG parameters (sinus 
rhythm, heart rate, RR interval, PR interval, QRS interval, QT and QTc) can be measured 
automatically. QTc will be calculated using Fridericia methodology. The ECG will be recorded 
with the subject in a supine position after 5 minutes of rest until four regular consecutive 
complexes are available. Automated ECG interval estimates taken from the ECG recorder will 
be used in this study.  
Any clinically significant abnormalities will be recorded as AEs. 
 
• 
Gallbladder echography 
Gallbladder echography will be conducted at Screening (Visit 1), Visit 7 (Week 24), for both 
cohorts, at Visit 9 (Week 48) for pNET cohort, and Visit 13 (Week 96) for midgut cohort, and 
at the end of study/early withdrawal visit for both cohorts, or at any time if symptoms are 
thought to be related to gallbladder lithiasis, as per study site procedures. The presence of 
lithiasis or sludge will be assessed and recorded (yes/no) on the eCRF. Any clinically significant 
abnormalities will be recorded as AEs. 
 
• 
Clinical Laboratory Tests 
Blood samples will be collected at all visits (except V3) for the evaluation of haematology and 
biochemistry panels, liver and pancreatic enzymes. Urine samples will be collected at screening 
(Visit 1), baseline (Visit 2), Visit 9 (Week 48) for both cohorts, Visit 13 (Week 96) for midgut 
cohort only, and at end of study/early withdrawal visit (for both cohorts).  
 
Haematology – the following parameters will be assessed: red blood cell (RBC) count 
(Erythrocytes), haemoglobin, haematocrit, mean corpuscular volume (MCV), mean 
corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), 
white blood cell (WBC) count (Leukocytes) with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, and others) and platelet count (platelets). 
 
Blood Biochemistry – the following parameters will be assessed: 
• 
urea, creatinine, total bilirubin, direct bilirubin 
• 
chloride, bicarbonate, sodium, potassium, calcium, calcium corrected, phosphate 
• 
alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), gamma glutamyl transferase (GGT) 
• 
albumin, protein, total cholesterol, triglycerides, fasting glucose (blood sample to be 
taken after at least 6 hours of fasting), random glucose, amylase and lipase 
Blood samples will be collected to assess Haemoglobin A1C (HbA1c). 
 
Urinalysis – the following parameters will be assessed: pH, urine color, protein, ketones, 
bilirubin, blood, urobilinogen, nitrites, leukocytes, glucose and specific gravity. 


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Microscopic urine - the following parameters will be assessed if clinically indicated: Urine 
White Blood Cells (WBC Cells), Urine Red Blood Count (RBC Cells), Squamous Epithelial 
Cells, Mucous Fibers Urine, Bacteria, U Amorphous, Crystals, Sperm Urine, Urine Waxy 
Casts, Granular Cast, Hyaline Cast, RBC Cast, WBC Cast, Trichomonas Vaginalis Urine, 
Glitter Cells, Renal Epithelial Cells and Transitional Epithelial Cells. 
 
1.3.2.3 
Other assessments 
The following parameters will be assessed at Screening (Visit 1) or prior to administration of 
study treatment at Baseline (Visit 2; Day 1): 
• 
Demographic data (country, age, sex and race), 
• 
Significant medical or surgical history, 
• 
All prior medications or therapies: prior surgical procedures for pancreatic/midgut 
NETs, prior radiotherapy for pancreatic/midgut NETs, prior therapies given to a subject for 
another indication than study disease (within 28 days before study drug administration), prior 
medications (within 28 days before study drug administration), prior non-drug therapies, prior 
medications for pancreatic/midgut NETs 
• 
NET 
diagnosis 
(location 
of 
primary 
tumour, 
histopathological 
type 
for 
pancreatic/midgut, tumour grading (according to WHO 2010 classification), proliferation index 
KI67, date of NET diagnostic), 
• 
SSTR2 assessment /Krenning Scale, 
• 
ECOG performance Status Scale. 
 
• 
Pharmacokinetic (PK) and Pharmacodynamic (PhD) analyses 
PK and PK/PhD analyses will be described in a separate Data Analysis Plan. 
 
1.3.2.4 
Withdrawal/discontinuation 
A subject may discontinue participation in the study at any time for any reason (for example 
lost to follow-up, withdrawal of consent, AE). The investigator and/or sponsor can withdraw a 
subject from the study at any time for any reason (for example protocol violation or deviation 
as defined in Section 12.1.2 of the protocol, noncompliance with the protocol conditions or 
AE).  
Subjects who complete all scheduled visits or who have progressed or died will be considered 
to have completed the study. 
1.3.3 
Schedule of assessments 
The schedule of procedures and assessments during the study for the pNET and midgut cohorts 
is summarised in Table 1 and Table 2, respectively. 


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Table 1 
Study Procedures and Assessments (pNET Cohort) 
Procedures and assessments 
Screening 
period 
Treatment period 
End of 
Study/Early 
withdrawal [a] 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
VX[b] 
EoS/EW 
-28 days 
Baseline 
(Day 1) 
W2 
W4 
W8 
W12 
W24 
W36 
W48 
q12W 
 
Informed consent 
X  
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Significant medical or surgical history 
X 
 
 
 
 
 
 
 
 
 
 
NET history 
X 
 
 
 
 
 
 
 
 
 
 
Prior treatments for study disease 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Imaging assessment of SSTR2 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X  
 
 
 
 
 
 
 
 
 
 
Radiology imaging assessments (CT or MRI)[c] 
X[d] 
 
 
 
 
X 
X 
X 
X 
X 
 
Physical examination (including height (Screening only) 
and weight) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptoms (diarrhoea, flushing) [e]  
 
X 
 
 
X  
X 
X 
X 
X 
X 
X 
Prior and concomitant medication, and concomitant 
surgery and nondrug therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of life questionnaires (QLQ-C30, 
QLQ-GI.NET21, EQ-5D-5L)  
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Study drug administration [f] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Gallbladder echography[g] 
X 
 
 
 
 
 
X 
 
X 
 
X 
Clinical laboratory tests (haematology and biochemistry 
panels, liver and pancreatic enzymes) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
X 
Nonspecific tumour biomarkers: 5-HIAA, NSE and CgA 
[h] 
 
X[i] 
 
 
 
X[i] 
X 
X 
X 
X 
X[i] 


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Procedures and assessments 
Screening 
period 
Treatment period 
End of 
Study/Early 
withdrawal [a] 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
VX[b] 
EoS/EW 
-28 days 
Baseline 
(Day 1) 
W2 
W4 
W8 
W12 
W24 
W36 
W48 
q12W 
 
pNET-specific tumour biomarkers (e.g. pancreatic 
polypeptide, gastrin, glucagon, SST, …,) [j]  
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
PK samples  
 
X[k] 
 
 
 
X[l] 
X[m] 
 
X[n] 
 
X[o] 
Antilanreotide antibodies 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
5-HIAA=5 hydroxyindoleacetic acid; CgA=chromogranin A; CT=computed tomography; 
; ECG=electrocardiogram; EoS=End of Study; EQ-5D-
5L=EuroQoL 5 dimensions, 5 levels; EW=early withdrawal; MRI=magnetic resonance imaging; NET=neuroendocrine tumour; NSE=neuron specific enolase; 
PK=pharmacokinetic; pNET=pancreatic NET; q12w=every 12 weeks; QLQ-C30=Quality of Life Questionnaire Core 30; QLQ-GI.NET21=Quality of Life 
Questionnaire Gastrointestinal Neuroendocrine Tumour 21; 
; SST=somatostatin; SSTR2=somatostatin receptor 2; ULN=upper limit of 
normal; V=Visit; W=Week. 
Note: for study visits up to and including Week 4, visit windows are ±2 days and for visits after Week 4, visit windows are ±7 days. 
a  
to be scheduled approximately 2 weeks after last treatment visit, once central review of radiological imaging is available. 
b 
additional visits every 12 weeks: only for subjects not progressing within 48 weeks until 25 events have been observed in the pNET cohort. 
c 
CT or MRI of the abdomen; additional scan of the pelvis and/or chest as deemed necessary or clinically indicated, or as per the centre's standard of care. 
d 
radiology imaging assessments (CT or MRI) performed prior to signature of the informed consent form but within 28 days of the Baseline Visit (Visit 2; Day 1) do 
not need to be repeated as a screening procedure provided that the radiology imaging was performed at the centre's radiology facility or that the radiology imaging 
was deemed by the centre's radiologist to be of sufficient quality to be used as the reference screening assessment for the evaluation of response during the study. 
e 
subjects will report the total number of stools and flushing episodes during the 7 days prior to the visit orally to the investigator. 
f 
study drug will be administered every 14 days (±1day). 
g 
may be performed at any time if symptoms are thought to be related to gallbladder lithiasis. 
h 
at all scheduled visits, except Baseline, plasma/urinary 5-HIAA should only be performed in subjects with symptoms of carcinoid syndrome (diarrhoea and/or 
flushing) or if urinary 5-HIAA was elevated (above ULN) at Baseline. 
i 
in addition to plasma 5-HIAA, urinary 5-HIAA will be assessed at Baseline, Week 12 and at the End of Study visit only. 
j 
only for the tumour biomarkers above normal range at Baseline. 
k 
collected prior to and 2 to 3 hours after the first injection (exact time to be recorded) at reduced dosing intervals. 
l 
collected prior to injection. 
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m 
collected prior to injection in all subjects, except in a subset of 30 subjects from selected sites who provide additional informed consent, where a sample will be 
collected 1 to 3 days after the injection instead. 
n 
collected prior to and 2 to 3 hours after the injection (exact time to be recorded). 
o 
at End of Study only: prior to any administration of commercial product (if applicable). 
p 
 
 
 
