Clinical trial NCT02683941
Conditions: Neuroendocrine Tumors in Lung
Sponsor: Ipsen
Start date: 2017-03-06; Completion date: 2020-02-28
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, prospective, multi-center, randomized, double-blind, study evaluating the efficacy and safety of LAN plus BSC versus placebo plus BSC for the treatment of well-differentiated, metastatic and/or unresectable, typical or atypical bronchopulmonary NETs.

This study contains two phases: the Double-Blind (DB) Phase, and the Open Label (OL) Phase. The DB Phase includes: Screening, Baseline and Treatment period. The OL Phase will consist of two periods: Treatment Period and Follow-Up Period.

The primary objective will be to describe the antitumour efficacy of Lanreotide Autogel/Depot 120 mg (LAN) plus Best Supportive Care (BSC) every 28 days, in terms of progression-free survival (PFS), measured by central review using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria, every 12 weeks, in subjects randomized to LAN with unresectable and/or metastatic well differentiated, typical or atypical bronchopulmonary neuroendocrine tumours.

Recent updates of National Cancer Institute Cancer Network (NCCN) \& European Neuroendocrine Tumor Society (ENETS) guidelines recommend SSA in first line for the treatment of locoregional unresectable or metastatic bronchopulmonary NETs as an option beyond 'observation' leading to slow and difficult recruitment in SPINET study. Consequently, it was decided to prematurely stop the recruitment in the SPINET study and to transition all subjects still treated in the double-blind phase to the open label (OL) treatment and follow-up phases following respective country approvals of Amendment #5.

The new aim of this Phase 3, multicenter, prospective, randomized placebo-controlled clinical study is to describe the antitumor efficacy and safety of Lanreotide Autogel/Depot 120 mg (LAN) plus Best Supportive Care (BSC) in subjects with well-differentiated, metastatic and/or unresectable, typical or atypical, bronchopulmonary NETs.

Detailed description:
As planned initially, a total of 216 eligible patients with well-differentiated typical or atypical, metastatic and/or unresectable bronchopulmonary NETs, and a positive somatostatin receptor imaging (SRI) (Octreoscan® ≥ grade 2 Krenning scale; Ga-PET scan: uptake greater than liver background), were to be randomized 2:1 to either LAN plus BSC (120mg/28 days) or placebo plus BSC following the stratification of 1) typical versus atypical and 2) prior chemotherapy versus no prior chemotherapy\*.

\* cytotoxic chemotherapy or molecular targeted therapy or interferon.

At the time of the premature stop of the recruitment (as per Protocol Amendment #5), 77 patients were enrolled. All patients still treated in the DB Phase were entered into the OL Phase (either for Follow up or for OL treatment periods). The transition to the OL periods was done on a country-basis and per patient, at the following planned scheduled visit (i.e. approximately 28 days from the last injection). Patients enrolled into the study not progressing at the time of study stop, and who agree to stay on LAN therapy (i.e. OL Treatment Period) receive the study active treatment until evidence of disease progression (based on local radiological assessment then confirmed centrally), development of unacceptable toxicity, or premature withdrawal for any reason or up a maximum of 18 months after the last patient randomized. After disease progression patients are followed for survival, QoL and all subsequent anticancer treatments in the OL Follow-up period up to the end of the study (i.e up to 18 months after the last patient randomized).

Arms: arm 1: 120mg every 28 days until disease progression, death, or unacceptable toxicity arm 2: 120mg every 28 days until disease progression, death, or unacceptable toxicity during the double-blind phase. The patient may enter open-label phase for treatment with Lanreotide.
Interventions: intervention 1: Lanreotide (Autogel formulation) intervention 2: Placebo intervention 3: Best Supportive Care
Intervention descriptions: intervention 1: 120mg every 28 days until disease progression, death, or unacceptable toxicity intervention 2: Saline solution 0.9% administered via deep subcutaneous injection every 28 days until disease progression. intervention 3: Best Supportive Care is best available therapy at the choice of the investigator

Protocol documents:
Prot_000.pdf: 
IPSEN GROUP 
A-US-52030-328 
 
CONFIDENTIAL 
 
PROTOCOL FINAL (INCLUDING AMENDMENT #5): 28 JANUARY 2019 
PAGE 1
 
 
A PHASE 3, PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, MULTI-CENTER, 
STUDY OF THE EFFICACY AND SAFETY OF LANREOTIDE AUTOGEL/ DEPOT 
120 MG PLUS BSC VS. PLACEBO PLUS BSC FOR TUMOUR CONTROL IN 
SUBJECTS WITH WELL DIFFERENTIATED, METASTATIC AND/OR 
UNRESECTABLE TYPICAL OR ATYPICAL LUNG NEUROENDOCRINE 
TUMOURS 
 
STUDY PROTOCOL 
STUDY number: A-US-52030-328 
 
Lanreotide Autogel/Depot 
EudraCT number 2015-004992-62 
 
Final Version (including Amendment #5): 28 January 2019 
 
Sponsor’s Medically Responsible Person: 
Study Sponsor: 
 
Ipsen Biopharmaceuticals, Inc. 
Ipsen Pharma SAS 
106 Allen Road  
65, quai George Gorse 
Basking Ridge, NJ 07920 
92100 Boulogne-Billancourt 
 
 
 
 
 
 
Monitoring Office 
Co-ordinating Investigators: 
Ipsen Pharma 
 
65, quai Georges Gorse 
   
92100 Boulogne Billancourt, France 
 
 
 
 
 
 
CRO 
 
Theradex 
 
4365 Route 1 South 
 
Princeton, NJ 08540 
 
USA 
 
 
 
 
 
 
 
 
 
 
 
 
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Pharmacovigilance/Emergency Contact: 
  
 
  
  
 
For SAEs reporting: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
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INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol A-US-52030-328 entitled A Phase 3, Prospective, 
Randomized, Double-Blind, Multi-Center, Study of the Efficacy and Safety of Lanreotide 
Autogel/ Depot 120 mg plus BSC vs. Placebo plus BSC for Tumour Control in Subjects with 
Well 
Differentiated, 
Metastatic 
and/or 
Unresectable 
Typical 
or 
Atypical 
Lung 
Neuroendocrine Tumours, with Amendment #5. 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] 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE:  
 
 
 
 
 
 
 
 
Sponsor’s Representative Signature: 
NAME: 
 
TITLE: 
 
SIGNATURE: 
 
 
DATE: 
OFFICE:  
 
 
 
 
 
 
PPD
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IPSEN GROUP 
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PROTOCOL FINAL (INCLUDING AMENDMENT #5): 28 JANUARY 2019 
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COORDINATING INVESTIGATOR’S AGREEMENT 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol A-US-52030-328 entitled A Phase 3, Prospective, 
Randomized, Double-Blind, Multi-Center, Study of the Efficacy and Safety of Lanreotide 
Autogel/ Depot 120 mg plus BSC vs. Placebo plus BSC for Tumour Control in Subjects with 
Well 
Differentiated, 
Metastatic 
and/or 
Unresectable 
Typical 
or 
Atypical 
Lung 
Neuroendocrine Tumours, with Amendment #5. 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 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE:  
PPD


IPSEN GROUP 
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PROTOCOL FINAL (INCLUDING AMENDMENT #5): 28 JANUARY 2019 
PAGE 5
 
 
 
COORDINATING INVESTIGATOR’S AGREEMENT 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol A-US-52030-328 entitled A Phase 3, Prospective, 
Randomized, Double-Blind, Multi-Center, Study of the Efficacy and Safety of Lanreotide 
Autogel/ Depot 120 mg plus BSC vs. Placebo plus BSC for Tumour Control in Subjects with 
Well 
Differentiated, 
Metastatic 
and/or 
Unresectable 
Typical 
or 
Atypical 
Lung 
Neuroendocrine Tumours, with Amendment #5. 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 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE:  
 
 
 
 
 
 
 
PPD


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SUMMARY OF CHANGES 
 
The current version of the protocol was released on 28 January 2019 and includes 
Amendment #5. The amendment forms were prepared and are provided in 
 to 
(Table 1). 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
14 December 2015 
 
2 
20 April 2016 
 
3 
13 June 2016 
 
4 
05 October 2016 
 
5 
28 January 2019 
 
 
 
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SYNOPSIS 
Study Title 
A Phase 3, prospective, randomized, double-blind, multi-center study 
of the efficacy and safety of lanreotide Autogel/Depot 120 mg plus 
BSC vs. placebo plus BSC for tumour control in subjects with well 
differentiated, metastatic and/or unresectable, typical or atypical, lung 
neuroendocrine tumours.  
Sponsor 
Name, 
Location 
 
IPSEN 
106 Allen Road, Basking Ridge, NJ 07920 
Ipsen Contact:  
  
Rationale 
Neuroendocrine tumours (NETs) comprise a heterogeneous group of 
neoplasms originating from neural crest cells, endocrine glands, 
endocrine islets or the diffuse endocrine system. The majority of NETs 
are sporadic and little is known about their risk factors. In some cases 
NETs form part of heritable tumour syndromes such as multiple 
endocrine neoplasia type 1 or tuberous sclerosis. 
 
Although considered rare malignancies, recent data suggest an increase 
in NETs incidence over the past 30 years, with 5.2 cases per 100,000 
population 
per 
year. 
NETs 
of 
pancreatic, 
intestinal 
and 
bronchopulmonary origin are the most common, with the incidence of 
bronchopulmonary or bronchial NETs at 1.35 per 100,000; this is 
seemingly a drastic increase from the annual incidence of 0.3 per 
100,000 of 1973 [Yao 2008].  Bronchial NETs account for 
approximately 1 to 2 percent of all lung malignancies in adults and 
roughly 20 to 30 percent of all NETs.  NETs of thorax include lung 
and thymus NETs. 
 
There are 4 types of lung neuroendocrine cancers - typical carcinoid, 
atypical carcinoid, large-cell neuroendocrine carcinoma (NECs), and 
small-cell lung cancer (SCLC). Like neuroendocrine tumours at other 
body sites, bronchial NETs are thought to derive from peptide- and 
amine-producing neuroendocrine cells that have migrated from the 
embryologic neural crest.  
 
While surgery remains the treatment of choice for patients with 
resectable tumours, there are limited options for those with advanced 
or metastatic disease with unresectable tumours. The primary goal in 
the treatment of unresectable, advanced NETs is to prevent tumour 
progression and reduce the symptoms related to carcinoid syndrome 
when present. Typical and atypical carcinoid metastatic lung NETs are 
associated with poor prognosis; with median survival averaging 17 
months and the 5-year survival rate approximately at 27%. However, 
recent studies dedicated to stage IV lung NETs suggest better median 
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OS of 5 to 10 years for atypical and typical carcinoids.  There is a clear 
unmet need in patients with advanced lung NETs. 
 
Limited data are available regarding treatment for advanced lung NETs 
due to the rarity of the disease.  In most cases, treatment guidelines are 
extrapolated from the clinical experience with the more common 
gastrointestinal (GI) NETs or mixed retrospective studies. Recently 
recommendations issued from the European Neuroendocrine Tumour 
Society for best practice for typical and atypical pulmonary carcinoid 
have been published. To date, available data on the application of 
Somatostatin analogs (SSAs) or other systemic intervention in lung 
NETs come from two prospective studies conducted in lung NETs 
progressive patients:  
- 
In RADIANT 2 study, the median PFS (measured by local and 
central review in the lung NET subgroup), was 2.8 and 5.6 
months, respectively, in the octreotide group (n=11) versus 8.8 
and 13.6 months, respectively, in the everolimus plus octreotide 
group (n=33). 
- 
In RADIANT 4 study, conducted in patients with well-
differentiated (G1/G2), advanced, progressive, non-functional 
NET of lung or GI origin, a reduction of 52% in the relative risk 
of progression or death with everolimus versus placebo (Hazard 
ratio = 0.48 (95% CI, 0.35-0.67); p<0.00001) was demonstrated 
in the overall population.  
There are also some data reported from retrospective single centre 
study involving 61 patients with lung NET treated with SSAs, the 
estimated median PFS was 17.4 months (12.8 months in the AC 
subgroup and 24.8 months in the TC subgroup). In another study 
where nine patients were treated with octreotide and 13 patients were 
treated with lanreotide, a median PFS of 18.1 months was reported for 
22 patients (32% of whom had AC). In a further study, a median PFS 
of 16.5 months was reported in 22 patients treated with SSAs.    
Recently, the CLARINET study demonstrated that first-line treatment 
with Lanreotide Autogel/Depot 120 mg, a somatostatin analogue 
(SSA), significantly prolonged progression free survival among 
subjects with metastatic grade 1 or 2 enteropancreatic NETs of (Ki 67 
<10%) [Caplin 2014]. This is the first and only registration study of an 
SSA (Lanreotide Autogel/Depot 120 mg) demonstrating a cancer 
treatment benefit in this gastrointestinal and pancreatic NET 
population. While, subjects with bronchial neuroendocrine tumours (B-
NETs) were not included in CLARINET, there is a well-established 
basis for the use of SSAs like Lanreotide Autogel/Depot 120 mg in the 
management of lung NETs  the high expression of the somatostatin 
receptors SSTR2A and SSTR3  
Besides their role in imaging for NETs (somatostatin receptor 
scintigraphy (SRS) or octreotide scan), SSAs are also therapeutically 
used mainly to control hormone related symptoms, which occur in up 


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to 40% of cases of hypersecretion in patients with advanced lung NET 
tumours.  
 
Recent updates of NCCN & ENETS guidelines recommend SSA in 
first line for the treatment of locoregional unresectable or metastatic 
lung NETs as an option beyond ‘observation’. Consequently, it was 
decided to prematurely stop the recruitment in the SPINET study and 
to transition subjects still treated in the double-blind phase to the OL 
treatment phase. The transition to the OL treatment period, will be 
done per subject, at the planned scheduled visit (ie, approximately 28 
days from the last injection) following the country approval of 
Amendment #5.  
 
The new aim of this Phase 3, multicenter, prospective, randomized 
placebo controlled clinical study is to describe the antitumour efficacy 
and safety of Lanreotide Autogel/Depot 120 mg (LAN) plus Best 
Supportive Care (BSC) in subjects with well differentiated, metastatic 
and/or unresectable, typical or atypical, lung NETs. 
 
Study Objectives 
Objectives 
Primary Objective 
• 
To describe the antitumour efficacy of LAN 
monotherapy plus BSC every 28 days in terms of 
progression free survival (PFS), measured by central 
review using Response Evaluation Criteria in Solid 
Tumours (RECIST) v1.1 criteria, every 12 weeks, in 
subjects with unresectable and/or metastatic well 
differentiated, typical or atypical lung neuroendocrine 
tumours in either the double-blind phase or the OL 
period. 
 
Secondary Efficacy Objectives 
• 
To describe the antitumour efficacy during the double-
blind phase of LAN monotherapy plus BSC every 
28 days and placebo plus BSC, in terms of progression 
free survival (PFS), measured by central review using 
RECIST v1.1 criteria, every 12 weeks, in subjects with 
unresectable and/or metastatic well differentiated, 
typical or atypical lung NETs  
• 
To describe the antitumour efficacy during the double-
blind phase of LAN monotherapy plus BSC every 
28 days and placebo plus BSC, in terms of progression 
free survival (PFS), measured by local review using 
RECIST v1.1 criteria, every 12 weeks, in subjects with 
unresectable and/or metastatic well differentiated, 


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typical or atypical lung NETs  
• 
To describe the objective response rate (ORR) of LAN 
monotherapy plus BSC every 28 days and placebo plus 
BSC, as assessed by RECIST v 1.1 criteria (proportion 
of subjects with an objective response of partial 
response (PR) or complete response (CR)) in the 
double-blind phase, 
• 
To describe time to treatment failure (Kaplan Meier 
estimates) of LAN monotherapy plus BSC every 28 
days and placebo plus BSC in the double-blind phase, 
• 
To describe the changes from Baseline in the 
biomarker chromogranin A (CgA) during the double-
blind and the OL treatment phases, 
• 
To describe the proportion of subjects with a decrease 
of CgA≥30% at week 8 in the population of subjects 
with an elevated CgA (≥2 x ULN) at Baseline during 
the double-blind and the OL treatment phases, 
• 
To describe the change in Quality of Life (QoL) from 
baseline, as assessed by the EORTC QLQ-C30 
questionnaire during the double-blind, the OL 
treatment and during the OL follow-up phases,  
• 
To describe the time to deterioration of QoL (using 
EORTC QLQ-C30) during the double-blind, the OL 
treatment and during the OL follow-up phases, 
• 
To 
describe 
the 
changes 
in 
urinary 
5-hydroxyindoleacetic acid (5-HIAA) in subjects with 
elevated urinary 5-HIAA (≥2 x ULN) at Baseline 
during the double-blind and the OL treatment phases. 
 
Secondary Safety Objective 
• 
To evaluate the clinical and biological safety profile.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Timelines 
Study duration  
• 
Trial recruitment: 25 months 
• 
Double Blind (DB) Phase: approximately 36 months 
• 
OL Extension Phases will end 18 months after the last subject 
randomised 
Study Design  
 
This is a Phase 3, prospective, multi-center, randomized, double-blind 
study describing the efficacy and safety of LAN plus BSC and placebo 
plus BSC for the treatment of well-differentiated typical or atypical, 
metastatic and/or unresectable lung NETs.  The study will be 
conducted at approximately 80 centers in the United States, Canada 
and Europe. At time of protocol Amendment #5, a total of 38 centers 
have actively recruited at least one subject (active recruitment is 
defined by at least one informed consent signed). 
 
As planned initially, a total of 216 eligible subjects with well-
differentiated typical or atypical, metastatic and/or unresectable lung 
NETs, and a positive somatostatin receptor imaging (SRI) 
(Octreoscan® ≥ grade 2 Krenning scale; Ga-PET scan: uptake greater 
than liver background), had to be randomized 2:1 to either LAN plus 
BSC (120mg/28 days) or placebo plus BSC following the stratification 
of 1) typical versus atypical and 2) prior chemotherapy versus no prior 
chemotherapy*. Due to the premature stop of the recruitment (as per 
Protocol Amendment #5), 77 subjects are enrolled. All subjects still 
treated in the DB Phase will enter into the OL Extension Period (either 
for follow-up or for OL treatment). The transition to the OL treatment 
period, will be done by country and per subject, at the next planned 
scheduled visit (i.e. approximately 28 days from the last injection). 
Subjects enrolled into the study will stay on LAN therapy (i.e. OL 
Treatment Period) until evidence of disease progression (assessed 
locally and confirmed centrally), development of unacceptable 
toxicity, or premature withdrawal for any reason or up to 18 months 
after the last subject randomised.  After disease progression subjects 
will be followed for survival, QoL and all subsequent anticancer 
treatments up to the end of the study.   
* cytotoxic chemotherapy or molecular targeted therapy or interferon. 
 
The study contains two phases: the DB Phase, and the OL Extension 
Phase. The DB Phase included: Screening, Baseline and Treatment 
periods and the OL Extension Phase consists of two periods: Treatment 
Period and Follow-Up Period.   
• 
The DB Phase included a Screening Period to establish 
protocol eligibility and disease characteristics. The Baseline 
Visit confirmed eligibility prior to randomization and 
treatment.  The DB Phase of the study will end with Protocol 
Amendment #5 and will be followed by the OL Treatment 


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Period.  
Before approval of Protocol Amendment #5: 
If a subject progresses during the DB phase, the subject will be 
proposed to enter the OL Extension phase:  
• 
If the subject was on placebo and progressed during the DB 
phase, the subject will be offered the opportunity to enter the 
treatment period of the OL extension phase and to receive 
LAN every 28 days. 
• 
If the subject was on LAN and progressed during the DB 
phase, the subject will enter the follow-up period of the OL 
extension phase and be followed for QoL/survival and all 
subsequent anticancer treatments received will be recorded. 
The OL Treatment Period will stop once all subjects will have 
centrally progressed or 18 months after the last subject randomised (i.e. 
end of study). 
 
After approval of Protocol Amendment #5: 
• 
All ongoing subjects in the DB Phase, who have no yet 
progressed, will enter the OL Treatment Period. The subjects 
in the OL Treatment Period will be followed up to disease 
progression (assessed locally and confirmed centrally), 
development of unacceptable toxicity, or withdrawal from the 
study treatment for any other reason or up to 18 months after 
the last subject randomised. 
• 
if a subject progresses during the DB phase, the subject will 
enter the OL follow-up period 
• 
If a subject progresses during the OL Treatment Period, the 
subject will enter the OL follow-up period.  
• 
The follow-up period of the OL extension phase will stop at 
the same time as the OL Treatment Phase (ie, end of study  
up to 18 months after the last subject randomised).  
At the end of the OL Extension Treatment period, if subjects are still 
benefiting from treatment (i.e. not progressing) and there is sufficient 
evidence of the safety and efficacy of it, the subjects will have the 
option, to continue to receive lanreotide 120 mg every 28 days up to 
disease progression or unacceptable toxicity. In such a situation, as 
permitted by local regulations, lanreotide 120 mg will be provided free 
of charge by the sponsor to the sites under its commercial packaging. 
During this period, the physician will report immediately to Ipsen 
Pharmacovigilance Contact any safety concerns arising from the use of 
the product. 
 
Study Population 
Study population consists of 77 randomized subjects (i.e. number of 
subjects enrolled at time of enrolment termination) who met the 


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selection criteria specified below: 
 
Inclusion criteria 
(1) 
Provision of written informed consent prior to any study related 
procedures, 
(2) 
Subjects aged ≥ 18 years, 
(3) 
Have metastatic and/or unresectable pathologically confirmed 
well-differentiated, typical or atypical neuroendocrine tumour of 
the lung, 
(4) 
Histologic evidence of well differentiated NETs of the lung 
(typical and atypical according to the WHO criteria evaluated 
locally), 
(5) 
Has a mitotic index <2 mitoses/2 mm2 for typical carcinoid (TC) 
and ≤10 mitoses/2 mm2 and/or foci of necrosis for atypical 
carcinoid (AC),  
(6) 
At least one measurable lesion of the disease on imaging (CT or 
MRI; RECIST v1.1), 
(7) 
Positive somatostatin receptor imaging (SRI) (Octreoscan® ≥ 
grade 2 Krenning scale; Ga-PET scan: uptake greater than liver 
background),  
(8) 
ECOG performance status 0-1,  
(9) 
Female subject of childbearing potential should have a negative 
urine or serum pregnancy test within 72 hours prior to 
randomization. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required, 
(10) Female subjects who are at risk of becoming pregnant must 
agree to use an effective method of contraception such as double 
barrier contraception, an injectable, combined oral contraceptive 
or an intra-uterine device (IUD). The subject must agree to use 
the contraception during the whole period of the study and for 
eight months after the last study drug administration. Non 
childbearing potential is defined as being postmenopausal for at 
least 1 year, or permanently sterilized at least 3 months before 
study entry,  
(11) Male subjects must agree that, if their partner is at risk of 
becoming pregnant, they will use an effective method of 
contraception (see above). The subject must agree to use the 
contraception during the whole period of the study and for eight 
months after the last study drug administration, 
(12) Signed HIPAA authorization where required, 
(13) Subjects must be willing and able to comply with study 
restrictions and to remain at the clinic for the required duration 
during the study period and willing to return to the study site for 
the follow-up evaluation as specified in the protocol. 


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Exclusion criteria 
(1) 
Poorly differentiated or high grade carcinoma, or subjects with 
neuroendocrine tumours not of lung origin are excluded, 
(2) 
Subjects with Multiple endocrine neoplasia type 1 (MEN 1), 
(3) 
Has been treated with an SSA at any time prior to 
randomization, except if that treatment was for less than 15 days 
(e.g. peri-operatively) of short acting SSA or one dose of long 
acting SSA and the treatment was received more than 6 weeks 
prior to randomization, 
(4) 
Has been treated with Peptide receptor radionuclide therapy 
(PRRT) at any time prior to randomization, 
(5) 
Has been treated for Lung NET with chemotherapy* within 4 
weeks of randomization (whatever the number of cycles), 
(6) 
Has been treated with more than two lines of chemotherapy* for 
Lung NET, 
* cytotoxic chemotherapy or molecular targeted therapy or interferon. 
 
(7) 
Treated with surgery within 6 weeks prior to randomization, 
(8) 
Previous local therapy (e.g. chemo-embolization, bland, or 
radio-embolization) is allowed if completed > 6 weeks prior to 
randomization.  For subjects who received local therapy prior to 
randomization, there must be documented growth of measurable 
disease within the embolization field prior to study,  
(9) 
Symptomatic subjects requiring SSA for symptom management 
(please also note the exclusion criteria 3), 
(10) Subjects with known ectopic production of adrenocorticotropic 
hormone (ACTH) or other hormonal secreting subjects allowed 
 ONLY if symptoms adequately controlled without SSAs, 
(11) Subjects on concomitant Growth Hormone (GH) antagonist, 
cyclosporine or bromocriptine 
(12) Inadequate bone marrow function as per investigator’s 
judgement 
(13) Severe renal insufficiency as defined by a calculated creatinine 
clearance <30 mL/min,  
(14) Total bilirubin >2x ULN, AST, ALT or Alk Ph >5xULN, lipase, 
amylase >2xULN,  
(15) Serum albumin <3.0 g/dL unless prothrombin time is within the 
normal range,  
(16) Known hypersensitivity to the study drug, 
(17) Present cholecystitis,  
(18) Uncontrolled congestive heart failure 
(19) Glycosylated hemoglobin (HbA1c) > 8.5%, 


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(20) Abnormal findings, any other medical condition(s) or laboratory 
findings that, in the opinion of the investigator, would 
compromise the subject’s safety or the outcome of the study,  
(21) Other known co-existing malignancies except non-melanoma 
skin cancer and carcinoma in situ of the uterine cervix, unless 
definitively treated and proven no evidence of recurrence for 5 
years, 
(22) Pregnant or lactating women or those of childbearing potential 
age and not practicing a medically acceptable method for birth 
control, 
(23) Subjects who have participated in any therapeutic clinical 
study/received any investigational agent within 30 days of 
randomization.  
(24) Clinically 
significant 
cardiac 
arrhythmia, 
bradycardia, 
tachycardia that would compromise patient safety or the 
outcome of the study 
(25) Uncontrolled hypothyroidism 
 
Study Treatment 
 
 
 
 
 
 
 
 
 
 
 
Off-Treatment 
Lanreotide Autogel/Depot 120mg (LAN) plus BSC every 28 days 
administered via deep subcutaneous (s.c.) injection until disease 
progression confirmed centrally, development of unacceptable toxicity 
or premature withdrawal for any reason. 
 