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Table 2 
Study Procedures and Assessments (Midgut Cohort) 
Procedures and assessments 
Screening 
period 
Treatment period 
End of 
Study/Early 
withdrawal[a] 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
VX[b] 
EoS/EW 
-28 days 
Baseline 
(Day 1) 
W2 
W4 
W8 W12 W24 W36 W48 W60 W72 W84 W96 q12W 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Significant medical or surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NET history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior treatments for study disease 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging assessment of SSTR2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiology imaging assessments (CT or 
MRI)[c] 
X[d] 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination (including height 
(Screening only) and weight) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptoms (diarrhoea, flushing)[e] 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medication, and 
concomitant surgery and nondrug therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of life questionnaires (QLQ-C30, 
QLQ-GI.NET21, EQ-5D-5L) 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration[f] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
Gallbladder echography[g] 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Clinical laboratory tests (haematology and 
biochemistry panels, liver and pancreatic 
enzymes) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 


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Procedures and assessments 
Screening 
period 
Treatment period 
End of 
Study/Early 
withdrawal[a] 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
VX[b] 
EoS/EW 
-28 days 
Baseline 
(Day 1) 
W2 
W4 
W8 W12 W24 W36 W48 W60 W72 W84 W96 q12W 
 
Nonspecific tumour biomarkers: 5-HIAA, 
NSE and CgA 
 
X[h] 
 
 
 
X[h] 
X 
X 
X 
X 
X 
X 
X 
X 
X[h] 
PK samples  
 
X[i] 
 
 
 
X[j] X[k] 
 
X[l] 
 
 
 
X[j] 
 
X[m] 
Antilanreotide antibodies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
] 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
5-HIAA=5-hydroxyindoleacetic acid; CgA=chromogranin A; CT=computed tomography; 
; ECG=electrocardiogram; EoS=End of Study; EQ-5D-5L=EuroQoL 5 
dimensions, 5 levels; EW=early withdrawal; MRI=magnetic resonance imaging; NET=neuroendocrine tumour; NSE=neuron specific enolase; PK=pharmacokinetic; pNET=pancreatic NET; 
q12w=every 12 weeks; QLQ-C30=Quality of Life Questionnaire Core 30; QLQ-GI.NET21=Quality of Life Questionnaire Gastrointestinal Neuroendocrine Tumour 21; 
; 
SST=somatostatin; SSTR2=somatostatin receptor 2; V=Visit; W=Week. 
Note: for study visits up to and including Week 4, visit windows are ±2 days and for visits after Week 4, visit windows are ±7 days. 
a 
to be scheduled approximately 2 weeks after last treatment visit, once central review of radiological imaging is available. 
b 
additional visits every 12 weeks: only for subjects not progressing within 96 weeks until 25 events have been observed in the midgut cohort. 
c 
CT or MRI of the abdomen; additional scan of the pelvis and/or chest as deemed necessary or clinically indicated, or as per the centre's standard of care. 
d 
radiology imaging assessments (CT or MRI) performed prior to signature of the informed consent form but within 28 days of the Baseline Visit (Visit 2; Day 1) do not need to be repeated as 
a screening procedure provided that the radiology imaging was performed at the centre's radiology facility or that the radiology imaging was deemed by the centre's radiologist to be of sufficient 
quality to be used as the reference screening assessment for the evaluation of response during the study. 
e 
subjects will report the total number of stools and flushing episodes during the 7 days prior to the visit orally to the investigator. 
f 
study drug will be administered every 14 days (±1day). 
g 
may be performed at any time if symptoms are thought to be related to gallbladder lithiasis. 
h 
in addition to plasma 5-HIAA, urinary 5-HIAA will be assessed at Baseline, Week 12 and at the End of Study visit only. 
i 
collected prior to and 2 to 3 hours after the first injection (exact time to be recorded) at reduced dosing intervals. 
j 
collected prior to injection. 
k 
collected prior to injection in all subjects, except in a subset of 30 subjects from selected sites who provide additional informed consent, where a sample will be collected 1 to 3 days after the 
injection instead. 
l 
collected prior to and 2 to 3 hours after the injection (exact time to be recorded). 
m at End of Study only: prior to any administration of commercial product (if applicable). 
n 
 
. 
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1.3.4 
Planned sample size 
The sample size in this pilot study is 100 subjects in total (50 subjects per cohort). This should 
be sufficient to explore the efficacy of lanreotide Autogel® 120 mg at a reduced dosing interval. 
 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) 
The following populations will be used during statistical analyses: 
The Screened population, i.e. all subjects screened (i.e. who signed the informed consent), the 
enrolled subjects, i.e the screened subjects included in the study and the Full analysis set (FAS), 
Per protocol (PP) population, the Pharmacokinetics Valid (PK Valid) population, as described 
below. 
2.1 
Efficacy  
2.1.1 
Full analysis set (FAS) 
The FAS includes all subjects who received at least one dose of lanreotide Autogel® 120 mg 
every 14 days during the study. 
 
2.1.2 
Per Protocol population (PP) 
The Per Protocol population includes all subjects in the FAS for whom no major protocol 
violations/deviations occurred. 
 
Criteria for exclusion from the Per Protocol population should be provided in the deviations 
specification document. Listings of subjects regarding inclusion in each population and 
satisfying the population definition and associated data will be reviewed by the study team. 
 
Reasons for exclusion from Per Protocol population will be presented in a summary table by 
cohort. 
2.2 
Safety 
The analyses of safety data will be performed on the FAS. 
 
2.3 
Pharmacokinetics 
2.3.1 
Pharmacokinetics Valid (PK Valid) population 
Pharmacokinetics Valid (PK Valid) population will consist of all subjects who received at least 
one dose and who have at least one serum lanreotide concentration. A subject having at least 
one valid PK concentration (including PK sampling with minor deviation) among other major 
deviations should be kept in the PK valid population. In case of a single major deviation, the 
corresponding timepoints are discarded but the subject is still included in the PK valid 
population. 
 


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2.4 
Primary population 
The primary analysis based on the primary efficacy endpoint will be performed on the FAS. All 
secondary and tertiary endpoints will be evaluated based on the FAS population. In addition, a 
PP population analysis will be performed on the primary and secondary endpoints of PFS (i.e. 
median PFS and PFS rate), median time to progression, ORR, DCR, best overall response and 
median duration of SD, if the difference in number of subjects between FAS and PP population 
is > 10%, based on subjects in FAS. 
The analyses of safety data will be performed on the FAS. 
PK endpoints will be analysed and population PK (POPPK) modelling will be performed on 
the PK Valid population. 
 
3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with ICH E9 guidelines [2] and will 
be based on the pooled data from the individual study sites, unless otherwise stated. 
When overall statistics are provided in addition to the statistics by cohort, it is for descriptive 
purpose only and not for inferential purpose to any population.   
Statistical analyses will be performed by Chiltern. 
3.1.1 
Primary efficacy endpoint(s) 
The primary endpoint is median PFS, where PFS is defined as the time from first injection of 
lanreotide Autogel® 120 mg every 14 days to progression or death (whichever occurs first). 
Disease progression will be assessed by tumour response evaluation according to RECIST v1.0, 
every 12 weeks, measured using the same imaging technique (CT scan or MRI) for each subject 
throughout the study, and by independent central review to ensure intra and intersubject 
consistency and reliability. 
 
3.1.2 
Secondary efficacy endpoint(s) 
The secondary efficacy endpoint(s) are: 
 
(a) 
Median time to progression  
Time to progression is defined as the time from first injection of lanreotide Autogel® 
120 mg every 14 days to progression. 
 
(b) 
Proportion of subjects alive and without progression every 12 weeks. 
 
(c) 
Overall survival (OS) at Week 48 and at the end of the study for each cohort.  
The overall survival is defined as the time in months from the first injection of lanreotide 
Autogel® 120 mg every 14 days to death due to any cause. 
 


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(d) 
Objective response rate (ORR) every 12 weeks as per RECIST v1.0.  
The ORR is defined as the proportion of subjects who achieve either CR or PR according 
to centralised RECIST v1.0 criteria. A responder is defined as a subject experiencing 
either a CR or PR by these criteria. 
 
(e) 
Disease control rate (DCR) at Weeks 24, 48 and End of study. 
The DCR is defined as the rate of CR plus PR plus SD, evaluated according to RECIST 
v1.0. 
 
(f) 
Best overall response  
The best overall response according to RECIST v1.0 is defined as the best response 
recorded from the initiation of lanreotide Autogel® 120 mg every 14 days until disease 
progression (Table 3). 
Table 3 
Overall Response 
Target lesion 
Non target lesion 
New lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non progressive disease 
No 
PR 
SD 
Non progressive disease 
No 
SD 
Progressive disease 
Any 
Yes or no 
Progressive disease 
Any 
Progressive disease 
Yes or no 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
CR=complete response; PR=Partial response; SD=stable disease [1]. 
 
(g) 
Median duration of stable disease (SD) 
Duration of SD according to RECIST v1.0 is defined as the time from first injection of 
lanreotide Autogel® 120 mg every 14 days until the first occurrence of progressive 
disease by central assessment (in months).  
 
(h) 
Factors associated with PFS 
To detect prognostic factors of PFS, the effects of the following factors will be explored 
simultaneously on PFS: hepatic tumour load ≤25% versus >25%, grade 1 versus grade 
2, previous surgery of the primary tumour (Yes versus No), Ki67 <10% versus ≥10%, 
duration of treatment with lanreotide Autogel® 120 mg every 28 days by category (≥ 
median value versus < median value) , age by category (≥65 years, <65 years), time from 
diagnostic to study entry (by category: ≥3 years versus < 3 years), Time interval between 
the 2 CT scans (pre-screening / screening) <12 months / >=12 months) and symptoms (diarrhoea 
or flushing at baseline: Yes / No). Other potential factors to consider will be discussed 
during the Blind Review Meeting. 
 
(i) 
Symptom control (diarrhoea, flushing), as measured by presence/absence of each 
symptom and by the total number of stools and flushing episodes during the 7 days prior 
to the visit reported orally by the subject to the investigator. 
 


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(j) 
Quality of life measured at Baseline, Week 12 and every 12 weeks thereafter, and at the 
End of Study visit, after diagnosis of progression, using EORTC QLQ-C30 v3.0 and 
QLQ-GI.NET21 (2006), and EQ-5D-5L v1.0 questionnaires. 
 