OR 
 
Placebo plus BSC every 28 days administered via deep s.c. injection 
until disease progression confirmed centrally, development of 
unacceptable toxicity or premature withdrawal for any reason. 
 
A subject may decide to discontinue participation in the study at any 
time for any reason (e.g. withdrawal of consent, AE).  
The investigator and/or sponsor can withdraw a subject from the study 
at any time for any reason. 
Subjects will also be withdrawn from the study treatment should any of 
the following occur: 
• 
Disease progression as per local review, but not 
confirmed by central review RECIST v1.1: the local 
investigator always has the option of taking a subject 
off study  
• 
Occurrence of any AE or serious adverse event (SAE) 
that may jeopardise the subject’s health. 
• 
A need to administer any of the drugs prohibited by 
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• 
Appearance of carcinoid syndrome or other hormone 
related syndrome necessitating the initiation of any 
SSA (short acting and/or long acting release SSA). 
• 
Appearance of biological and/or clinical symptoms for 
Gallbladder inflammation confirmed by an echography 
• 
Pregnancy 
• 
Deviations from protocol 
• 
Investigator’s discretion 
 
Subjects will also be withdrawn from the study should any of the 
following occur: 
• 
Withdrawal of consent 
• 
Investigator’s discretion 
• 
Subject is lost to follow-up 
• 
Study is completed or terminated 
 
Any change in the administration of study drug or its discontinuation 
will be documented in the electronic case report form (eCRF).  
Endpoints 
Primary Endpoint 
Progression-free survival (PFS) for subjects randomized in LAN 
group, assessed by central review using RECIST v1.1 criteria every 
12 weeks, defined as the time from randomization to disease 
progression or death from any causes in either the double blind phase, 
or in the open label period.  
 
Secondary Efficacy Endpoints 
• 
Progression-free survival (PFS), assessed by central 
review using RECIST v1.1 criteria every 12 weeks, 
defined as the time from randomization to disease 
progression or death from any causes during the 
double-blind phase,  
• 
Progression-free survival (PFS), assessed by local 
review using RECIST v1.1 criteria every 12 weeks, 
defined as the time from randomization to disease 
progression or death from any causes during the 
double-blind phase, 
• 
ORR: objective response rate of CR or PR measured by 
RECIST v1.1 criteria every 12 weeks until the Post 
Treatment/Early Withdrawal Visit during the double-
blind phase, 
• 
Time to treatment failure during the double-blind 
phase, defined as the time from randomization to 
disease progression [defined as the minimum (time to 


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event according to central review, time to event 
according to local review)] using RECIST v1.1, death, 
consent withdrawn, an AE, protocol deviations, lost to 
follow-up, the appearance of carcinoid syndrome or 
other hormone related syndrome necessitating the 
initiation of SSAs (rescue octreotide and/or LAR SSA), 
or initiation of anticancer treatment,  
• 
Mean changes from Baseline in biomarker CgA at 
Week 8, Week 12 and every 12 weeks thereafter until 
the Post DB and in the OL treatment phases, 
• 
Proportion of subjects with decrease in CgA ≥30% at 
Week 8, in the population of subjects with an elevated 
CgA (≥2 x ULN) at Baseline during the double-blind 
and the OL treatment phases, 
• 
Change in QoL, as assessed by the European 
Organisation for Research and Treatment of Cancer 
Quality 
of 
Life 
Questionnaire 
Core-30 (EORTC 
QLQ-C30) questionnaire from Baseline to Week 12, 
every 12 weeks and at the Post Treatment /Early 
Withdrawal Visit and in OL Extension Treatment and 
Follow-up Phases, 
• 
Time to QoL deterioration, defined by a decrease from 
baseline in EORTC QLQ-C30 score of at least10 points 
during the double-blind, the OL treatment and during 
the follow-up phases,  
• 
Mean changes from Baseline in urinary 5-HIAA levels 
at Week 8, and every 12 weeks thereafter, and at the 
Post Treatment/Early Withdrawal Visit and in OL 
Extension Treatment in subjects with elevated urinary 
5-HIAA (≥2 x ULN) at Baseline. 
 
Secondary Safety Endpoints 
Safety and tolerability assessments throughout the study:  
• 
Adverse Events (AEs) grouped by Medical Dictionary 
for Regulatory Activities (MedDRA) Preferred Term, 
and graded by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI 
CTCAE) v4.03, 
• 
Clinical evaluations (medical and surgical history and 
physical 
evaluations, 
including 
biochemistry/hematology, 
ECG, 
 
), 
• 
Gallbladder echography, if biological and/or clinical 
inflammatory symptoms appear during the course of 
the study. 
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Assessments 
with 
Brief Summary of 
Methods 
and 
Procedures 
A signed and dated informed consent form will be obtained at 
Visit 1 before screening procedures. 
 
 
 
 Evaluations obtained as part of routine medical care and 
performed during the screening period may be used in place of the 
study specific evaluations.  
Screening will take place at Visit 1 and the following assessments will 
be performed: 
• 
Eligibility check (inclusion/exclusion criteria) 
• 
Demographic data (year of birth, age, sex and, ethnicity 
and race (as per local regulations))  
• 
Medical and surgical history, including ongoing 
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medical history 
• 
Prior 
surgery, 
radiotherapy 
chemotherapy 
and 
medications related to lung NETs in an adjuvant setting 
• 
Pregnancy test 
• 
Clinical evaluation 
• 
ECOG status 
• 
NYHA classification and ECG 
• 
Disease history/disease diagnosis (mitotic count and 
foci 
of 
necrosis, 
Ki67 
value 
if 
available, 
tumour-node-metastasis (TNM) staging, location of 
primary 
tumour, 
number 
of 
metastatic 
organs, 
presence/absence of hormone related syndrome)  
• 
CT scans/MRIs performed within 12 months of 
baseline collected if available (sent for analysis by 
central review as part of an ancillary study)  
• 
SRI, if not available within the previous 6 months 
(Octreoscan® ≥ grade 2 Krenning scale; Ga-PET scan: 
uptake greater than liver background)  
• 
Gallbladder echography if biological and/or clinical 
inflammatory symptoms are present 
• 
Clinical 
laboratory 
tests 
(blood 
sampling 
for 
haematology and biochemistry panels) 
• 
Start collection of AEs/SAEs  
• 
Prior and concomitant medications/therapies unrelated 
to lung NETs  
• 
Prior and concomitant non drug therapies unrelated to 
lung NETs 
• 
Concomitant surgical procedures unrelated to lung 
NETs 
 
Under no circumstances will subjects be screened more than once.  
 
Baseline visit  
• 
QoL rated by the EORTC QLQ-C30 
• 
Clinical evaluation 
• 
Baseline subject and tumour characteristics 
• 
ECOG status 
• 
Heamatology/biochemistry 
• 
Pregnancy test 
• 
CT scan or MRI: CT scan of thorax and abdomen, or 
MRI of the abdomen with CT scan of the thorax 
• 
  
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• 
CgA and urinary 5-HIAA  
• 
 
 
• 
 
• 
AEs/SAEs 
• 
Concomitant medications 
• 
Concomitant non drug therapies  
• 
Concomitant surgical procedures 
• 
Concomitant 
medication/chemotherapy/molecular 
targeted therapy related to lung NET 
 
During treatment in the Double Blind Phase 
• 
QoL rated by the EORTC QLQ C30  
• 
Clinical evaluation 
• 
ECOG status 
• 
Hematology and biochemistry 
• 
ECG and NYHA classification 
• 
CT or MRI (thorax & abdomen) using the same mode 
as per baseline, utilising the RECIST 1.1 
• 
Urinary 5-HIAA (only for subjects with elevated 
urinary 5-HIAA (≥2 x ULN) at Baseline Visit) and 
plasma CgA. 
• 
Gallbladder echography, if biological and/or clinical 
inflammatory symptoms appear during the course of the 
study.  
• 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
• 
 
• 
AEs/SAEs 
• 
Concomitant medications 
• 
Concomitant non drug therapies 
• 
Concomitant surgical procedures 
• 
Concomitant medication/chemotherapy/molecular 
targeted therapy related to lung NET 
 
 
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During OL Extension 
OL Extension Treatment Period 
• 
Clinical evaluation 
• 
ECOG status 
• 
ECG, NYHA classification 
• 
CT or MRI (thorax & abdomen) using the same mode 
as per baseline, utilising the RECIST 1.1 
• 
QoL rated by the EORTC QLQ-C30. 
• 
Hematology, biochemistry. 
• 
Urine 5-HIAA and plasma CgA. 
• 
Gallbladder echography, if biological and/or clinical 
inflammatory symptoms appear during the course of the 
study. 
• 
 
• 
 
 
 
 
 
 
 
 
 
 
• 
AEs/SAEs 
• 
Concomitant medications 
• 
Concomitant non-drug therapies 
• 
Concomitant surgical procedures 
• 
Concomitant medication/chemotherapy/molecular 
targeted therapy related to lung NET 
 
OL Extension Follow-Up Period 
• 
Clinical evaluation 
• 
Survival status. 
• 
QoL rated by the EORTC QLQ C30. 
• 
Concomitant 
medication/chemotherapy/molecular 
targeted therapy related to lung NET 
 
After approval of Protocol Amendment #5, the subjects will receive an 
addendum to Informed Consent Form (ICF) including changes in study 
rationale and explanations about the conduct of the study end. If the 
subject agrees to continue to participate to this study, this addendum to 
ICF will have to be signed. 
Sample 
size 
justification  
Due to the premature stop of the study recruitment, 77 subjects are 
enrolled.  
Statistical analyses  Primary efficacy endpoint analysis: 
Progression-free survival (PFS) for subjects randomized in LAN group 
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will be measured from the date of randomization to the documented 
date of centrally confirmed progressive disease (PD) or death (from 
any cause), whichever occurs first in either the double-blind phase, or 
in the OL period. Subjects who start a new cancer therapy, who are lost 
to follow-up, and those who are alive without documented PD will be 
censored at the date of the last evaluable response assessment (prior to 
initiation of a new cancer therapy.  
Distribution of PFS times on LAN plus BSC group will be estimated 
using the Kaplan-Meier product-limit method.  
As a sensitivity analysis of the primary endpoint, a similar PFS 
analysis will be performed using the local assessment of progression. 
 
Secondary endpoint analyses: 
• 
Progression-free survival (PFS) will be measured from the 
date of randomization every 12 weeks to the documented date 
of centrally confirmed progressive disease (PD) or death 
(from any cause) during the double-blind phase, whichever 
occurs first. Subjects who start a new cancer therapy, who are 
lost to follow-up, and those who are alive without 
documented PD during the double-blind phase will be 
censored at the date of the last evaluable response assessment 
during the double-blind phase (prior to initiation of a new 
cancer therapy). Distribution of PFS times for each treatment 
arm will be estimated using the Kaplan Meier method. A 
stratified Cox proportional hazards model will be used to 
estimate the hazard ratio, and its two-sided 95% confidence 
interval. 
• 
Progression-free survival (PFS) will be measured from the 
date of randomization every 12 weeks to the documented date 
of locally confirmed progressive disease (PD) or death (from 
any cause) during the double-blind phase, whichever occurs 
first. Subjects who start a new cancer therapy, who are lost to 
follow-up, and those who are alive without documented PD 
during the double-blind phase will be censored at the date of 
the last evaluable response assessment during the double-
blind phase (prior to initiation of a new cancer therapy). 
Distribution of PFS times for each treatment arm will be 
estimated using the Kaplan Meier method. A stratified Cox 
proportional hazards model will be used to estimate the 
hazard ratio, and its two-sided 95% confidence interval. 
• 
The ORR in each treatment arm, with their corresponding 
exact 95% CIs, will be estimated. These analyses will be 
performed using data from local and central review of 
RECIST v1.1. 
• 
Treatment failure is defined as progression [defined as the 
minimum (time to event according to central review, time to 
event according to local review)] using RECIST v1.1, death, 


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CONFIDENTIAL 
 
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consent withdrawn, an AE, protocol deviations, lost to 
follow-up, the appearance of carcinoid syndrome or other 
hormone related syndrome necessitating the initiation of 
SSAs (rescue octreotide and/or LAR SSA), or initiation of 
anticancer treatment. Time to treatment failure will be 
defined as the time from randomization to treatment failure. 
The distribution of times to treatment failure for each 
treatment arm will be estimated using the Kaplan Meier 
method.  
• 
Mean changes from Baseline in biomarker CgA will be 
presented descriptively by time point and treatment group, 
using summary statistics. Raw values and change from 
Baseline will be presented. The proportion of subjects with a 
decrease of CgA≥30% from baseline from Baseline to 
Week 8 will be estimated, with the corresponding 95% CI in 
each treatment arm.  
• 
EORTC QLQ-C30 will be described at Baseline, and every 
12 Weeks, for double blind and OL extension (both treatment 
and follow-up phases). Raw values and change from Baseline 
will be presented.  
• 
Time to EORTC QLQ-C30 deterioration will be analyzed in 
a similar fashion to time to treatment failure. EORTC QLQ-
C30 deterioration is defined as a reduction of at least 10 
points between baseline and the given assessment. 
• 
Mean changes from Baseline in urinary 5-HIAA levels in 
subjects with elevated urinary 5-HIAA (≥2 x ULN) at 
Baseline will be presented descriptively by time point and 
treatment group, using summary statistics. 
 