EORTC QLQ-C30 v3.0 
The European Organisation for Research and Treatment of Cancer (EORTC) score 
questionnaire (QLQ-C30) will be used for quality of life (QoL) evaluation. 
Following the EORTC recommendations, fifteen scales can be derived from the initial 30 
questions: 
- A global health status/QoL scale, 
- Five functional, scales (physical, role, cognitive, emotional and social), 
- Nine “symptoms” scales /items (nausea and vomiting, pain, fatigue, dyspnoea, insomnia, 
appetite loss, constipation, diarrhoea and financial difficulties). 
Of note, for functional scales, a higher value reflects a better level of function, but for symptoms 
scales /items a higher value reflects worse symptoms; moreover high score for the global health 
status represents a high QoL. 
 
Each scale in the questionnaire will be scored (0 to 100) according to the EORTC 
recommendations in the EORTC QLQ-C30 Scoring Manual. The scoring method is 
summarized below. In this summary, Qi refers to the ith question on the EORTC QLQ-C30. 
 
Scoring and scale dimension: 
 
 
Number of 
items (range*) 
Item number 
Global health status / QoL 
Global health status/QoL 
2 (6) 
29,30 
Functional scales 
Physical functioning 
5 (3) 
1 to 5 
Role functioning 
2 (3) 
6, 7 
Emotional functioning 
4 (3) 
21 to 24 
Cognitive functioning 
2 (3) 
20, 25 
Social functioning 
2 (3) 
26, 27 
Symptom scales / items 
Fatigue 
3 (3) 
10, 12, 18 
Nausea and vomiting 
2 (3) 
14, 15 
Pain 
2 (3) 
9, 19 
Dyspnoea 
1 (3) 
8 
Insomnia 
1 (3) 
11 
Appetite loss 
1 (3) 
13 
Constipation 
1 (3) 
16 
Diarrhoea 
1 (3) 
17 
Financial difficulties 
1 (3) 
28 
* Item range is the difference between the possible maximum and the minimum response to individual items; most items take 
values from 1 to 4, giving range = 3. 
 


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For all scales, the RawScore, RS, is the mean of the component items: 
RawScore RS = 
n
I
I
I
n)
...
(
2
1



  
Then for Functional scales: 
 
Score = 
100
)1
(
1








range
RS
 
and for Symptom scales / items and Global health status / QoL: 
Score 
100
)1
(








range
RS
 
 
Missing value (item) consideration for scoring: 
The scale scores will only be calculated if at least half of the items from the scale have been 
answered. Otherwise, no score will be calculated and the scale score will be set to missing. 
For single-item measures, the score will be missing if the question is not answered. 
 
EORTC QLQ-GI.NET21 (2006) 
The QLQ-GI.NET21 module is intended for use among subjects with gastro-intestinal-related 
(G.I.-related) neuroendocrine tumours, who vary in disease stage and treatments. 
 
The module comprises 21 questions, consisting of 5 scales and 4 single items, assessing disease 
symptoms, side effects of treatment, body image, disease related worries, social functioning, 
communication and sexuality. The module has been developed according to the EORTC 
guidelines. The QLQ-GI.NET21 has been translated into several European languages. 
 
Each question is quoted from 1 (Not at all) to 4 (very much). The scoring algorithm for the 
scales and single items is described below: 
 
 
Number of 
items (range*) 
Item number 
Scales 
Endocrine symptoms scale 
3 (3) 
31, 32, 33 
G.I. symptoms scale 
5 (3) 
34 to 38 
Treatment related symptom scale 
3 (3) 
39, 40, 46 
Social function scale 
3 (3) 
42, 44, 49 
Disease related worries scale 
3 (3) 
41, 43, 47 
Single items 
Muscle /bone pain symptom 
1 (3) 
48 
Sexual function 
1 (3) 
51 
Information/communication function 
1 (3) 
50 
Body Image 
1 (3) 
45 
* Item range is the difference between the possible maximum and the minimum response to individual items; most items take 
values from 1 to 4, giving range = 3. 
 
For all scales, a high score is equivalent to worse or more problems. 


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For all scales, the RawScore, RS, is the mean of the component items: 
RawScore RS = 
n
I
I
I
n)
...
(
2
1



 
Then for each of the five scales and for each single item: 
 
Score = 
100
)1
(








range
RS
 
 
Missing value (item) considerations for scoring are the same as for the QLQ-C30 questionnaire 
presented above. 
EQ-5D-5L v1.0  
The EQ-5D-5L consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale 
(VAS).  
The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, 
usual activities, pain / discomfort and anxiety / depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, extreme problems.  
The EQ-5D-5L was created based on the EQ-5D-3L, questionnaire with the same dimensions 
but 3 levels only (no problem, some problems, extreme problems) to improve its sensitivity and 
reliability. 
With the EQ-5D-5L, a unique health state is defined by combining 1 level from each of the 5 
dimensions. There are 3125 possible health states defined in this way. Each state is referred to 
in terms of a 5 digit code.  
For example, state 11111 indicates no problems on any of the 5 dimensions, while state 12345 
indicates no problems with mobility, slight problems with washing or dressing, moderate 
problems with doing usual activities, severe pain or discomfort and extreme anxiety or 
depression 
Any missing values will be set to missing (and hence no health state value will be calculated).  
Ambiguous values (e.g., 2 boxes ticked for a single dimension) should be treated as missing 
values. 
 
The EQ VAS records the subject’s self-rated health on a 20 cm vertical, visual analogue scale 
where the endpoints are ‘the best health you can imagine’ and ‘the worst health you can 
imagine’. The subject has to mark an X on the scale to indicate how his health is today, and 
then has to write the number marked on the scale in a box.  
Missing values will be set to missing.  
 
If there is a discrepancy between where the subject has placed the X and the number he/she has 
written in the box, the number in the box should be used. 
 
The EQ-5D-5L health states, defined by the EQ-5D-5L descriptive system, can be converted 
into a single index value. 
 


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A crosswalk link function between the EQ-5D-3L descriptive systems and the EQ-5D-5L 
descriptive systems has been developed and can be used to calculate index values for EQ-5D-
5L, based on the existing value sets for the EQ-5D-3L. 
By using the crosswalk link function and the individual responses to the EQ-5D-5L descriptive 
system, index values for the EQ-5D-5L can be calculated. 
Documents containing information on the crosswalk project, tables of values for all 3125 health 
states and the ‘EQ-5D-5L Crosswalk Index Value Calculator’ can be downloaded from the 
EuroQol website.  
The SAS syntax files were received from the EuroQol Office for Denmark, France, Germany, 
Italy, Netherlands, Spain, UK. It is not available for Poland. 
Of note, for Ireland, the SAS syntax crosswalk values EQ-5D-5L United Kingdom will be used 
; for Belgium, the one for France, and for Poland, the one for Germany. 
 
(a) 
Biomarkers 
pNET cohort:  
• 
nonspecific tumour biomarkers (CgA, NSE and 5-HIAA) at Baseline, every 
12 weeks thereafter and at the End of Study visit (plasma 5-HIAA at all scheduled 
visits; urinary 5-HIAA at Baseline, Week 12 and at the End of Study visit only). 
Note: at all scheduled visits, except Baseline, plasma/urinary 5-HIAA should only 
be performed in subjects with symptoms of carcinoid syndrome (diarrhoea and/or 
flushing) or if urinary 5-HIAA was elevated (above ULN) at Baseline. 
• 
pNET-specific tumour biomarkers (e.g. pancreatic polypeptide, gastrin, glucagon, 
SST, …) at Baseline, every 12 weeks thereafter and at the End of Study visit: only 
for the tumour biomarkers above normal range at Baseline.  
Midgut cohort:  
• 
nonspecific tumour biomarkers (CgA, NSE and 5-HIAA) at Baseline, every 
12 weeks thereafter and at the End of Study visit (plasma 5-HIAA at all scheduled 
visits; urinary 5-HIAA at Baseline, Week 12 and at the End of Study visit only). 
 
Primary, secondary and tertiary efficacy endpoints and evaluations are summarised in Table 4 


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Table 4 
Primary, Secondary and Tertiary Efficacy Endpoints and Evaluations 
Measure 
Timepoint 
Variable 
Endpoint 
Disease 
progression 
or death 
Screening 
and 
every 12 weeks 
or death date 
PFS 
Median PFS by centralised CT/MRI scan 
assessment (RECIST v1.0) or death. 
Time 
to 
progression 
Screening 
and 
every 12 weeks 
Time to progression 
Median time to progression 
PFS 
Screening 
and 
every 12 weeks  
PFS rate 
Proportion of subjects alive and without 
progression every 12 weeks 
Overall 
survival 
Week 48 and 
EoS 
Overall survival 
Overall survival 
ORR 
Screening 
and 
every 12 weeks 
ORR 
ORR every 12 weeks as per RECIST v1.0. 
DCR 
Weeks 24 and 
48, and EoS 
DCR 
DCR evaluated according to RECIST v1.0. 
Best 
overall 
response 
Screening 
and 
then 
every 
12 weeks until 
disease 
progression 
Best overall response 
Best overall response according to RECIST 
v1.0 
Duration 
of 
SD 
Screening 
and 
until the first 
occurrence 
of 
progressive 
disease 
by 
central 
assessment 
Duration of SD 
Median duration of SD by centralised CT/MRI 
scan assessment (RECIST v1.0) 
Factors 
associated 
with PFS 
Screening 
for 
all 
factors, 
every 12 weeks 
and death date 
PFS 
and 
associated 
factors, 
to 
include: 
hepatic tumour load, 
tumour severity, tumour 
functionality, surgery of 
the primary tumour, 
Ki67 
level, 
prior 
duration of treatment 
with lanreotide Autogel® 
Factors associated with PFS will include but 
will not be limited to: 
 hepatic tumour volume ≤25% versus >25%,  
 grade 1 versus grade 2, 
 previous surgery of the primary tumour 
(yes/no),  
 Ki67 <10% versus ≥10%, 
 duration of treatment with lanreotide 
Autogel® at standard dose every 28 days 
 time from diagnosis to progressive disease 
during the study (≥3 years; < 3 years). 
 Time interval between the 2 CT scans (pre-
screening / screening) <12 months / >=12 
months)  
 Symptoms (diarrhoea or flushing at 
baseline: Yes / No) 
Symptom 
control 
Baseline, 
Weeks 8 and 
12, 
every 
12 weeks 
thereafter, and 
at EoS 
Presence/ 
absence 
of 
diarrhoea and flushing, 
Total number of stools, 
total number of flushing 
episodes 
in 
previous 
7 days 
(reported 
by 
subject) 
Symptom control (diarrhoea and flushing) at 
Baseline, Weeks 8 and 12 and every 12 weeks 
thereafter, and at the End of Study visit, as 
measured by total number of stools and 
flushing episodes during the 7 days prior to the 
visit reported orally by the subject to the 
investigator. 
Quality of life 
Baseline, 
Week 12, every 
12 weeks 
thereafter and at 
EoS 
EORTC QLQ-C30 v3.0 
and 
QLQ-GI.NET21 
(2006), and EQ-5D-5L 
v1.0 questionnaires 
Quality of life measured at Baseline, Week 12 
and every 12 weeks thereafter, and at the EoS 
visit, after diagnosis of progression, using 
EORTC QLQ-C30 v3.0 and QLQ-GI.NET21 
(2006), and EQ-5D-5L v1.0 questionnaires. 




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3.1.4 
Multiplicity 
No multiple testing will be performed in this study. 
3.1.5 
Significance testing and estimation 
Analyses will be descriptive and p-values will be provided only for descriptive exploratory 
purposes. All statistical tests will be two sided at the α=0.05 level. 
3.2 
Analysis methods 
3.2.1 
Efficacy 
The efficacy analyses using the centralised review performed by Bioclinica will only be 
performed using the accepted evaluation (defined as either the main reader evaluation if there 
is no adjudication, or the reader chosen by the adjudicator if there was an adjudication). 
 
3.2.1.1 
Primary efficacy analysis 
The primary efficacy variable is median PFS (defined as time from first injection of lanreotide 
Autogel® 120 mg every 14 days to progression or death).  
Disease progression will be assessed by tumour response evaluation according to RECIST v1.0, 
every 12 weeks, measured using the same imaging technique (CT scan or MRI) for each subject 
throughout the study, and by independent central review.  
Event dates are assigned to:  
• 
The first time when progressive disease was noted, or  
• 
Date of death.  
In case of progressive disease followed by death, the first event will be considered in the 
analysis. 
 
The progressive disease date is assigned to the first time at which progressive disease can be 
declared. 
• 
For progressive disease based on a new lesion, the progressive disease date is the date of 
the first radiological assessment when the new lesion was detected. 
• 
For progressive disease based on an increase in the sum of the target lesion 
measurements, the progressive disease date is the date of the last radiological assessment 
of target lesions that shows the predefined increase in the sum of the target lesion 
measurements.   
 
Censoring dates are defined in subjects with no progressive disease or death before end of study 
or withdrawal. In these subjects, the censoring date is defined as the last date on which 
progression status was ‘adequately’ assessed. This is taken to be the date of the last radiological 
assessment at which the target lesions were evaluated by central review (see Table 5).  
 


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Table 5 
Censoring Rules for PFS 
Reason for censoring 
Rule 
No screening evaluable* assessment 
Date of first treatment administration 
Two or more not evaluable (NE) assessments before 
progressive disease or death 
Date of last evaluable disease assessment before the 
second NE assessment 
No progressive disease 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented 
progression 
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or other reason 
Date of last evaluable disease assessment 
Initiation of medications or therapy not permitted 
during the study 
Date of initiation of non permitted medication or 
therapy 
* An assessment is considered NE when no imaging/measurement is done at all at a particular time point, or only a subset of 
lesion measurements are made at the time point. The subject is considered NE at that time point. 
 
The PFS time will be calculated as the time from first injection of lanreotide Autogel® 120 mg 
every 14 days to either progressive disease or death.   
 
PFS time (in months) = [(Date of event – date of first injection of lanreotide Autogel® 120 mg 
every 14 days) + 1] / 30.4375 
 
Data will be analysed by cohort only. The distribution of PFS times will be estimated using the 
Kaplan Meier method for each cohort. The median PFS time will be presented with its 
associated 95% CI. The results will also be presented graphically in Kaplan Meier plots. 
 
Completely missing tumour data: 
When tumour assessment visits are completely missing, FDA Guidance “Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics” [4] states that "events occurring 
after two or more missed radiological assessments will be censored in the analysis at the last 
adequate assessment’.  
This will be implemented as follows: 
PDs occurring after two or more missed radiological assessments will be censored in the 
analysis at the last adequate* assessment before the missing assessments:   If a subject has one 
missed radiological assessment before a PD the event will be analysed as an event (i.e. a PD is 
analysed as an event if the previous radiological assessment was performed within 
approximately the last 6 months). 
The following table shows the event status for various scenarios with missing data: 
 
Scan Time 
Visit 6 
(V6) 
Visit 7 
(V7) 
Visit 8 
(V8) 
Visit 9 
(V9) 
Event status 
Scenario 1  
missing 
PD 
Censored at V2 if 
(V7 – Screening) >= 
26 weeks  
Scenario 2 
missing 
PD 
 
 
Event at V7.if (V7 – 
screening) < 26 
weeks 
Scenario 3 
missing 
missing 
PD 
Censored at V2 
Scenario 4 
missing 
SD 
PD 
Event at V8 


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Scenario 5 
missing 
missing 
SD 
PD 
Event at V9 
Scenario 6 
SD 
SD 
missing 
PD 
Event at V9 
Scenario 7 
SD 
missing 
missing 
PD 
Censored at V6 
 
The following SAS® code will be used: 
 
                
 
                
 
 
 
3.2.1.2 
Secondary efficacy analysis 
(a) 
Median time to progression 
A similar analysis to the primary analysis will be performed. Time to progression is defined as 
time from first injection of lanreotide Autogel® 120 mg every 14 days to progression. Data will 
be analysed by cohort only. 
Subjects who are lost to follow up or who die during the study will be censored at the date of 
the last disease assessment subject to the rules summarised Table 6. 
 
Table 6 
Censoring Rules for Time to Progression 
Reason for censoring 
Rule 
No screening evaluable assessment 
Date of first treatment administration 
Two or more NE assessments before progressive 
disease 
Date of last evaluable disease assessment before the 
second NE assessment 
No progressive disease 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented 
progression 
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or other reason 
Date of last evaluable disease assessment 
Death 
Date of last evaluable disease assessment 
Initiation of medications or therapy not permitted 
during the study 
Date of initiation of non permitted medication or 
therapy 
The distribution of time to progression will be estimated using the Kaplan Meier method for 
each cohort. The median time to progression will be presented with its associated 95% CI. The 
results will also be presented graphically in Kaplan Meier plots. 
 
(b) 
Proportion of subjects alive and without progression every 12 weeks 
The proportion of subjects alive and without progression will be presented by cohort only every 
12 weeks with the corresponding 95% CIs.  
CCI


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(c) 
Overall survival at Week 48 and at the end of the study for each cohort 
The overall survival, defined as the time in months from the first injection of lanreotide 
Autogel® 120 mg every 14 days to death due to any cause, will be analysed similarly to the 
primary efficacy endpoint. 
Subjects without death date will be censored at the date the subject was last known to be alive. 
OS time (in months)= [(date of death/date subject last known to be alive - date of first injection 
of lanreotide Autogel® every 14 days)+ 1]/30.4375. 
 
Kaplan-Meier curves and estimates including survival rates at Visit 9 (Week 48) and at End of 
Study and the associated 95% CIs will be provided for each cohort separately and overall. If 
the median is not reached, the first quartile (i.e. 25 % percentile) will be provided instead. 
 
(d) 
Objective response rate (ORR)  
For analysis of the ORR, summary tables will be generated, presenting the number and 
proportion of responders and non-responders every 12 weeks in each cohort and overall, 
together with two-sided 95% Pearson-Clopper CIs. Subjects with no tumour assessment after 
the start of study treatment will be considered as non-responders. The denominator at each 
timepoint will be all subjects in the population regardless whether they are still in the study at 
that timepoint or not. 
Responses for each subject will be listed at each visit. Responders will be identified. 
 
The following SAS® code will be used for tables that need exact 95% Pearson-Clopper CIs: 
 
  
 
   
 
  
 
 
 
(e) 
Disease control rate (DCR) 
The number and proportion of subjects with disease control and with no disease control at 
Weeks 24, Week 48 and End of Study will be presented by cohort and overall, together with 
two-sided 95% Pearson-Clopper CIs. Subjects with no tumour assessment after the start of 
study treatment will be considered as with no disease control. The denominator at each 
timepoint will be all subjects in the population regardless whether they are still in the study at 
that timepoint or not. 
 
(f) 
Best overall response 
The number and percentage of subjects with each best overall response and those who were 
non-evaluable (i.e. with no tumour assessment after the start of study treatment) will also be 
tabulated with two-sided 95% Pearson-Clopper CIs. 
 
CCI


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(g) 
Median duration of stable disease (SD) 
A similar analysis to the primary analysis will be performed for the median duration of stable 
disease. Duration of SD, according to the central assessment, will be analysed in subjects who 
experienced stable disease until the first occurrence of progressive disease. Subjects who are 
lost to follow up or who die during the study will be censored at the date of the last disease 
assessment subject to the rules summarised Table 7. 
 
Table 7 
Censoring Rules for Median Duration of Stable Disease 
Reason for censoring 
Rule 
No screening evaluable assessment 
Date of first treatment administration 
Two or more NE assessments before progressive 
disease 
Date of last evaluable disease assessment before the 
second NE assessment 
No progressive disease 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented 
progression  
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or other reason 
Date of last evaluable disease assessment 
Death 
Date of last evaluable disease assessment 
Initiation of medications or therapy not permitted 
during the study 
Date of initiation of non permitted medication or 
therapy 
The distribution of duration of SD will be estimated using the Kaplan Meier method for each 
cohort. The median duration of SD will be presented with its associated 95% CI. The results 
will also be presented graphically in Kaplan Meier plots. 
 