  
 
 
 
 
 
 
 
 
 
 
 
Safety analyses:  
The safety population comprises all subjects in the ITT Population who 
received at least one injection of the study drug. Safety analyses will 
be performed separately by study phase (DB, OL extension treatment 
and follow-up phases). All treatment emergent adverse events 
(TEAEs) reported from signature of the informed consent form up to 
the end of the study will be graded according to the NCI CTCAE, 
summarized according to the Medical Dictionary for Regulatory 
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Activities (MedDRA, version 18.1 or later) System Organ Class (SOC) 
and Preferred Terms (PT), and classified by worst grade severity per 
subject by treatment group. 
 
Clinical laboratory results will be collected prior to each dose, up to 30 
days post last administration of any study drug. Clinically significant 
laboratory abnormalities, namely tests that result in treatment 
modification and/or require intervention, will be recorded as AEs. 
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 by subject and by 
visit will be listed. 


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TABLE OF CONTENTS 
SUMMARY OF CHANGES ................................................................................................... 6 
TABLE OF CONTENTS ....................................................................................................... 25 
LIST OF ABBREVIATIONS ................................................................................................ 30 
1 
BACKGROUND INFORMATION ............................................................................ 34 
1.1 
Introduction ................................................................................................................... 34 
1.2 
Compound Review ........................................................................................................ 34 
1.3 
Clinical Trial Rationale ................................................................................................ 35 
1.4 
Compliance Statement .................................................................................................. 36 
1.5 
Population to be Studied .............................................................................................. 37 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 37 
2.1 
Purpose of the Study ..................................................................................................... 37 
2.2 
Study Objectives ........................................................................................................... 37 
2.2.1 
Primary Objective ........................................................................................ 37 
2.2.2 
Secondary Efficacy Objectives .................................................................... 37 
2.2.3 
Secondary Safety Objectives ....................................................................... 38 
 
 
3 
STUDY DESIGN ........................................................................................................... 39 
3.1 
General Design and Study Schema ............................................................................. 39 
3.1.1 
Double-Blind Phase .................................................................................... 40 
3.1.1.1 
Screening Visit ............................................................................................. 40 
3.1.1.2 
Baseline Visit ............................................................................................... 40 
3.1.1.3 
Randomization and Treatment Period ......................................................... 40 
3.1.2 
Open Label Extension Phase ...................................................................... 41 
3.1.2.1 
Treatment Period (Optional Open Label Lanreotide Autogel/Depot) of 
the Open Label Extension Phase ................................................................. 41 
3.1.2.2 
Follow-up Period of the Open Label Extension Phase ................................ 42 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 43 
3.2.1 
Primary Endpoint ........................................................................................ 43 
3.2.2 
Secondary Endpoints .................................................................................. 43 
3.2.3 
Safety Endpoints ......................................................................................... 43 
 
 
3.3 
Randomization and Blinding ....................................................................................... 44 
3.4 
Study Treatments and Dosage ..................................................................................... 45 
3.5 
Study Duration .............................................................................................................. 46 
3.6 
Stopping Rules and Discontinuation Criteria ............................................................ 47 
3.7 
Early Study Termination ............................................................................................. 47 
3.8 
Study Drug Preparation Storage and Accountability ............................................... 48 
3.8.1 
Study Drug Storage and Security ............................................................... 48 
3.8.2 
Study Drug Preparation and Accountability.............................................. 48 
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3.9 
Maintenance of Randomization and blinding ............................................................ 48 
3.10 Source Data Recorded on the Case Report Form ...................................................... 49 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 51 
4.1 
Inclusion criteria ........................................................................................................... 51 
4.2 
Exclusion Criteria ......................................................................................................... 51 
4.3 
Subject Withdrawal Criteria and Procedures ........................................................... 52 
 
 
5 
STUDY PROCEDURES .............................................................................................. 55 
5.1 
Study Schedule for the DB phase ................................................................................ 55 
5.2 
Study Visits .................................................................................................................... 59 
5.2.1 
Pre-Randomization ..................................................................................... 59 
5.2.1.1 
Screening Period Procedures ...................................................................... 59 
5.2.1.2 
Baseline assessments and procedures on Day 1 .......................................... 60 
5.2.2 
Double Blind Phase Assessments and Procedures .................................... 61 
5.2.2.1 
Post Treatment Visit Assessments and Procedures ..................................... 63 
5.2.2.2 
Post Treatment Visit Procedures for Subjects Not Receiving or Do Not 
Qualify for Open Label Lanreotide Autogel/Depot ..................................... 63 
5.2.2.3 
Post Treatment Visit Procedures for Subjects Receiving Open Label 
Lanreotide Autogel/Depot plus BSC (Extension Phase OL Lanreotide 
Autogel/Depot plus BSC Treatment Period) ................................................ 64 
5.2.3 
Open Label Extension Phase Assessments and Procedures ..................... 64 
5.2.3.1 
Open Label Extension Treatment Phase Baseline Procedures .................... 66 
5.2.3.2 
Open Label Extension Treatment Phase Assessments and Procedures ....... 67 
5.2.3.3 
Post Treatment/Early Withdrawal Visit Procedures of OL Extension 
Treatment Phase .......................................................................................... 68 
5.2.3.4 
Open Label Extension Follow-Up Phase Baseline Procedures .................. 69 
5.2.3.5 
Open Label Extension Follow-Up Phase and Post-Extension Follow-up 
Phase Visit Procedures ................................................................................ 70 
6 
TREATMENT OF SUBJECTS ................................................................................... 71 
6.1 
Study drugs Administered ........................................................................................... 71 
6.1.1 
Lanreotide Autogel/Depot ........................................................................... 71 
6.1.2 
Placebo ........................................................................................................ 72 
6.2 
Prior and Concomitant Medication/Therapy ............................................................. 72 
6.2.1 
Prior Medication/Therapy .......................................................................... 72 
6.2.2 
Concomitant Medication/Therapy .............................................................. 72 
6.3 
Procedures for Monitoring Subject Compliance ....................................................... 73 
7 
ASSESSMENT OF EFFICACY .................................................................................. 74 
7.1 
Primary Efficacy Endpoint and Evaluation ............................................................... 74 
7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 74 
 
 
7.4 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 76 
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7.4.1 
Time to Disease Progression or Death ....................................................... 76 
7.4.2 
Tumour Response ....................................................................................... 76 
7.4.3 
Biomarkers (Chromogranin A and 5-Hydroxyindoleacetic Acid) ............ 77 
7.4.3.1 
Chromogranin A .......................................................................................... 77 
7.4.3.2 
5-Hydroxyindoleacetic Acid ......................................................................... 77 
7.4.4 
Somatostatin Receptor Imaging ................................................................. 78 
7.4.5 
Time to Treatment Failure ......................................................................... 79 
7.4.6 
Quality of Life ............................................................................................. 79 
7.4.7 
Subsequent Therapies ................................................................................. 79 
8 
ASSESSMENT OF SAFETY ....................................................................................... 79 
8.1 
Adverse Events .............................................................................................................. 79 
8.1.1 
Definition of an Adverse Event .................................................................. 79 
8.1.2 
Categorisation of Adverse Events ............................................................... 80 
8.1.2.1 
Intensity Classification ................................................................................. 80 
8.1.2.2 
Causality Classification ............................................................................... 80 
8.1.2.3 
Assessment of Expectedness ......................................................................... 81 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 81 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 81 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 81 
8.1.3 
Recording and Follow up of Adverse Events ............................................. 81 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 82 
8.1.5 
Pregnancy .................................................................................................... 84 
8.1.6 
Deaths .......................................................................................................... 84 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 85 
8.1.8 
Reporting to Competent Authorities/IRBs/IECs/Other Investigators ....... 85 
8.2 
Clinical Laboratory Tests ............................................................................................ 86 
8.2.1 
Hematology .................................................................................................. 86 
8.2.2 
Blood Biochemistry ..................................................................................... 86 
8.2.3 
Pregnancy Test ............................................................................................ 87 
8.2.4 
Antibodies .................................................................................................... 87 
8.3 
Physical Examination ................................................................................................... 88 
8.4 
Vital Signs ...................................................................................................................... 88 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 89 
 
 
 
 
 
 
9.2 
Pharmacodynamics ....................................................................................................... 89 
10 
STATISTICS ................................................................................................................. 91 
10.1 Analyses Populations .................................................................................................... 91 
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10.1.1 
Populations Analyzed .................................................................................. 91 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 91 
10.2 Sample Size Determination .......................................................................................... 91 
10.3 Significance Testing and Estimations ......................................................................... 92 
10.4 Statistical/Analytical Methods ..................................................................................... 92 
10.4.1 
Demographic and Other Baseline Characteristics .................................... 93 
10.4.2 
Homogeneity of Treatment Groups ............................................................ 93 
10.4.3 
Subject Disposition and Withdrawals ......................................................... 93 
10.4.4 
Pharmacokinetic Data ................................................................................ 93 
10.4.5 
Efficacy Evaluation ..................................................................................... 93 
10.4.5.1 
Primary Efficacy Variable ........................................................................... 93 
10.4.5.2 
Secondary Efficacy Variables ...................................................................... 95 
 
 
10.4.6 
Adjustment for Country/Center Effect ....................................................... 97 
10.4.7 
Safety Evaluation ........................................................................................ 98 
10.5 Subgroup Analyses ....................................................................................................... 99 
10.6 Interim Analyses ........................................................................................................... 99 
11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................. 100 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 101 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................. 101 
12.1.1 
Protocol Amendments ............................................................................... 101 
12.1.2 
Protocol Deviations, Violations, and Exceptions ..................................... 101 
12.2 Information to Study Personnel ................................................................................ 101 
12.3 Study Monitoring ........................................................................................................ 102 
12.4 Audit and Inspection .................................................................................................. 102 
12.5 Data Quality Assurance .............................................................................................. 102 
13 
ETHICS ....................................................................................................................... 104 
13.1 Compliance with Good Clinical Practice and Ethical Considerations .................. 104 
13.2 Informed Consent ....................................................................................................... 104 
13.3 Health Authorities and Institutional Review Boards/Independent Ethics 
Committees .................................................................................................................. 105 
13.4 Confidentiality Regarding Study Subjects ............................................................... 105 
14 
DATA HANDLING AND RECORD KEEPING ..................................................... 106 
14.1 Data Recording of Study Data ................................................................................... 106 
14.2 Data Management ....................................................................................................... 106 
14.3 Record Archiving and Retention ............................................................................... 107 
15 
FINANCING AND INSURANCE ............................................................................. 108 
15.1 Contractual and Financial Details ............................................................................. 108 
15.2 Insurance, Indemnity and Compensation ................................................................ 108 
16 
REPORTING AND PUBLICATIONS OF RESULTS ........................................... 109 
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LIST OF ABBREVIATIONS 
 
ABBREVIATION 
WORDING DEFINITION  
5-HIAA 
5-hydroxyindoleacetic acid 
βHCG 
Beta human chorionic gonadotropin 
AC 
Atypical carcinoid 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse event 
Alk Ph 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
 
 
  
 
 
 
BSC 
Best supportive care 
BP-NET 
Broncho-Pulmonary Endocrine Tumour 
CA 
Competent Authorities 
 
 
CFR 
Code of Federal Regulations (United States of America) 
CI 
Confidence interval 
 
 
 
 
 
 
 
CMC-SC 
Chemistry Manufacturing and Control  Supply Chain 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CSR 
Clinical study report 
CRO 
Contract research organisation 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT 
Computerized tomography 
CTSU 
Clinical Trial Supplies Unit (relates to sponsor) 
DB 
Double blind 
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DMC 
Data Monitoring Committee 
 