(h) 
Factors associated with PFS 
A multivariate analysis of the progression free survival will be performed in order to take into 
account prognostic factors. These analyses will be conducted on the FAS. A Cox proportional 
hazards model for PFS will be performed for each cohort, to estimate the Hazard Ratio (HR) 
and its two-sided 95% CI. 
The factors included in this analysis will include: hepatic tumour load ≤25% versus >25%, 
grade 1 versus grade 2, previous surgery of the primary tumour (Yes versus No), Ki67 <10% 
versus ≥10%, duration of treatment with lanreotide Autogel® 120 mg every 28 days by category 
(≥ median value versus < median value), age by category (≥65 years, <65 years), time from 
diagnostic to study entry (by category: ≥3 years versus < 3 years), Time interval between the 2 
CT scans (pre-screening / screening) <12 months / >=12 months) and symptoms (diarrhoea or flushing 
at baseline: Yes / No).  
In a first step, each factor will be assessed for its importance in the Cox model for PFS in a 
univariate fashion. All variables associated with PFS with a p-value < 0.20 will be pre-selected 
to be entered in the multivariate model. 
 
The following SAS® code will be used 
 
   
 
   
 
                         
 
; 
CCI


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In a second step, each pre-selected parameter will be tested with the other retained parameters 
at the 0.001 level to confirm that there is no strong link between them. For continuous variables 
the Pearson correlation will be tested. For a mix of categorical and continuous variables 
Kendall’s tau (τ) correlation coefficient will be used and for categorical variables a Chi2 test 
will be used. If the independence is not met for two parameters (p < 0.001) and/or the correlation 
coefficient is moderate or high (i.e. ≥ 0.5), the choice will be done according to clinical and 
statistical relevance. 
 
A multivariate Cox regression model will then be run with the selected variables remaining 
after first and second steps. 
The stepwise variable selection method in the SAS® procedure 
 will be performed with 
p=0.20 to enter variables in the model, and p=0.05 to remove variables from the model, to select 
the best model. 
 
The following SAS® code will be used 
 
 
   
 
                         
 
                           
 
                           
 
 
 
The stepwise regression analysis will be composed of different steps:  
 
- 
Individual score tests will be used to determine which of the explanatory variables has to 
be first selected into the model. In this case, the score test for each variable is the global 
score test for the model containing that variable as the only explanatory variable. The 
variable with the largest chi-square value significant at the 
 level will 
be selected first to enter the best model. 
 
- 
The next step will consist of selecting another variable to add to the model. Chi-square 
statistics and p-values of individual score tests (adjusted for the first variable selected) 
for the remaining variables will be calculated. The second variable to be selected will be 
the one with the highest chi-square value and significant at the 
 level. 
- 
This step will be repeated until a variable has to be removed from the model at the 
. The best model will be the model with this last variable tested removed. 
 
Tied events will be handled with the Exact approximation. 
 
When the stepwise selection process will result in a best model, further exploratory analyses 
may be carried out assessing interaction effects, where stratum sizes are sufficiently large. 
 
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The assumptions of proportional hazards (PH) will be examined both graphically and 
statistically. 
 
The graphical methods used will be: 
- 
Plot ln(-ln(S(t))) versus t or ln(t) and look for parallelism 
- 
Plot Observed and predicted S(t) and look for close fit. 
- 
Use the PH graph by using the 
 option of the 
 procedure of SAS®. 
statement in SAS® includes plot of randomly generated residual processes to 
allow for graphic assessment of the observed residuals in terms of what is “too large”: 
i.e. the path from the actual data is compared to the randomly-generated paths under PH. 
The following SAS® code will be used with the best model retained (with 
 
 
 
 
   
  
                         
 
                           
 
  
 
 
 
 
.The second method to check the proportional hazards assumption will be using the time-
dependent covariates, i.e. time*covariate interactions will be added to the model. 
 
The following SAS® code will be used 
 
   
  
                         
 
                           
 
   
 
; 
 
 
  
 
If an added interaction is not statistically significant at the level of 0.10, this indicates that 
proportional hazard assumption is satisfied for the concerned variable. 
 
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On the contrary, if the interaction is statistically significant, it means that the effect of the given 
covariate is not constant over time, so PH assumption is violated. To solve this problem (i.e. to 
model the non-PH), the interaction will be left in the model. 
If PH fails for a covariate xi, previously checked covariates will be re-check after adjusting for 
the non-PH of xi. 
The second method used to handle non-PH will be to enter the covariate xi as a stratification 
variable in the model to have the estimation for each level of the covariate. 
Therefore, the model with interaction and stratified model will be run, and the model with best 
fit statistics (AIC criterion) will be chosen. 
Finally the estimation of the best model (selected with the stepwise procedure) will be 
presented, as well as the best model adjusted for non-PH and a graph of HR over time will be 
provided for non-PH variable(s) based on the best model adjusted for non-PH, if applicable. 
 
(i) 
Symptom control (diarrhoea, flushing) at each visit 
Symptom control will be assessed by presence/absence of each symptom and by the total 
number of stools and flushing episodes during the 7 days prior to the visit reported orally by 
the subject to the investigator. The presence/absence of each symptom will be presented as a 
frequency table per visit, as well as a shift table. The total number of stools episodes and the 
total number of flushing episodes by visit as well as the change from baseline will be 
summarised by cohort and overall using summary statistics, including 95% CIs of the mean. 
Incidence of symptoms (presence/absence) and number of episodes will be listed, along with 
urinary 5-HIAA level (xULN) and plasma 5-HIAA level (ng/ml).   
 
(j) 
Quality of life 
Quality of life questionnaire overall and subscale scores will be derived according to the 
standard algorithms recommended for their derivation. Data will be summarised by cohort and 
overall every 12 weeks through summary statistics and 95% CIs of the mean values.  
 
For subject reported outcomes, descriptive statistics will be presented for the raw data and for 
the changes from baseline during treatment. 
 
Individual responses to each question will be listed. For each question the number and 
percentage of subjects who recorded each response will be presented by cohort and visit. For 
the EQ-5D-5L questionnaire, levels will also be dichotomised into “no problems” (i.e level 1) 
and 'problems' (i.e. levels 2 to 5) and tabulated. 
Raw scores and transformed scores will be listed. Transformed scores (i.e. scales) will be 
summarised by cohort, scale (as defined in section 3.1.2) and visit. Changes from baseline in 
transformed scale scores will be calculated, listed and summarised by cohort, scale and visit. 
An analysis of covariance (ANCOVA) will be performed using a SAS® PROC mixed 
procedure for each scale of the three questionnaires, in overall:  
For each visit, an ANCOVA mixed model will be fitted with the change from baseline results 
as dependant variable; including cohort group as fixed effect; subject as random effect; and 
baseline QoL score as a covariate (fixed effect). 
Least squares (LS) means (with 95% CIs) will be presented.  


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Calculations will be performed using REML (restricted maximum likelihood) estimation.  
Type III tests will be used for the differences in least-square means. 
 
The following SAS® code will be used for the model run for each visit: 
 
  
 
 
 
 
 
 
In this model, the overall cohort effect (i.e. the average cohort effect over the whole study 
period) will be tested (at the 0.05 level).  
 
Normality assumption checking: 
Based on the fitted ANCOVA model for each QoL scale score, the Shapiro-Wilk test statistic, 
(W), for testing the hypothesis of normality will be calculated for the Studentised residuals. The 
test statistic, W, and plots of the studentised residuals will be visually checked for the 
assumption of normality. In the event that normality is revealed to be unreasonable, the data 
will be log transformed. Again using the Shapiro-Wilk test statistic, if the assumptions of 
normality are revealed still to be unreasonable then the SAS® procedure 
 will be 
considered.  
 
  
 
 
 
  
 
 
 
 
Original data will be presented in all tables and will be used in analysis unless log 
transformation is necessary. If log-transformation is used, results will be back transformed and 
will be presented in the tables in the original scale. 
In SAS®, validity assumptions for the ANCOVA mixed model will be explored using the 
option 
 
 
 
 
For each questionnaire, the score values for each visit will be plotted against time (by cohort). 
 
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(k) 
Tumour biomarkers  
Nonspecific tumour peptide biomarkers (CgA, NSE and plasma/urinary 5-HIAA) will be 
summarised descriptively at Baseline (Visit 2) and Week 12 and every 12 weeks thereafter by 
cohort and overall. Changes from Baseline will be displayed for continuous variables and for 
categorical variables shift tables (above, within and below normal range) will be presented. 
pNET-specific tumour peptide biomarkers (e.g. pancreatic polypeptide, gastrin, glucagon, SST, 
where above normal range at Baseline) will be summarised descriptively at Baseline (Visit 2) 
and Week 12 and every 12 weeks thereafter for the pNET cohort. Changes from Baseline will 
be displayed for continuous variables and for categorical variables shift tables (above, within 
and below normal range) will be presented. 
All data will be analysed and listed regardless of the timing of the assessment with regards to 
the injection.  
 
3.2.2 
Safety 
All safety data will be included in the data listings and summary tables will be based on the 
FAS and presented by cohort and overall. 
3.2.2.1 
Adverse events 
All AEs will be recorded and graded by investigators using the NCI-CTCAE classification 
(Version 4.03, dated 14 June 2010) and will be coded using MedDRA Version 20.0 or higher, 
and will be classified by MedDRA preferred term and system organ class. 
 
Listings will be presented and sorted by cohort, center, subject, system organ class and preferred 
term for all adverse events recorded during the study. 
Listings of serious adverse events (SAE), adverse events leading to study treatment withdrawal 
and listings of deaths will also be presented. 
 
A TEAE is defined as any AE that occurs during the study if:  
(1) 
it was not present prior to receiving the first dose of lanreotide Autogel® 120 mg at a 
reduced dosing interval, i.e every 14 days, or  
(2) 
it was present prior to receiving the first dose of lanreotide Autogel® 120 mg at a reduced 
dosing interval, i.e every 14 days but the intensity increased during the study, or  
(3) 
it was present prior to receiving the first dose of lanreotide Autogel® 120 mg at a reduced 
dosing interval, i.e every 14 days the intensity is the same but the drug relationship 
became related during the study.  
(4) 
AEs starting > 28 days after last treatment intake will not be considered as TEAEs. 
All TEAEs will be flagged (*) in the AEs listings. 
 
An overall summary table of all adverse events will be presented by cohort and overall.  
TEAEs will be summarised by cohort and overall with the number and percentage of subjects 
with adverse events classified by primary system organ class and preferred term. The number 
of occurrences of a TEAE will also be presented. 
 


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Incidence of all reported treatment emergent AEs (TEAEs), SAEs, non SAEs, TEAEs by 
associated NCI-CTCAE worst grade and by causality, TEAEs by decreasing frequency will be 
tabulated by cohort and overall. For these incidence tables by primary system organ class and 
preferred term, in the event of multiple occurrences of the same AEs (same PT term) being 
reported by the same subject, the maximum intensity (grade 5> grade 4> grade 3> grade 2> 
grade 1 > missing> not applicable) and the most serious causality (related> missing> not 
related) will be chosen. For intensity*causality combined description, the most serious causality        
prevails. All occurrences of this worst grade, causality, intensity*causality by PT term will be 
taken into account in the number of occurrences (m). Nonetheless, for the overall summary of 
events, in the cross classification of causality and intensity, any subject experiencing multiple 
AEs with different intensities for each causality category will be counted for each intensity. 
 
AEs resulting in dose interruptions and withdrawal will be listed and presented in summary 
tables by worst grade.  
Haematological and biochemistry toxicities will be recorded and graded according to the NCI-
CTCAE criteria (Version 4.03, dated 14 June 2010). The NCI-CTCAE grade 3 and 4 
haematology and biochemistry parameters will be listed by cohort, subject and visit. 
3.2.2.2 
Laboratory data 
Laboratory data (serum haematology and biochemistry panels, liver and pancreatic enzymes, 
urinalysis) will be listed in SI units in individual data listings by cohort, center, subject id and 
visit and abnormal values will be flagged (High, [H], Low [L], clinically significant [C], NCI-
CTC grade (G)) where applicable. Any unscheduled laboratory assessments will be flagged [U] 
in the listings. A list of clinically significant abnormal values will be presented. 
A listing of microscopic urine parameters will be provided. 
 
Baseline values will be defined as the last measurement of the specific laboratory parameter 
collected prior to the first dose of study drug (Day 1). 
Since all samples will be analysed by a central laboratory, the same reference value ranges 
apply to subjects from all study centres. A separate listing of normal ranges for SI units will be 
provided by gender and age where appropriate. 
 
Summary tables with actual values and changes from Baseline to each post-baseline visit will 
be presented for each cohort and overall. 
Shift tables will be presented of the number and percentage of subjects with low, normal or 
high values. 
 
Haematological and biochemistry toxicities will be recorded and graded according to the NCI-
CTC criteria (Version 4.03, dated 14 June 2010). The NCI-CTC grade (0 to 4) of haematology 
and biochemistry by visit and by subject will be listed in the Section 16.2.8. Listings of the 
laboratory parameters in section 14.3.4 & 14.3.5 will include listings of NCI-CTC Grade 3 and 
4 haematological toxicities, listings of NCI-CTC Grade 3 and 4 biochemical toxicities and 
listings of out of range biochemistry parameters that could not be graded using NCI-CTC grade 
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Also, listing of lipase increased (any grade) and listing of hypocalcemia (any grade) will be 
provided. 
 
Diarrhoea status at baseline (presence/absence) will be summarised by baseline urinary and 
plasma 5-HIAA level (≤ULN, >ULN, missing) overall and by cohort.  
Baseline level of urinary and plasma 5-HIAA (raw and in xULN) will be analysed according to 
baseline diarrhoea status (presence/absence) overall and by cohort. 
 
3.2.2.3 
Vital signs  
Vital signs (body temperature, supine and standing blood pressure and heart rate) will be listed 
at each assessment by cohort and subject. Any unscheduled vital signs will be flagged [U] in 
the listing.   
Baseline values will be defined as the last vital signs measurement collected prior to the first 
dose of study drug.  
Summary tables with actual values and changes from Baseline to each post-baseline visit will 
be presented for each cohort and overall. 
 
3.2.2.4 
Physical examination 
Physical examination and weight will be listed by cohort, subject identifier and visit. Any 
unscheduled physical examination will be flagged [U] in the listings. 
Baseline values will be defined as the last physical examination performed prior to the first dose 
of study drug. 
A summary table of weight and BMI with actual values and changes from Baseline to each 
post-baseline visit will be presented for each cohort and overall.  
 
3.2.2.5 
ECG 
ECG results will be listed at each assessment by cohort and subject. Any unscheduled ECG will 
be flagged [U] in the listings. 
Baseline will be defined as the last ECG measurement collected prior to the first dose of study 
drug. 
For continuous ECG parameters, summary statistics, by cohort and overall, will be presented 
at each scheduled assessment for actual values and changes from baseline. 
For sinus rhythm, a frequency table by cohort and overall, will be presented at each scheduled 
assessment. 
For interpretation of clinical significance (within normal limits / abnormal, not clinically 
significant / abnormal, clinically significant / not evaluable), a frequency table will be 
presented, by cohort and overall, at each post-dose assessment and for the worst value between 
post-dose assessments (abnormal, clinically significant > abnormal, not clinically significant > 
not evaluable > within normal limits) as well as a shift table between baseline and each of the 
visits with the following categories: improved, stable, worsened, clinically significant 
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3.2.2.6 
Gallbladder Echography 
Gallbladder echography will be listed. Any unscheduled visits will be flagged [U] in the listings. 
A frequency table of the presence and/or absence of lithiasis and sludge will be presented at 
each assessment by cohort and overall. 
A shift table from the screening period with number and percentage of subjects with presence 
and absence of lithiasis and sludge will be presented at each visit by cohort and overall. 
3.2.2.7 
 Specific analysis of cholecystectomy, gallbladder surgery, lithiasis or sludge during 
the study 
The following analyses will be provided, based on occurrence of cholecystectomy, gallbladder 
surgery, lithiasis or sludge during the study (source data will be concomitant surgical 
procedures for cholecystectomy or gallbladder surgery, and post-screening gallbladder 
echography for lithiasis and sludge): 

The number and percentage of subjects with cholecystectomy or gallbladder surgery or
lithiasis or sludge during the study will be calculated, among subjects in the FAS
population. Among the subpopulation of subjects having presented at least one of the
four events during the study, the number and percentage of subjects having presented
each of the four events will be displayed in the same table.
•
In addition, shift tables of those four events will be provided, displaying the prior 
occurrence (ie during their treatment with lanreotide Autogel® 120 mg administered 
every 28 days, see section 3.2.9) versus the occurrence during the study as defined above. 
Five shift tables will be provided: “cholecystectomy, gallbladder surgery, lithiasis or 
sludge”, “cholecystectomy”,”gallbladder surgery”, “lithiasis”, “sludge”.
3.2.3 
Missing data and outliers 
3.2.3.1 
Missing data 
•
Efficacy endpoints
When tumour assessment visits are completely missing, rules from FDA Guidance “Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics” [4] will be implemented as 
described in section 3.2.1.1.  
Any missing QoL data (EORTC QLQ-C30, QLQ-GI.NET21 and EQ-5D-5L questionnaires) 
will be handled as described in section 3.1.2.j. 
•
Safety endpoints
If a value requires a retest (for laboratory values, vital signs, ECG, gallbladder echography), the 
closest non-missing reliable value to the scheduled visit is used in the summary tables. An 
assessment is considered reliable if it is performed without any technical problem or altered 
blood samples and if the result is within the range of plausible values. 
For adverse events with missing information for the intensity and causality, the value will not 
be replaced and will be summarized as a separate category.  
For all other variables, no imputations will be made for missing data. 


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3.2.3.2 
Missing or incomplete dates 
In all listings, missing or incomplete dates should be left as they have been recorded. However, 
for calculation / sorting / assignation based on dates, the following methods will be used: 
The most conservative approach will be systematically considered (i.e. if the onset date of an 
AE/concomitant medication is missing / incomplete, it is assumed to have occurred during the 
study treatment phase (i.e. a TEAE for AEs) except if the partial onset date or other data [stop 
date, …] indicates differently). 
For partially missing dates for efficacy endpoints derived using tumour assessments, the 
following imputation rules will be used: if the day of the month is missing, but month and year 
are known (UN-MMM-YYYY), it will be imputed by the 1st of the month (01-MMM-YYYY). 
If this implementation rule produces a date before the first injection of lanreotide Autogel® 120 
mg every 14 days, then the date of start of study treatment is used. 
A missing/incomplete date of medical history or disease diagnosis will be assumed to have 
occurred before any study treatment. The imputation rules described for efficacy endpoints will 
be applied.  
 
If a partial date and the associated information do not allow to state about the assignation to a 
group / category, all the possible groups / categories will be considered (i.e.: an AE could be 
assigned to several possible doses at event onset according to its partial onset date and stop 
date. Particularly an AE with missing start date will be assigned to each dose received before 
its end date. Similarly a medication with partial start and stop dates could be considered as prior 
and concomitant treatment. However if the medication is lanreotide Autogel® 120 mg every 
28 days with partial stop date and month and year are the same as month and year of the first 
study drug administration every 14 days (within the study) then the medication would be 
considered as ended prior to the start of study treatment.). 
Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e.: for an AE started in FEB2004 after the administration performed on 
31JAN2004, the days since last dose will be “≥2”, similarly the duration of ongoing AEs or 
medication will be“≥xx” according to the start and last visit dates). 
 
3.2.3.3 
Outliers 
A search of outliers should be performed before the database lock and the impact may be 
assessed by performing the statistical analysis with the actual values and at least one other 
analysis eliminating or reducing the outlier effect. The decision of how to handle these outliers 
will be made during the Data Review Meeting and documented. 
 


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3.2.4 
Subject disposition 
The number and percentage of subjects included in each of the FAS and PP population will be 
tabulated by cohort, country and centre. 
The numbers and percentages of subjects screened, enrolled and included in each of the FAS, 
PP and PK population will be tabulated in total and by cohort. The reasons for subject 
exclusions from FAS and PP population will also be tabulated. 
 