 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
ENETS 
European Neuroendocrine Tumor Society 
EORTC QLQ-C30 
Cancer Quality of Life Questionnaire Core-30  
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GH 
Growth Hormone 
HbA1c 
Hemoglobin A1c 
HCG 
Human chorionic gonadotropin 
HIPAA 
Health insurance portability and accountability 
HPF 
High Powered Field 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent ethics committee 
i.m. 
Intramuscular 
IND 
Investigational New Drug 
INR 
International normalised ratio 
IRB 
Institutional review board 
ISF 
Interim storage facility 
ITT 
Intention to treat 
IUD 
Intra-uterine device 
IWRS 
Interactive web response system 
Ki 67 
Proliferation index 
LAN 
Lanreotide autogel/depot 120 mg 
LAR 
Long acting release 
LC-MS/MS 
Liquid chromatography-mass spectrometry 
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MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN 1 
Multiple endocrine neoplasia type 1 
MRI 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dose (Dosage) 
NA 
Not applicable 
NCCN 
National Comprehensive Cancer Network 
NCI-CTC 
National Cancer Institute  Common Toxicity Criteria 
NET 
Neuroendocrine tumour 
NOS 
Not otherwise specified 
NYHA 
New York Heart Association 
OL 
Open label 
OLITT 
Open Label Intention to Treat 
ORR 
Objective Response Rate  
OS 
Overall Survival 
PhD 
Pharmacodynamics 
PD 
Progressive Disease 
PET 
Positron emission tomography 
PFS 
Progression Free Survival 
PP 
Per protocol 
 
 
PR 
Partial response 
PRRT 
Peptide receptor radionuclide therapy 
PT 
Preferred term 
PTT 
Partial thromboplastin time 
QoL 
Quality of Life 
RBC 
Red blood cell(s) 
RECIST 
Response Evaluation Criteria In Solid Tumours 
 
 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
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SAS® 
Statistical Analysis System® 
s.c. 
Subcutaneous 
SCLC 
Small-cell lung cancer 
SPECT 
Single photon emission computed tomography 
SRI 
Somatostatin receptor imaging 
SRS 
Somatostatin receptor scintigraphy 
SSA 
Somatostatin analogs 
StD 
Standard deviation 
SD 
Stable Disease 
SDV 
Source document verification 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SSTR 
Somatostatin receptors 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TC 
Typical carcinoid 
TEAE 
Treatment emergent adverse event 
TFLs 
Tables, figures and listings 
 
 
TMF 
Trial master file 
UDS 
Urine drug screen 
ULN 
Upper limit of normal range 
US(A) 
United States (of America) 
V/F 
Apparent volume of distribution 
WBC 
White blood cell(s) 
WHO 
World Health Organisation 
WHO-DD 
World Health Organization (WHO) drug dictionary 
 
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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Neuroendocrine tumours (NETs) comprise a heterogeneous group of neoplasms originating 
from neural crest cells, endocrine glands, endocrine islets or the diffuse endocrine system. 
The majority of NETs are sporadic and little is known about their risk factors. In some cases 
NETs form part of heritable tumour syndromes such as multiple endocrine neoplasia type 1 or 
tuberous sclerosis [1]. 
 
Although considered rare malignancies, recent data suggest an increase in NETs incidence 
over the past 30 years, with 5.2 cases per 100,000 population per year [2]. NETs of pancreatic 
intestinal and bronchopulmonary origin are the most common, with the incidence of 
bronchopulmonary or bronchial NETs at 1.35 per 100,000 [2]; this is seemingly a drastic 
increase from the annual incidence of 0.3 per 100,000 of 1973 [2]. Bronchopulmonary NETs 
account for approximately 1 to 2 percent of all lung malignancies in adults and roughly 20 to 
30 percent of all NETs [2, 3, 4, 5].  NETs of thorax include lung NETs and thymus NETs [5, 
6]. 
 
Pulmonary NETs are classified in four categories, typical carcinoid, atypical carcinoid, large-
cell NETs, and small-cell lung cancer (SCLC) [7]. Like neuroendocrine tumours at other body 
sites, bronchial NETs are thought to derive from peptide- and amine-producing 
neuroendocrine cells that have migrated from the embryologic neural crest.  
 
While surgery remains the treatment of choice for patients with resectable tumours, there are 
limited options for those with advanced or metastatic disease with unresectable tumours [8, 
5]. The primary goal in the treatment of unresectable, advanced NETs is to prevent tumour 
progression and reduce the symptoms related to carcinoid syndrome when present. Current 
treatment guidelines, including the 2015 National Comprehensive Cancer Network (NCCN) 
Guidelines for advanced lung NETs include observation or active surveillance as an option 
[9]. Typical and atypical carcinoid metastatic lung NETs are associated with poor prognosis; 
with median survival averaging 17 months and the 5-year survival rate approximately at 27% 
[2, 5]. However, recent studies dedicated to stage IV lung NETs suggest better median OS of 
5 to 10 years for atypical and typical carcinoids [10, 11, 12]. There is a clear unmet need in 
patients with advanced lung NETs. 
 
1.2 
Compound Review 
 
INN: Lanreotide Autogel/Depot  
Chemical formula: S-----------------------------S 
D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 
Empirical formula: C54H69N11O10S2 
Molecular weight: 1096.34 
 
Lanreotide is an octapeptide analogue of somatostatin. The depot formulation is a novel, 
prolonged release preparation of Lanreotide acetate and water for injection, which together 
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form a supersaturated solution of the peptide. Prolonged release of the peptide occurs by the 
physical nature of the supersaturated solution. The formulation enables active serum levels to 
be maintained for 1 to 2 months. The approved dosing regimen for gastroenteropancreatic 
neuroendocrine tumours is one deep subcutaneous (SC) injection of Lanreotide 
Autogel/Depot 120 mg (LAN), every 28 days in adults.   
The most commonly reported side effects for Lanreotide Autogel/Depot are: diarrhea (or 
loose stools), abdominal pain, and cholelithiasis.  Other common side effects are:  pancreatic 
enzyme decrease, weight decrease, nervous system disorders, headache, lethargy, dizziness, 
nausea, vomiting, gas, bloating, constipation, fatty stool, heartburn, hair loss, low blood sugar, 
decreased appetite, diabetes mellitus, high blood sugar, injection site reactions (e.g. pain, 
mass, hardness, nodule, itching), fatigue, weakness, musculoskeletal pain, and muscle pain. 
A more detailed description of the product is given in Section 3.4. 
 
1.3 
Clinical Trial Rationale 
Limited data are available regarding treatment for advanced lung NETs due to the rarity of the 
disease.  Cytotoxic chemotherapeutic agents have resulted in only minor activity in this 
disease and there is no standard therapeutic regimen. Participation in clinical trials testing new 
strategies is the preferred approach [13]. In most cases, treatment guidelines are extrapolated 
from the clinical experience with the more common gastrointestinal (GI) NETs or mixed 
retrospective studies. To date, available data on the application of Somatostatin analogs 
(SSAs) or other systemic intervention in lung NETs come from two prospective studies 
conducted in lung NETs progressive patients:  
• 
In RADIANT 2 study, the median PFS (measured by local and central review in the 
lung NET subgroup), was 2.8 and 5.6 months, respectively, in the octreotide group 
(n=11) versus 8.8 and 13.6 months, respectively, in the everolimus plus octreotide 
group (n=33) [14]. 
• 
In RADIANT 4 study, conducted in patients with well-differentiated (G1/G2), 
advanced, progressive, non-functional NET of lung or GI origin, a reduction of 52% in 
the relative risk of progression or death with everolimus versus placebo (Hazard ratio = 
0.48 (95% CI, 0.35-0.67); p<0.00001) was demonstrated in the overall population [15]. 
There are also some data reported from retrospective single centre study involving 61 patients 
with lung NET treated with SSAs, the estimated median PFS was 17.4 months (12.8 months 
in the AC subgroup and 24.8 months in the TC subgroup) [16]. In another study where nine 
patients were treated with octreotide and 13 patients were treated with lanreotide, a median 
PFS of 18.1 months was reported for 22 patients (32% of whom had AC) [17]. In a further 
study, a median PFS of 16.5 months was reported in 22 patients treated with SSAs [18]. 
 
Recently, the CLARINET study demonstrated that treatment with Lanreotide Autogel/Depot 
120 mg, a somatostatin analogue (SSA), significantly prolonged PFS among subjects with 
metastatic enteropancreatic NETs of grade 1 or 2 (Ki-67 <10%) [19]. This is the first and only 
registration study of an SSA (Lanreotide Autogel/Depot 120 mg) demonstrating a tumour 
control benefit in this patient population. While, patients with bronchial neuroendocrine 
tumours (BPNETs) were not included in CLARINET, there is a well-established basis for the 
use of SSAs like Lanreotide Autogel/Depot 120 mg in the management of lung NETs  the 
high expression of the somatostatin receptors SSTR2A and SSTR3 [20].  
 


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Besides their role in imaging for NETs (somatostatin receptor scintigraphy (SRS) such as 
octreotide scan), SSAs are also therapeutically used mainly to control hormone related 
symptoms, which occur in up to 40% of cases of hypersecretion in patients with advanced 
lung NET tumours [12]. 
 
Recent updates of NCCN & ENETs guidelines recommend SSA in first line for the treatment 
of locoregional unresectable or metastatic lung NETs as an option beyond ‘observation’ [21, 
22]. Consequently, it was decided to prematurely stop the recruitment in the SPINET study 
and to transition subjects still treated in the double-blind phase to the OL treatment phase.  
 
The new aim of this Phase 3, multicenter, prospective, randomized placebo controlled clinical 
study is to describe the antitumour efficacy and safety of Lanreotide Autogel/Depot 120 mg 
(LAN) plus Best Supportive Care (BSC) in subjects with well differentiated, metastatic and/or 
unresectable, typical or atypical, lung NETs. Placebo plus BSC/best supportive care was 
chosen as the control arm because there are no definitive, well-controlled studies 
demonstrating the efficacy and safety of SSAs in this setting. Current 2015 NCCN 
recommendations for Lung NET include observation for asymptomatic low-bulk typical 
pulmonary carcinoids. 2015 European Neuroendocrine Tumor Society (ENETS) guidance 
includes observation for asymptomatic pulmonary carcinoids of low proliferative index [9].  
 
Further details can be found in the Investigator Brochure (IB). 
 
1.4 
Compliance Statement 
The study will be conducted in compliance with institutional review boards/independent 
ethics committees (IRBs/IECs), 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. 
 
This study will utilize Electronic Data Capture (EDC) which will be conducted in compliance 
with the following regulations: Food and Drug Administration (FDA), 21 Code of Federal 
Regulations (CFR) Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance 
for Industry: Computerized Systems Used in Clinical Trials. 
 
In addition, this study will adhere to all USA FDA and other local regulatory requirements 
and relevant company policies.  
 
Before initiating this study, the investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC and local Regulatory Authority(ies) where 
required for the study protocol/amendment(s), written informed consent form, 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 IRB/IEC that they comply with GCP requirements. The IRB/IEC approval must identify 
the protocol version as well as the documents reviewed. 
 


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1.5 
Population to be Studied 
The study enrolled adult subjects with well differentiated, metastatic and/or unresectable, 
typical or atypical lung NETs. These subjects must not require SSAs treatment for symptom 
control. It was planned to enrol 216 subjects at approximately 30 centers across the United 
States, 6 in Canada and 40 in Europe (including, but not limited to Austria, Denmark, France, 
Germany, Italy, Poland, Spain, Sweden and the United Kingdom). At time of Protocol 
Amendment #5, a total of 38 centers have actively recruited at least one subject in 10 
countries. 
Due to the premature stop of the recruitment, 77 subjects are enrolled. 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
The purpose of this study is to describe the role of LAN plus BSC in the management of 
metastatic and/or unresectable, well differentiated, typical or atypical lung NETs.  There have 
been very limited data in this subject setting, except for sub-analyses of larger randomized 
studies; but there is a clear molecular rationale that establishes the potential role of SSAs like 
LAN plus BSC in advanced lung NETs [20]. 
2.2 
Study Objectives 
2.2.1 
Primary Objective 
• 
To describe the antitumour efficacy of LAN monotherapy plus BSC every 28 days, in 
terms of progression-free survival (PFS), measured by central review using Response 
Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria, every 12 weeks, in 
subjects with unresectable and/or metastatic well differentiated, typical or atypical lung 
neuroendocrine tumoursin either the double blind phase, or in the OL period. 
2.2.2 
Secondary Efficacy Objectives 
• 
To describe the antitumour efficacy during the double-blind phase of LAN 
monotherapy plus BSC every 28 days and placebo plus BSC, in terms of progression 
free survival (PFS), measured by central review using RECIST v1.1 criteria, every 
12 weeks, in subjects with unresectable and/or metastatic well differentiated, typical or 
atypical lung NETs. 
• 
To describe the antitumour efficacy during the double-blind phase of LAN 
monotherapy plus BSC every 28 days and placebo plus BSC, in terms of progression 
free survival (PFS), measured by local review using RECIST v1.1 criteria, every 
12 weeks, in subjects with unresectable and/or metastatic well differentiated, typical or 
atypical lung NETs. 
• 
To describe the objective response rate (ORR) of LAN monotherapy plus BSC every 
28 days and placebo plus BSC, as assessed by RECIST v 1.1criteria (proportion of 
subjects with an objective response of partial response (PR) or complete response 
(CR)) in the double blind phase, 
• 
To describe time to treatment failure (Kaplan Meier estimates) of LAN monotherapy 
plus BSC every 28 days and placebo plus BSC in the double blind phase, 
• 
To describe the changes from Baseline in the biomarker chromogranin A (CgA) during 
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• 
To describe the proportion of subjects with a decrease of CgA ≥30% at week 8 in the 
population of subjects with an elevated CgA (≥2 x ULN) at Baseline during the double-
blind and the OL treatment phases, 
• 
To describe the change in Quality of Life (QoL) from baseline, as assessed by the 
EORTC QLQ-C30 questionnaire during the double-blind, the OL treatment and the 
follow-up phases, 
• 
To describe the time to deterioration of QoL (using EORTC QLQ-C30) during the 
double-blind, the OL treatment and the follow-up phases, 
• 
To describe the changes in urinary 5-hydroxyindoleacetic acid (5-HIAA) in subjects 
with elevated urinary 5-HIAA (≥2 x ULN) at Baseline during the double-blind and the 
OL treatment phases. 
2.2.3 
Secondary Safety Objectives 
• 
To evaluate the clinical and biological safety profile. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a Phase 3, prospective, multi-center, randomized, double-blind, study describing the 
efficacy and safety of LAN plus BSC and placebo plus BSC for the treatment of well 
differentiated, metastatic and/or unresectable, typical or atypical lung NETs. 
 