A summary table and a flow chart will be presented for each subject population presenting the 
number of subjects in each cohort at each visit and identifying the number of subjects who 
withdrew over time. 
 
A summary table will present the study drug exposure in the study for each cohort and in 
overall.  Study drug exposure (days) is defined as last drug intake - date of first drug intake +28 
(c.f. in Section 6 Appendix 1 Derived Data). 
A listing of dates of assessments (relative day) and their study exposure will be presented by 
subject for each cohort. 
 
3.2.5 
Withdrawals 
The number of subjects who were treated, who discontinued and completed the study will be 
tabulated by cohort and listed. Primary reasons for discontinuation of study treatment will first 
be tabulated by cohort and overall, then by visit, by cohort and overall. 
 


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3.2.6 
Demographic and baseline characteristics 
In order to characterise the pNET and midgut cohorts, descriptive summary statistics (n, mean, 
StD, median, minimum, maximum, 95% Confidence Interval [CI] of the mean) or frequency 
counts of demographic and baseline data will be presented by cohort and overall for the FAS 
and the PP population (on PP if difference in number of subjects enrolled between FAS and PP 
is >10%) 
 
All demographic and baseline characteristics will be listed by cohort and subject. 
Summary statistics will be provided for demographic and baseline characteristics (sex, race, 
age, height, weight and BMI in categories at screening, ECOG performance status). 
 
Summary statistics of the tumour characteristics will be provided: histopathological type of the 
tumour, proliferation Index Ki67, categories of proliferation Index Ki67: <10% (with details 
for categories ≤ 2, ]2; 10[) versus ≥10%, tumour grade according to World Health Organisation 
(WHO) 2010 classification, time since diagnostic (see refer to section 6, Appendix 1, Derived 
data), time since diagnostic by category (≥3 years versus < 3 years), hepatic tumour load ≤25% 
(with details for categories ≤ 10, >10%) versus >25%, previous surgery of the primary tumour 
(Yes versus No). 
 
Summary statistics of the duration of treatment with lanreotide Autogel® 120 mg every 28 days 
by category (<6 months [should be 0 as per inclusion criterion 4]; [6- 12[; [12-24[; ≥24) will 
also be provided by cohort and overall, as well as summary statistics of the Krenning scale 
(grade 0 to 4). 
 
Presence/absence of symptoms at baseline will be summarised overall and by cohort.  A 
description of the frequency of the symptoms (over the last 7 days (prior to baseline)) will also 
be provided. 
 
3.2.7 
Medical and surgical history 
Medical and surgical history will be coded using MedDRA Version 19.1 or higher. 
Listings will present the preferred term and verbatim text. The listings will be sorted by cohort, 
subject, primary system organ class, preferred term and verbatim text.  
A frequency table of the number and percentage of subjects will be provided for all medical 
and surgical history by primary system organ class and preferred term for each cohort and 
overall on the FAS. 
 
3.2.8 
Prior Surgical Procedures for Pancreatic/Midgut NETs 
Prior Surgical Procedures for Pancreatic/Midgut NETs will be tabulated and listed in a similar 
way to medical and surgical history. 


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3.2.9 
Specific analysis of prior cholecystectomy, gallbladder surgery, lithiasis or 
sludge  
The following analysis will be provided, based on the medical and surgical history and prior 
surgical procedures for Pancreatic/Midgut NETs: 
 The number and percentage of subjects with prior cholecystectomy or gallbladder 
surgery or lithiasis or sludge during their treatment with lanreotide Autogel® 120 mg 
administered every 28 days will be calculated, among subjects in the FAS population. 
Among the subpopulation of subjects having presented at least one of the four events 
during their treatment with lanreotide Autogel® 120 mg administered every 28 days, 
the number and percentage of subjects having presented each of the four events will be 
displayed in the same table. 
 
3.2.10 
Radiotherapy for Pancreatic/Midgut NETs 
Prior Radiotherapy for Pancreatic/Midgut NETs will be tabulated and listed in a similar way to 
medical and surgical history. 
3.2.11 
Subject compliance 
A listing will be presented for drug administration (all captured data in the eCRF) by subject 
for each cohort. Deviations from observed and scheduled times will be presented (with tables 
and listings displaying anticipation/delayed injections/missed injections). 
 
The compliance (%) will be calculated as the ratio of the actual number of injections according 
to eCRF over the planned number of injections, then multiplied by 100 (c.f. in Section 6 
Appendix 1 Derived Data).  
A summary table of compliance by cohort and overall will be presented on the FAS. 
Additionally, the number and percentage of subjects with a compliance in the categories <70%, 
[70%; 100% [, 100%, ]100%; 130% [ and ≥130% will be provided by cohort and overall. 
Moreover, a listing of subjects with difficulties during drug administration will be provided. 
 
3.2.12 
Prior and concomitant therapies 
All prior treatments for the study disease will be recorded on the eCRF. Any prior or 
concomitant therapy or medication given to a subject for another indication within 28 days 
before study drug administration or during study drug administration will be indicated on the 
eCRF. Dose and generic name or tradename will be indicated. 
All recorded data will be included in data listings. 
 
3.2.12.1 Prior and concomitant medication 
Prior and concomitant medications will be coded using WHO Drug Dictionary, version June 
2016 or higher. Medications which started and stopped before start of study treatment are 
considered as prior medications. 
Medications which started before start of study treatment but are continuing will be considered 
as both prior and concomitant medications. 


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Listings will include the therapeutic class (i.e., the second level of Anatomical Therapeutic 
Chemical [ATC] classification system code, that is, corresponding to the first 3 figures), 
preferred term and verbatim text. The listings will be sorted by cohort, subject id, chronological 
start date, stop date, therapeutic class, preferred name and verbatim name.  
A frequency table of the number and percentage of subjects will be provided for prior 
medications and concomitant medications by therapeutic class and preferred name for each 
cohort and overall on the FAS population. 
 
3.2.12.2 Prior and concomitant non-drug therapies 
Concomitant non-drug therapies will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 19.1 or higher. Therapies which started and stopped before start 
of study treatment are considered as prior therapies. 
Therapies which started before start of study treatment but are continuing will be considered as 
both prior and concomitant therapies. 
Listings will include the system organ class, preferred term and verbatim text. The listings will 
be sorted by cohort, subject id, chronological start date, stop date, system organ class, preferred 
term and verbatim name.  
A frequency table of the number and percentage of subjects will be provided for prior therapies 
and concomitant therapies by system organ class and preferred term for each cohort and overall 
on the FAS population. 
 
3.2.12.3 Prior and concomitant medications for Pancreatic/Midgut Neuroendocrine Tumours  
Prior and concomitant medications for Pancreatic/Midgut Neuroendocrine Tumours will be 
coded using WHO Drug Dictionary, version June 2016 or higher. Medications which started 
and stopped before start of study treatment are considered as prior medications. 
Medications which started before start of study treatment but are continuing will be considered 
as both prior and concomitant medications. 
Listings will include the therapeutic class (i.e., the second level of ATC classification system 
code, that is, corresponding to the first 3 figures), preferred term and verbatim text. The listings 
will be sorted by cohort, subject id, start date, stop date, therapeutic class, preferred name and 
verbatim name.  
A frequency table of the number and percentage of subjects will be provided for prior 
medications and concomitant medications by therapeutic class and preferred name for each 
cohort and overall on the FAS population. 
 


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3.2.12.4 Concomitant surgical procedures 
Concomitant surgical procedures will be coded using the MedDRA Dictionary, Version 19.1 
or higher. Surgical procedures which started after start of study treatment will be considered as 
concomitant surgical procedures. 
Listings will include the system organ class, preferred term and verbatim text. The listings will 
be sorted by cohort, subject id, chronological start date, stop date, system organ class, preferred 
term and verbatim name.  
A frequency table of the number and percentage of subjects will be provided for concomitant 
surgical procedures by system organ class and preferred term for each cohort and overall for 
FAS population. 
 
3.2.13 
Pharmacokinetics  
Analysis of pharmacokinetic (PK) and PK/PhD data will be performed by a Contract Research 
Organisation (CRO) under IPSEN supervision (Clinical PK and Pharmacometry department). 
A listing of PK and antibodies sampling time and any deviation from the scheduled time will 
be provided. A listing of individual lanreotide concentrations per timepoint will be provided. A 
listing of individual antibodies results will also be provided as well as three tables including: 
• 
the percentage of subjects developing anti-lanreotide antibodies at baseline and at the 
EOS, 
• 
descriptive statistics on anti-lanreotide antibodies titer. 
• 
descriptive statistics on individual lanreotide concentrations per timepoint. 
Further details of the PK analysis will be provided in a separate document. 
 
3.2.14 
Derived data 
The derived data are variables which are calculated from the raw data recorded in the eCRF or 
any other support and not included in the database. The derived data will be calculated to be 
included in tables and listings. 
Some specifications of the data derivations necessary for this study are provided in Appendix 
1 Derived Data. 
 
3.2.15 
Visit windows  
All data will be organised and analysed according to the scheduled visits outlined in the 
protocol. However, actual observation times may differ from the scheduled visit times and 
where this occurs the results should be allocated to the most appropriate visit.  Therefore, time 
intervals (e.g. visit windows) have been constructed so that every observation collected can be 
allocated to a particular time point. If more than one record occurs within the same visit window 
where only one assessment is expected then the following rule should be applied: for pre-study 
assessments the last non-missing result prior to study drug administration should be used; for 
post-treatment assessments the closest non-missing result to the scheduled visit should be used. 