As planned initially, a total of 216 eligible subjects with well-differentiated typical or 
atypical, metastatic and/or unresectable lung NETs, and a positive somatostatin receptor 
imaging (SRI) (Octreoscan® ≥ grade 2 Krenning scale; Ga-PET scan: uptake greater than liver 
background), had to be randomized 2:1 to either LAN plus BSC (120mg/28 days) or placebo 
plus BSC following the stratification of 1) typical versus atypical and 2) prior chemotherapy 
versus no prior chemotherapy*. Due to the premature stop of the recruitment (as per Protocol 
Amendment #5), 77 subjects are enrolled. All subjects still treated in the DB Phase will enter 
into the OL Treatment Period (either for follow up or for OL treatment). The transition to the 
OL treatment period, will be done by country and per subject, at the next planned scheduled 
visit (i.e. approximately 28 days from the last injection). Subjects enrolled into the study will 
stay on LAN therapy (i.e. OL Treatment Period) until evidence of disease progression 
(assessed locally and confirmed centrally), development of unacceptable toxicity, or 
premature withdrawal for any reason or up to 18 months after the last subject randomised.  
After disease progression subjects will be followed for survival, QoL and all subsequent 
anticancer treatments up to the end of the study.   
* cytotoxic chemotherapy or molecular targeted therapy or interferon. 
 
This study contains two phases: the Double-Blind (DB) Phase, and the Open Label (OL) 
Extension Phase.  The DB Phase included: Screening, Baseline and Treatment period. The OL 
Extension Phase consists of two periods: Treatment Period and Follow-Up Period.   
 
The DB Phase included a Screening Visit to establish protocol eligibility and disease 
characteristics. The Baseline Visit confirmed eligibility prior to randomization and treatment.  
The DB Phase of the study will end with Protocol Amendement #5 and will be followed by 
the OL Treatment Period.  
 
At the end of the OL Extension Treatment period, if subjects are still benefiting from 
treatment (i.e. not progressing) and there is sufficient evidence of safety and efficacy of it, the 
subjects will have the option, to continue to receive lanreotide 120 mg every 28 days up to 
disease progression or unacceptable toxicity. In such a situation, as permitted by local 
regulations, lanreotide 120 mg will be provided free of charge by the sponsor to the sites 
under its commercial packaging. During this period, the physician will report immediately to 
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Subjects underwent safety and efficacy assessment as defined in Table 2.  
 
The DB Phase will end with Protocol Amendment #5 and will be followed by the OL 
Treatment Period.  
Before approval of Protocol Amendment #5: 
If a subject progresses during the DB phase, the subject will be proposed to enter the OL 
Extension phase:  
• 
If the subject was on placebo and progressed during the DB phase, the subject will 
be offered the opportunity to enter the treatment period of the OL extension phase 
and to receive LAN every 28 days. 
• 
If the subject was on LAN and progressed during the DB phase, the subject will 
enter the follow-up period of the OL extension phase and be followed for 
QoL/survival and all subsequent anticancer treatments received will be recorded. 
The OL Treatment Period will stop once all subjects will have centrally progressed or 18 
months after the last subject randomised (i.e. end of study). 
 
After approval of Protocol Amendment #5: 
• 
All ongoing subjects in the DB Phase, who have not yet progressed, will enter the 
OL Treatment Period. The subjects in the OL Treatment Period will be followed up 
to disease progression (assessed locally and confirmed centrally), development of 
unacceptable toxicity, or withdrawal from the study treatment for any other reason 
or up to 18 months after the last subject randomised. 
• 
If a subject progresses during the DB phase, the subject will enter the OL follow-up 
period 
• 
If a subject progresses during the OL Treatment Period, the subject will enter the OL 
follow-up period.  
• 
The follow-up period will stop at the same time as the OL Treatment Phase (i.e. end 
of study  up to 18 months after the last subject randomised).  
 
3.1.2 
Open Label Extension Phase 
The OL Extension Phase will consist of: 
 the Treatment Period, where subjects will receive OL LAN plus BSC,  
 and the Follow-up Period. 
 
3.1.2.1 
Treatment Period (Optional Open Label Lanreotide Autogel/Depot) of the Open 
Label Extension Phase  
 
Before approval of Protocol Amendment #5, subjects will qualify for optional OL LAN plus 
BSC if they meet the following additional inclusion criteria: 
(14) Subjects have central review confirmed/documented disease progression according to 
RECIST 1.1  
(15) There is a request from the subject to receive OL LAN plus BSC  
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The following inclusion criteria 9-11 and exclusion criteria 6, 9-15, 17-22 listed in Section 4.1 
and Section 4.2 must continue to be satisfied. 
 
After approval of Protocol Amendment #5, all ongoing subjects in the DB Phase who have 
not yet progressed (assessed locally and confirmed centrally), will enter the OL Treatment 
Period. The subjects in the OL Treatment Period will be followed up to disease progression 
(assessed locally and confirmed centrally), development of unacceptable toxicity, or 
withdrawal from the study treatment for any other reason or up to 18 months after the last 
subject randomised. 
 
Please refer to Section 5.2.3 for more details. 
 
Subjects who qualify to receive OL LAN plus BSC will receive LAN plus BSC via deep s.c. 
injection every 4 weeks (28 days) until documentation of disease progression (local review 
confirmed by the central review via RECIST 1.1) within the Extension Phase, development of 
intolerable toxicity, appearance of carcinoid syndrome or other hormone related syndrome 
necessitating the initiation of any SSA (short acting and/or long acting release SSA), subject 
noncompliance with required safety and efficacy assessments, subject voluntary 
discontinuation, study termination by sponsor except those subjects who will continue in the 
study, or up to 18 months after the last subject randomised.   
 
Subjects who discontinue OL LAN plus BSC during the Treatment Period of the Extension 
Phase will perform the Post Treatment/Early Withdrawal visit assessments as detailed in 
Table 4 and will enter the Follow-up period (except in case of consent withdrawal) for 
assessment of QoL and survival and all subsequent anticancer treatments received will be 
recorded up to the end of the study. 
 
3.1.2.2 
Follow-up Period of the Open Label Extension Phase 
Subjects who experience disease progression during the DB Phase and do not enter or qualify 
for the optional OL Extension Treatment Period Phase will enter the Follow-up Period of the 
Extension Phase after completing the Post Treatment/Early Withdrawal Visit assessments 
listed in Table 2 and Table 5. 
 
Subjects who have entered the optional OL LAN plus BSC Treatment Period of the Extension 
Phase and have progressed or subsequently discontinued OL LAN plus BSC administration 
will enter the Follow-up Period after completing the Post Treatment/Early Withdrawal Visit 
assessments listed in Table 4. 
 
During the Follow-up Period of the OL Extension Phase, subjects will undergo follow-up visit 
every 12 weeks for QoL and survival. All anticancer treatments administered will be recorded 
until the time of death or up to 18 months after the last subject randomised.  
The OL Extension Phase will continue as long as the study subject is alive, or until 
discontinuation of survival follow-up by the Sponsor or up to 18 months after the last subject 
randomised.  


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3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Endpoint 
Progression-free survival (PFS) for subjects randomized in LAN group, assessed by central 
review using RECIST v1.1 criteria every 12 weeks, defined as the time from randomization to 
disease progression or death from any causes in either the double blind phase, or in the open 
label period. 
 
3.2.2 
Secondary Endpoints 
• 
Progression-free survival (PFS), assessed by central review using RECIST v1.1 criteria 
every 12 weeks, defined as the time from randomization to disease progression or death 
from any causes during the double-blind phase.  
• 
Progression-free survival (PFS), assessed by local review using RECIST v1.1 criteria 
every 12 weeks, defined as the time from randomization to disease progression or death 
from any causes during the double-blind phase.  
• 
ORR: objective response rate of CR or PR measured by RECIST v1.1 criteria every 12 
weeks until the Post Treatment/Early Withdrawal Visit during the double-blind phase, 
• 
Time to treatment failure during the double-blind phase, defined as the time from 
randomization to disease progression [defined as the minimum (time to event according 
to central review, time to event according to local review)] using RECIST v1.1, death,  
consent withdrawn, an AE, protocol deviations, lost to follow-up, the appearance of 
carcinoid syndrome or other hormone related syndrome necessitating the initiation of 
SSAs (rescue octreotide and/or LAR SSA), or initiation of anticancer treatment, 
• 
Mean changes from Baseline in biomarker CgA at Week 8, Week 12 and every 12 
weeks thereafter until the Post DB and in the OL Extension Treatment Phase, 
• 
Proportion of subjects with decrease in CgA ≥30% at Week 8, in the population of 
subjects with an elevated CgA (≥2 x ULN) at Baseline during the double-blind and the 
OL treatment phases, 
• 
Change in QoL, as assessed by the European Organisation for Research and Treatment 
of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) questionnaire 
from Baseline to Week 12, every 12 weeks and at the Post Treatment/Early Withdrawal 
Visit and in OL Extension Treatment and Follow-up Phases, 
• 
Time to QoL deterioration, defined by a decrease from baseline in EORTC QLQ-C30 
score of at least 10 points during the double-blind, the OL treatment and the follow-up 
phases,  
• 
Mean changes from Baseline in urinary 5-HIAA levels at Week 8, and every 12 weeks 
thereafter, and at the Post Treatment/Early Withdrawal Visit and in OL Extension 
Treatment in subjects with elevated urinary 5-HIAA (≥2 x ULN) at Baseline. 
3.2.3 
Safety Endpoints 
Safety and tolerability assessments throughout the study:  
• 
Adverse events (AEs) grouped by Medical Dictionary for Regulatory Activities 
(MedDRA) Preferred Term, and graded by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v4.03, 
• 
Clinical evaluations (medical and surgical history and physical evaluations, including 
biochemistry/hematology, ECG, 
), 
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• 
Gallbladder echography if biological and/or clinical inflammatory symptoms appear 
during the course of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.3 
Randomization and Blinding  
The Ipsen Randomization manager who is a statistician independent from the study prepared 
two lists, which were performed in blocks and were based on computer-generated 
randomizations lists: 
• 
List A: a list of randomization numbers stratified by 1) tumour subtype (typical versus 
atypical) and 2) prior chemotherapy* vs no prior chemotherapy* at baseline and 
generated with a 2:1 ratio LAN plus BSC: Placebo plus BSC. 
• 
List B: a list of treatment numbers, which are specified on the treatment packs to be 
dispatched to the sites in order to dispense drug. This list was generated with a 2:1 ratio 
LAN plus BSC: Placebo plus BSC. 
* cytotoxic chemotherapy or molecular targeted therapy or interferon  
 
The randomization, as well as the treatment numbers assignations at each drug dispensation, 
was managed by an Interactive Web response System (IWRS). 
 
After eligibility was confirmed, subjects were randomized at baseline (Day 1), and were 
assigned to a randomization number and to the associated treatment arm, in sequential order 
within each study center and within each stratum. 
 
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Subjects meeting the randomization criteria were assigned to a randomization number and 
were allocated to the associated treatment arm, by the IWRS. An appropriate treatment 
number was allocated and will continue to be allocated by the IWRS at each drug 
dispensation, according to the allocated treatment group. The IWRS managed and continue to 
manage logistical aspects of treatment (e.g. drug supplies replacement of lost, damaged, 
quarantined, expiring and expired kits). 
 
IWRS will continue to provide Investigators, site coordinators and project team members with 
a 24-hour per day, 7 day per week service, the details of which may be found in the IWRS 
reference manual).  In case of medical or technical randomization or dispensation queries, a 
24-hr helpline will continue to be available (see supporting information in the Investigator 
Site File). 
 