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Reallocation of a visit to a time window for the FAS and PP analyses will be as follows: 
Study phase 
Scheduled visit 
Time interval (days) 
 
 
 
Pre treatment 
Screening (visit 1)* 
-28 to -1 
 
 
 
Treatment 
period 
Baseline (visit 2)* 1 
Day 1  
Study drug administration 
commences 
at 
Visit 
2 
(Baseline) 
following 
completion of the Baseline 
assessments 
Visit 3 (Week 2)* 
2 to 21 
Visit 4 (Week 4)* 
22 to 42 
Visit 5 (Week 8)* 
43 to 70 
Visit 6 (Week 12)* 
71 to 126 
 
Visit 7 (Week 24)* 
127 to 210 
 
Visit 8 (Week 36)* 
211 to 294 
 
Visit 9 (Week 48)* 
295 to 378  
 
Visit 10 (Week 60) 
379 to 462 
 
Visit 11 (Week 72) 
463 to 546 
 
Visit 12 (Week 84) 
547 to 630 
 
Visit 13 (Week 96) 
631 to 714  
 
Visit X  
Every 12 weeks 
 
 
 
After 
study 
treatment 
End of Study/Early 
Withdrawal Visit 
Last visit + 1 day 
to 
Last visit + 30.4375 days 
  *Common visit for pNEt cohort and Midgut cohort (up to Week 96) 
1 When Visit 2 (Day 1) is missing, baseline value is based on screening value for change from baseline analysis. 
 
Following the first dose at the reduced dosing interval at Visit 2 (Baseline), lanreotide Autogel® 
will be administered every 14 days (± 1 day) thereafter for up to 48 weeks (pNET cohort) and 
up to 96 weeks (midgut cohort), or until disease progression, death, or unacceptable toxicity or 
tolerability. For subjects who have not progressed at 48 weeks (pNET cohort) or 96 weeks 
(midgut cohort), study drug administration will continue and additional visits will be performed 
every 12 weeks after this time until 25 events have been observed in the respective cohort. 
'Injection only' visits will not be considered as study visits. 


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3.2.16 
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the number of 
decimal places used does not imply undue precision).  Raw data will be presented to the number 
of decimal places collected, and derived data will be presented to an appropriate number of 
decimal places. The appropriate number of decimal places will be determined by general 
practice, mathematical rationale or scientific rationale (e.g. age should be presented in whole 
numbers).  
For descriptive analyses, summary statistics will be presented at each scheduled visit. Summary 
statistics will include sample size, number of available observations (N), number of missing 
observations (missing), mean, 95% CI of the mean, standard deviation (StD), number of 
nonmissing observations (n), median and range for continuous variables and scores.  
For categorical or discrete variables, the absolute and relative (percentage) numbers based on 
the nonmissing number of observations for each category will be presented, including 95% CIs. 
Mean, median, standard deviation and standard errors of the mean (SE) values will be reported 
to one decimal place greater than the raw/derived data that they summarise.  Minimum and 
maximum values will be reported with the same precision as the raw data. 
Percentages will be reported to one decimal place and 0% will not be presented.  Percentages 
will be calculated using a denominator of non-missing observations. The denominator will be 
specified in a footnote to the tables for clarification if necessary.  
P-values will be reported to four decimal places (e.g.: p=0.0037), after rounding. P-values 
which are less than 0.0001 will be presented as ‘<0.0001’. 
All values below or above a limit of detection will be listed as such.   
All text fields must be left justified and numeric or numeric with some text specification (e.g.: 
not done, unknown, <4.5) must be decimal justified.  Dates will be presented in the format 
[ddmmmyyyy] and times in the format [hh:mm]. 
 
3.2.17 
Pooling of Centres 
It is not planned to perform a subgroup analysis on individual or groups of centres. 
 


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3.2.18 
Interim analysis 
 A baseline analysis will be performed on all subjects enrolled until data extraction. This interim 
analysis (descriptive analysis of baseline data) was planned and Agencies/Committees were 
informed in October 2018. Visit 1 and Visit 2 only will be used for this interim analysis. The 
following baseline assessments will be described on the FAS population :  
 Subjection disposition 
 Demographic data (country, center, age, sex, height, weight, race, BMI, ECOG 
performance status), 
 Tumours characteristics, 
 Significant medical or surgical history, 
 Presence/absence of symptoms at baseline 
 Prior surgical procedures for pancreatic/midgut NETs, prior radiotherapy for 
pancreatic/midgut NETs, prior medications for pancreatic/midgut NETs, 
 SSTR2 assessment /Krenning Scale, 
 Quality of life questionnaires (QLQ C30, QLQ GI.NET21, EQ-5D-5L), Visit 2 day 1 
only, 
 Concentrations of nonspecific tumour peptide biomarkers, Visit 2 day 1 only, 
 Gallbladder echography, Screening only 
 Progression at pre-screening and screening as assessed by an independent central 
reviewer (only listed). 
 
3.2.19 
Role of the Data Safety Monitoring Board (DSMB) 
A DSMB covering both cohorts combined will be appointed to review data, as determined in a 
DSMB charter, at the following timepoints:  
(1) 
when 20 subjects from both cohorts have reached the Week 4 evaluation,  
(2) 
when 20 subjects from both cohorts have reached the Week 12 evaluation, and  
(3) 
when 50 subjects from both cohorts have reached the Week 12 evaluation.  
The DSMB will be composed of independent experts. The purpose of the DSMB will be to 
evaluate safety early (Week 4) and at steady state (Week 12) of the reduced dosing interval, 
and to make recommendations to the sponsor as to whether the study should continue as planned 
or whether any changes are recommended to the trial conduct or protocol. The Chair of the 
DSMB will be responsible for communicating the DSMB’s recommendations. Full details of 
the operating model for the DSMB will be provided in a DSMB charter, and details of the data 
analysis (e.g. parameters, frequency, stopping rules) will be provided in a separate DSMB SAP. 
 


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3.2.20 
Covariates and analysis of subgroups 
Descriptive statistics for the following efficacy endpoints will be presented by cohort (pNET 
and midgut) and overall: ORR, DCR, OS, best overall response, tumour biomarkers, symptoms 
(diarrhoea and flushing) and quality of life. In addition, safety analyses will be performed on 
the cohorts separately and on the overall population.  
Survival rates, ORR and DCR will also be presented for hepatic tumour load ≤25% versus 
>25%, grade 1 versus grade 2, previous surgery of the primary tumour and Ki67 <10% versus 
≥10, Time interval between the 2 CT scans (pre-screening / screening) <12 months / >=12 
months) and symptoms (diarrhoea or flushing at baseline: Yes / No) 
 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Hardware 
The statistical analysis will be performed using Windows 7. 
4.2 
Software 
All tables, listings and figures will be produced and statistical analysis performed using SAS® 
version 9.4. All outputs will be in Microsoft Word Format, and delivered by the CRO as one 
single file per tables, listing, figure, and a compilation per ICH section. 
4.3 
Validation programs 
SAS® programs are developed to produce clinical study output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. Chiltern International 
 
“
 
s. 
Chiltern 
 
 describes the quality 
control procedures that must be performed for all SAS® programs and outputs. Quality control 
(QC) is defined here as the operational techniques and activities undertaken to verify that the 
SAS® programs produce the proper clinical study output by checking for their logic, efficiency 
and commenting, and by inspection of the produced outputs. 
A Program Output Release form (
 will be prepared to document the methods of 
validation.  
Copies of the QC documentation produced as confirmation that the validation process has been 
followed will be provided by Chiltern and will be retained by the sponsor. 
4.4 
Restitution of the programs 
All programs (including Macros and analysis datasets) producing the tables, listings and 
statistical output along with associated logs should be given to the sponsor when the tables, 
listings, figures and statistical analysis has been finalised. 
CCI
CCI
CCI
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5 
CHANGES FROM PROTOCOL 
2.4 
Primary population 
A change from the protocol has been made in this SAP, concerning section 10.1.1 Populations 
Analysed of the protocol, were it is stated that a PP population analysis will be performed on 
the primary and secondary endpoints of PFS (i.e. median PFS and PFS rate), median time to 
progression, ORR, DCR, best overall response and median duration of SD. In the section 2.4 
Primary population of this SAP, it has been added that these analyses will be performed only if 
the difference in number of subjects between FAS and PP population is > 10%, based on 
subjects in FAS. 
Table 6 Censoring Rules for PFS of the protocol section 10.4.5 Efficacy Evaluation has been 
updated in this SAP, from: 
Reason for censoring 
Rule  
No Screening evaluable assessment 
Date of first treatment administration  
Two or more not evaluable (NE) assessments before 
progressive disease or death 
Date of last evaluable disease assessment before the 
second NE assessment  
No progressive disease  
Date of last evaluable disease assessment  
Treatment discontinuation for undocumented 
progression  
Date of last evaluable disease assessment  
Treatment discontinuation for toxicity or other reason  Date of last evaluable disease assessment  
to: 
Reason for censoring 
Rule 
No screening evaluable* assessment 
Date of first treatment administration 
Two or more not evaluable (NE) assessments before 
progressive disease or death 
Date of last evaluable disease assessment before the 
second NE assessment 
No progressive disease 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented 
progression 
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or other reason 
Date of last evaluable disease assessment 
Initiation of medications or therapy not permitted 
during the study 
Date of initiation of non permitted medication or 
Therapy 
* An assessment is considered NE when no imaging/measurement is done at all at a particular time point, or only a subset of 
lesion measurements are made at the time point. The subject is considered NE at that time point. 
 (see Table 5, section 3.2.1.1 Primary analysis of this SAP) 
 
3.1.2 Secondary efficacy endpoint(s) 
A change from the protocol has been made in this SAP, concerning section
 
 
 
). 
 
 
 
 
 
CCI
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6 
APPENDICES TO THE SAP TEMPLATE 
 
6.1 
List of TFLs 
List of TFLs to be produced for the analysis are provided in this section. Tables and 
listings to be performed for the baseline interim analysis are flagged with an asterisk 
(*) 
6.1.1 
Listings index 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7 
REFERENCES 
1 
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response 
to treatment in solid tumors. European Organization for Research and Treatment of 
Cancer, National Cancer Institute of the United States, National Cancer Institute of 
Canada. J Natl Cancer Inst. 2000;92:205 216. 
2 
International Conference on Harmonisation (ICH) E9 Guidance on statistical principles 
for clinical trials. Federal register Vol 63, No. 179 (September 1998). 
3 
Ferté C, Fernandez M, Hollebecque A et al. Tumor growth rate is an early indicator of 
antitumor drug activity in phase I clinical trials. Clin Cancer Res. 2014;20:246 252 
4 
US Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for 
the Approval of Cancer and Drugs and Biologics. Rockville, MD: US Food and Drug 
Administration, US Dept of Health and Human Services; 2007