The investigator under no circumstances changed (or will change) the Randomization 
number, the treatment numbers and the treatment arm allocated to the subject. 
 
Recruitment was prematurely stopped and 77 subjects were randomized. Randomised subjects 
who terminated their study participation for any reason before starting the treatment retained 
their Randomization and treatment numbers (the treatment number was not [and will not be] 
reused). The next subject was given the next Randomization number and another treatment 
number even if they received the same treatment. Randomized subjects who left (or will 
leave) the study early were not (or will not be) replaced. 
 
The sponsor’s Randomization manager will continue to keep the master lists. A copy of the 
list of treatment numbers (list B) was confidentially supplied to the Chemistry Manufacturing 
and Control  Supply Chain (CMC-SC; 
 
 
 
) CE supply chain department in charge of study drug packaging, to the 
CRO in charge of IWRS. Similarly, a copy of the list of Randomization numbers (list A) was 
also confidentially supplied to the CRO in charge of IWRS. The master lists and the copies 
supplied to the CMCE supply chain department in charge of study drug packaging, to the 
CRO in charge of IWRS will continue to be kept confidential in a secure location. Access to 
the Randomization lists will continue to be restricted until authorisation is given to release 
them for final analysis. 
 
3.4 
Study Treatments and Dosage 
The test product, Lanreotide Autogel/Depot 120 mg and placebo will be administered via 
deep subcutaneous injection, every 28 days until signs of tumour progression (assessed locally 
and centrally confirmed), development of unacceptable toxicity or withdrawal for any reason. 
 
A more detailed description of administration procedures is given in Section 6.  
 
The study drug will be packaged by Creapharm [
 
] and delivered to the interim storage facility (ISF) in the 
United States and directly to each investigational site in European countries. The ISF will 
send treatment kits to each investigational site in US and Canada.  
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A sufficient quantity of study drug 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 study 
drug has been used under their study, Certificate of Compliance, Material Safety Data Sheet 
for study drug, which reflect the product release statement. 
 
The core label texts for all packaging units will 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 study drug labels is displayed below: 
• 
Name, address and telephone # of sponsor 
• 
Study Number, 
• 
Trial reference code, 
• 
Product Name, 
• 
Pharmaceutical dosage form, 
• 
Route of administration, 
• 
Quantity of dose units, 
• 
Batch number, 
• 
Treatment number, 
• 
Randomization number/Blank space for subject number (this information will be 
completed by the investigator), 
• 
“Caution: new drug limited by Federal Law to investigational use” for US only, 
• 
‘For Clinical study use only’, 
• 
Storage Conditions, 
• 
Expiry date. 
 
The investigator, or designee, will only dispense study treatment to subjects included in this 
study.  Each subject will only be given the study treatment carrying his/her number.  
Dispensing for each subject will be documented in the eCRF. 
 
Study treatment will be administered deep s.c. at the study center by an independent non-
blinded representative designated by the Investigator.  Drug accountability records will be 
maintained by the Investigator, documenting that subject received allocated drug. 
3.5 
Study Duration 
This study will consist of a screening period of a maximum of 28 days, followed by a DB 
period and an OL extension. Subjects are expected to participate in the DB phase of the study 
until disease progression (assessed locally and confirmed centrally), death from any causes, 
premature withdrawal whatever the reason or up to approval of Protocol Amendment #5.  
The subject’s participation in the study will be considered to have ended at the time of their 
last study visit or death.  
The overall duration of the study will be approximately 4 years (25 month duration of 
recruitment, approximately 36 month duration of DB treatment and an OL Extension Phase 


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which will end 18 months after the last subject randomised). 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 their last visit 
in the study, which will occur at the latest 18 months after the last subject randomised 
The DB Phase of the study will end once protocol amendment #5 has been approved in all the 
countries and all subjects entered the OL Extension periods. All ongoing subjects in the DB 
Phase, who have not yet progressed, will enter the OL Treatment Period. The subjects in the 
OL Treatment Period will be followed up to disease progression (assessed locally and 
confirmed centrally), development of unacceptable toxicity, or withdrawal from the study 
treatment for any other reason or up to 18 months after the last subject randomised. If a 
subject progresses during the OL Treatment Period, the subject will enter the OL follow-up 
period. The follow-up period of the OL extension phase and the OL Treatment Phase will last 
up to 18 months after the last subject randomised.  
 
3.6 
Stopping Rules and Discontinuation Criteria 
A subject may decide to discontinue participation in the study at any time for any reason 
(e.g. withdrawal of consent, AE). The investigator and/or sponsor can withdraw a subject 
from the study at any time for any reason (e.g. protocol violation or deviation as defined in 
Section 12.1.2, noncompliance with the protocol conditions or AE). In addition, a subject may 
be withdrawn from the study as described in Sections 4.3 and 8.1.7 
 
During the conduct of the study, study drug can be temporarily discontinued (see Section 
8.1.7). 
 
Any change in the administration of study drug or its discontinuation will be documented in 
the eCRF.  
During the conduct of the study, SAEs will be reviewed (see Section 8.1.4) as they are 
reported from the study centre to identify safety concerns. The study may be terminated by 
the sponsor at any time. 
 
3.7 
Early Study Termination 
The sponsor may terminate this study at any time. Reasons for termination may include but 
are not limited to, the following: 
• 
The incidence or severity of adverse events (AEs) in this or other studies point to a 
potential health hazard for trial subjects, 
• 
Insufficient subject enrolment, 
• 
Any information becoming available during the study that substantially changes the 
expected benefit risk profile of the study treatments. 
Due to the recruitment stop, all enrolled subjects will be followed up to disease progression or 
up to 18 months after the last subject randomised. 
At the end of the OL Extension Treatment period, if subjects are still benefiting from 
treatment (i.e. not progressing) and there is sufficient evidence of the safety and efficacy of it, 
the subjects will have the option, to continue to receive lanreotide 120 mg every 28 days up to 
disease progression or unacceptable toxicity. In such a situation, as permitted by local 


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regulations, lanreotide 120 mg will be provided free of charge by the sponsor to the sites 
under its commercial packaging. During this period, the physician will report immediately to 
Ipsen Pharmacovigilance Contact any safety concerns arising from the use of the product. 
3.8 
Study Drug Preparation Storage and Accountability 
3.8.1 
Study Drug Storage and Security 
In order to maintain the blinded conditions of the study the investigator must assign an 
independent non-blinded representative (e.g. pharmacist), who will ensure that all study drug 
and any other study related material is stored in a secured area, under recommended 
temperature monitored storage conditions (between +2°C and +8°C), in accordance with 
applicable regulatory requirements. 
3.8.2 
Study Drug Preparation and Accountability 
The non-blinded qualified person will ensure that all study drugs are dispensed by qualified 
staff members. 
All study drug and any other study related material is to be accounted for on the study drug 
accountability log provided by the sponsor or designated CRO. It is essential that all used and 
unused supplies are retained for verification (by the sponsor or sponsor’s representative). The 
investigator should ensure adequate records are maintained in the study drug accountability 
log. 
 
Drug accountability will be performed by an unblinded monitor from the Sponsor of its 
representative. The unblinded monitor will ensure that study drug administration, study drug 
dispensing/accountability logs and the number of used/non used treatments are consistent. 
 
Study drug will be destroyed preferably on site or returned to CMC-SC (
 
). 
 
The destruction of used and unused study drugs should be carried out only after any 
discrepancies have been investigated and satisfactorily explained and the reconciliation has 
been accepted.  
 
3.9 
Maintenance of Randomization and blinding 
All of the boxes of study treatments will be identical in appearance but the content of boxes 
will be different to each other. In addition, since LAN and placebo are not similar in 
appearance, an independent qualified person appointed by the investigator will be required to 
prepare and inject the study drug, allowing the blinded conditions of the study to be 
maintained. These unblinded individuals will be fully trained in the method of blinding for the 
subject, the investigator and the remainder of the project team and must not be involved in 
any of clinical or safety assessments. 
 
In an emergency situation, which requires the identification of the study treatment group, the 
Investigator may break the treatment code immediately, or as quickly as possible if he/she 
finds it is in the best interest of the trial subject. The investigators have direct and immediate 
access to break the treatment code through the IWRS. At the earliest opportunity the 
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investigator is requested to inform the blinded monitor in charge of his/her centre that the 
blind has been broken for an emergency. 
 
In addition, a set of hard copy sealed code break envelopes will be held by Global Patient 
Safety at Ipsen, in case of IWRS failure (this set will be prepared by Ipsen Randomization 
manager). 
If the code-break was performed using the IWRS, the investigator must store the email 
notification revealing the unblinded treatment in a sealed envelope. The investigator will then 
sign, date and provide the reason for the code break on the emergency code break form, and 
on the sealed envelope. The date and reason for identifying the treatment group will be 
recorded in the eCRF. 
 
The study treatment will be administered in double-blind fashion. Neither subjects nor staff 
site personnel in charge of the clinical and safety evaluations will know who is receiving 
placebo plus BSC or LAN plus BSC. If progression is confirmed by the central assessment, 
and the subject agrees to enter the OL Extension then the investigator will ask the IWRS 
whether the subject is eligible to enter the OL Treatment Extension Period. 
• 
Subject assigned to placebo plus BSC: will be allowed to enter the OL Extension 
Treatment Period to receive OL LAN plus BSC 
• 
Subject assigned to LAN plus BSC: will stop study treatment and attend the Post 
Treatment Visit and subsequently enter the Follow-Up Period of the Extension Phase 
At time of Protocol Amendment #5, all subjects who are still treated in the DB Phase and who 
have not yet progressed will be moved to the OL Treatment Period without any unblinding. 
 
3.10 
Source Data Recorded on the 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. 
 
As required by ICH GCP Section 6.4.9, if some items are recorded directly on the eCRF and 
are considered as source data, the identification of these data must be documented and agreed 
between the investigator and the sponsor. 
 
Definition for source data and source documents are given below: 
 
• 
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). 


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• 
Source Documents: Original documents, data and records (e.g. 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. This 
information is included in the informed consent. 
 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion criteria 
(1) 
Provision of written informed consent prior to any study related procedures, 
(2) 
Subjects aged ≥ 18 years, 
(3) 
Have metastasic and/or unresectable pathologically confirmed well-differentiated, 
typical or atypical neuroendocrine tumour of the lung,  
(4) 
Histologic evidence of well differentiated NETs of the lung (typical and atypical 
according to the WHO criteria evaluated locally), 
(5) 
Has a mitotic index < 2 mitoses/2 mm2 for typical carcinoid (TC) and ≤ 10 mitoses/2 
mm² and/or foci of necrosis for atypical carcinoid (AC),  
(6) 
At least one measurable lesion of the disease on imaging (CT or MRI; RECIST v1.1), 
(7) 
Positive somatostatin receptor imaging (SRI) (Octreoscan® ≥ grade 2 Krenning scale; 
Ga-PET scan: uptake greater than liver background), 
(8) 
ECOG performance status 0-1, 
(9) 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to randomization. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required, 
(10) Female subjects who are at risk of becoming pregnant must agree to use an effective 
method of contraception such as double barrier contraception, an injectable, combined 
oral contraceptive or an intra-uterine device (IUD). The subject must agree to use the 
contraception during the whole period of the study and for eight months after the last 
study drug administration. Non childbearing potential is defined as being 
postmenopausal for at least 1 year, or permanently sterilized at least 3 months before 
study entry,  
(11) Male subjects must agree that, if their partner is at risk of becoming pregnant, they will 
use an effective method of contraception (see above). The subject must agree to use the 
contraception during the whole period of the study and for eight months after the last 
study drug administration, 
(12) Signed HIPAA authorization where required, 
(13) Subjects must be willing and able to comply with study restrictions and to remain at the 
clinic for the required duration during the study period and willing to return to the study 
site for the follow-up evaluation as specified in the protocol. 
 
4.2 
Exclusion Criteria 
(1) 
Poorly differentiated or high grade carcinoma, or neuroendocrine tumours not of lung 
origin,  
(2) 
Subjects with multiple endocrine neoplasia type 1 (MEN 1), 
(3) 
Has been treated with an SSA at any time prior to randomization, except if that 
treatment was for less than 15 days (e.g. peri-operatively) of short acting SSA or one 
dose of long acting SSA and the treatment was received more than 6 weeks prior to 
randomization, 
(4) 
Has been treated with Peptide receptor radionuclide therapy (PRRT) at any time prior 
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(5) 
Has been treated for lung NET with chemotherapy* within 4 weeks of randomization 
(whatever the number of cycles), 
(6) 
Has been treated with more than two lines of chemotherapy * for lung NET, 
(* cytotoxic chemotherapy or molecular targeted therapy or interferon) 
(7) 
Treated with surgery within 6 weeks prior to randomization, 
(8) 
Previous local therapy (e.g. chemo-embolization, bland, or radio-embolization) is 
allowed if completed > 6 weeks prior to randomization.  For subjects who received 
local therapy prior to randomization, there must be documented growth of measurable 
disease within the embolization field prior to study,  
(9) 
Symptomatic subjects requiring SSA for symptom management (please also note the 
exclusion criteria No. 3), 
(10) Subjects with known ectopic production of adrenocorticotropic hormone (ACTH) or 
other hormonal secreting subjects allowed  ONLY if symptoms adequately controlled 
without SSAs, 
(11) Subjects on concomitant Growth Hormone (GH) antagonist, cyclosporine or 
bromocriptine 
(12) Inadequate bone marrow function as per investigator’s judgement, 
(13) Severe renal insufficiency as defined by a calculated creatinine clearance <30 mL/min,  
(14) Total bilirubin >2 x ULN, AST, ALT or Alk Ph >5xULN, lipase, amylase >2xULN,  
(15) Serum albumin <3.0 g/dL unless prothrombin time is within the normal range, 
(16) Known hypersensitivity to the study drug, 
(17) Present cholecystitis, 
(18) Uncontrolled congestive heart failure 
(19) Glycosylated hemoglobin (HbA1c) > 8.5%, 
(20) Abnormal findings, any other medical condition(s) or laboratory findings that, in the 
opinion of the investigator, would compromise the subject’s safety or the outcome of 
the study, 
(21) Other known co-existing malignancies except non-melanoma skin cancer and 
carcinoma in situ of the uterine cervix, unless definitively treated and proven no 
evidence of recurrence for 5 years, 
(22) Pregnant or lactating women or those of childbearing potential age and not practicing a 
medically acceptable method for birth control, 
(23) Subjects who have participated in any therapeutic clinical study/received any 
investigational agent within 30 days of randomization. 
(24) Clinically significant cardiac arrhythmia, bradycardia, tachycardia that would 
compromise patient safety or the outcome of the study 
(25) Uncontrolled hypothyroidism 
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, or 
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All subjects will be asked to return to the sites for discontinuation or off-treatment 
assessments, if possible. If a subject fails to appear for a scheduled study visit, the investigator 
will make every attempt to contact the subject and determine the reason(s) for the missed visit 
as completely and accurately as possible. Subjects will only be judged as lost to follow-up if 
they cannot be reached following 3 documented attempts by the site to contact them (1 week 
apart). 
Subjects will also be withdrawn from the study treatment should any of the following occur: 
• 
Disease progression as per local review, but not confirmed by central review RECIST 
v1.1: the local investigator always has the option of taking a subject off study. 
• 
Occurrence of any AE or serious adverse event (SAE) that may jeopardise the subject’s 
health. 
• 
A need to administer any of the drugs prohibited by the study protocol to a subject, as 
described in Section 6.2.2. 
• 
Appearance of carcinoid syndrome or other hormone related syndrome necessitating 
the initiation of SSAs (rescue octreotide and/or long acting release (LAR) SSA). 
• 
Appearance of biological and/or clinical symptoms for Gallbladder inflammation 
confirmed by an echography 
• 
Pregnancy (see Section 8.1.5) 
• 
Deviations from protocol 
• 
Investigator’s discretion 
 
Subjects will also be withdrawn from the study should any of the following occur: 
• 
Withdrawal of consent 
• 
Investigator’s discretion 
• 
Subject is lost to follow-up 
• 
Study is completed or terminated 
 
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) and an explanation given of why the subject is withdrawing or being withdrawn 
from the study. 
 
During the conduct of the study, study drug can be temporarily discontinued (see Section 
8.1.7). 
 
Subjects will be considered for crossover to OL LAN after local documented progression has 
been confirmed centrally per RECIST 1.1.  Progression will be assessed in-stream by an 
independent review, prior to crossover. Crossover is optional for subjects and at the discretion 
of the investigator.  
The subject will enter the Follow-up Period of the Extension Phase (Section 3.1.2.2) after 
completing the Post Treatment Visit assessments as listed in Table 2 and be followed for 
survival and QoL unless the subject withdraws consent. If a subject withdraws consent, the 


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date will be documented in the source documents. Subjects who discontinue study treatment 
for reasons other than disease progression locally assessed and confirmed centrally will not be 
eligible to receive OL LAN but are eligible to enter the Follow-up Extension Period (Table 5).  
 
All subjects will be followed for QoL, survival and all subsequent cancer treatments 
administered will be recorded until death, except where a subject withdraws consent or the 
sponsor chooses to halt survival follow-up before the 18 month OL Extension Treatment and 
Follow-up Phases. 
 
The Post Treatment Visit in the Double Blind Phase or OL Treatment Period should be 
performed within 30 days after the subject has received the last study drug injection. 
 
Where the subject has withdrawn due to an AE the investigator should follow the procedures 
documented in Section 8.1.2 in order to assess the safety of the study drug. 
 
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 and the subject 
has not yet progressed on study treatment: 
 
(1) 
the subject will be monitored for the given abnormality according to local standard of 
practice until event has resolved, or 30 days after the final administration of the study 
drug administration  whichever occurs first. 
(2) 
the subject should also continue to be assessed according to Table 5 (OL Extension 
Follow-up Period). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5 
STUDY PROCEDURES 
5.1 
Study Schedule for the DB phase 
Table 2 presents the Schedule of Visits and Procedures for the DB Phase of this study. 


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Table 2 
Schedule of Visits and Procedures in the Double-blind Phase 
 
STUDY PHASE 
 
DB RANDOMIZATION AND TREATMENT PHASE 
 
 
Study Period 
Screening 
a 
Baseline 
a 
Wk  
4 
Wk  
8 
Wk  
12b 
Wk 
16 
Wk 
20 
Wk 
24 b 
Wk 
28 
Wk 
32 
Wk 
 36 b 
 
Wk 
40 
Wk 
44 
Wk  
48 b 
 
Every 
4/12 weeks 
* b 
Post treatment/Early 
Withdrawal Visit (n)  
 
V1 
V2 
 
V3 
V4 
 
 
V5 
 
 
V6 
 
 
V7 
V8 to Vx 
Vx+1 
 
Day 
Day-28 
To 
Day -1 
Day 1 
Day 
28 
(±3) 
Day 
56 
(±3) 
Day  
84 
(±3) 
Day 
112 
(±3) 
Day 
140 
(±3) 
Day 
168 
(±3) 
Day 
196 
(±3) 
Day 
224 
(±3) 
Day 
252 
(±3) 
Day 
280 
±3) 
Day 
308 
±3) 
Day 
336 
(±3) 
Day 
364-
Day 
504 
(±3) 
Per 
Visit Day 
Within 30 days from 
last 
injection/When 
applicable 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior surgery, radiotherapy, chemotherapy 
and medications related to lung NETs 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical /surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease history/disease diagnosis h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluationd 
X 
X a 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
ECOG statusd 
X 
X a 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
ECG,  NYHA classificationc 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Xc 
X 
Hematology & Biochemistrye 
X 
X a 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Pregnancy test f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biochemical markers (CgA & Urinary 
5-HIAA)g 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
CT/MRIi 
Xi 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
SRIj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gallbladder echography k 
TO BE DONE IN CASE OF CLINICAL SYMPTOMS 
QoL (EORTC QLQ-C30) l 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
LAN or placebo injection every 28 days   
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AEs/SAEsq 
THROUGHOUT THE STUDY 
Prior and concomitant medications 
THROUGHOUT THE STUDY 
Prior and concomitant non drug therapies 
THROUGHOUT THE STUDY 
Concomitant surgical procedures 
THROUGHOUT THE STUDY 
Concomitant 
medication/chemotherapy/targeted therapy 
related to lung NET 
THROUGHOUT THE STUDY 
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5-HIAA=5-hydroxyindoleacetic acid; AE=adverse event; CgA=chromogranin A; CT=computed tomography; 
 
 ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30; EW=early withdrawal; 
LAN=lanreotide; MRI=magnetic resonance imaging; NET=neuroendocrine tumour; NYHA=New York Heart Association; OL=Open label; PET=positron emission tomography; 
 QoL=Quality of Life; RECIST=Response Evaluation Criteria in Solid Tumours; SAE=serious adverse event; 
 SPECT=single photon emission 
computed tomography; SRI= somatostatin receptor imaging; TNM=tumour-node-metastasis;; V=Visit; Wk=week 
* Subjects will continue to receive LAN Injection or Placebo every 28 days up to centrally confirmed disease progression, development of unacceptable toxicity, withdrawal for any reason or up to 18 months after the 
last subject randomised 
(a) 
The Baseline assessment should be performed on Day 1, prior to treatment.  The Screening assessments can serve as Baseline if performed within 3 days (72 hours) before Day 1 (randomization).  
(b) 
Efforts should be made to conduct study visits on the day scheduled (± 3 days). Clinical laboratory assessments may be conducted anytime within 72 hours prior to the scheduled visit, unless otherwise specified 
in the Schedule of Visits and Procedures. 
(c) 
ECGs will be performed at Screening, Week 24, Week 48, every 24 weeks thereafter and at the Post Treatment/Early Withdrawal Visit. The NYHA classification will be performed as per investigator judgement. 
(d) 
Physical examination and vital signs (supine and standing blood pressure and heart rate), height (Screening only) and weight will be performed at Screening, Baseline, Week 8 and every 12 weeks thereafter until 
the Post Treatment /Early Withdrawal Visits  
(e) 
Blood samples for hematology and biochemistry (fasting for biochemistry); Refer to Section 8.2.1 and 8.2.2 for details 
(f) 
Urine or serum test; must be completed within 72 hours of randomization; if positive with urine, confirm with serum 
(g) 
CgA will be measured for all the subjects at Baseline, Week 8, Week 12 and every 12 weeks thereafter and at the Post Treatment/Early Withdrawal Visit, urinary 5-HIAA will be measured at Baseline, and if 
elevated at Baseline or clinically indicated, again at Week 8, Week 12 and every 12 weeks thereafter and at the Post Treatment/Early Withdrawal Visits. 
(h) 
Disease history/diagnosis includes: mitotic count and foci of necrosis, Ki67 value if available, TNM staging, location of primary tumour, number of metastatic organs, presence/absence of hormone related 
syndrome 
(i) 
CT/MRI of the thorax and abdomen should be performed within 28 days prior to Day 1.  During the DB Phase, tumour assessments (by RECIST 1.1) will be performed every 12 weeks. At the Post 
Treatment/Early Withdrawal Visit, scans will only be conducted if not performed within the previous 4 weeks. For subjects being followed with abdominal MRI, the requirement for gallbladder echography is 
eliminated. Should CT scans/MRIs, performed within 12 months of baseline, be available they should be sent for analysis by central review as part of an ancillary study.  
(j) 
SRI if not available within the previous 6 months (Octreoscan® ≥ grade 2 Krenning Scale; Ga-PET scan: uptake greater than liver background) 
(k) 
A gallbladder echography has to be performed if the subject presents biological and/or clinical symptoms of gallbladder inflammation.  This assessment is not required for subjects undergoing abdominal MRI. 
Gallbladder inflammatory changes are included in the study discontinuation criteria.  
(l) 
Subjects will complete the QoL (EORTC QLQ-C30) at Screening, Baseline, then every 12 weeks thereafter until the Post Treatment /Early Withdrawal Visit. As it is preferable to reduce all sources of potential 
bias it is recommended that the questionnaire is completed prior to seeing the physician [23]. 
 
 
 
(n) 
For subjects continuing into the OL Extension Treatment Period, the Post Treatment/Early withdrawal Visit can serve as the Baseline visit for the OL Extension Phase.  
 
 
(p) 
Predose sample and 2 hours post-dose sample. 
(q) 
If a subject presents thyroid function disturbances (identified through thyroid function abnormalities (TSH, FT4) considered clinically significant by the investigator) these should be reported as AEs in the e-
CRF.
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During the DB Phase and the OL Treatment phase, the volume of blood drawn for all 
haematology, serum chemistry, biomarkers 
evaluations is around 16 
mL. A further 16 mL will be taken at each subsequent study visit throughout the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The approximate total amount of blood to be collected from each subject is presented in 
Table 3. 
Table 3 
Blood Volume Calculation 
Description 
Approximate Volume 
(mL) per visit ( DB 
Phase + OL treatment 
Extension Phase) 
Haematology [a] 
3 (EDTA tube) + (3 (SC 
tube) at Screening) 
Serum chemistry [a] 
5 (SST) 
Biomarkers (CgA) [a] 
5 (SST) 
 
 
 
 
Serum 
5 (SST) 
 
 
 
 
 
Total volume (mL) 
43.5 [b] 
5-HIAA=5-hydroxyindoleacetic acid; CgA=chromogranin A; 
 
 EDTA=ethylenediamine 
tetraacetic acid; 
 SST=serum separator tube. 
a 
additional samples will be taken every 12 weeks (±3 days) for subjects continuing to attend study visits after the 72 week 
treatment period. 
b    please note that not all samples are taken at every visit, therefore the subject does not always have 43.5 mL taken each 
time (eg 
 coagulations parameters at Screening) 
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5.2 
Study Visits 
5.2.1 
Pre-Randomization 
5.2.1.1 
Screening Period Procedures 
Prior to performing any procedures or assessments, the nature of the study and the potential 
risks associated with the trial were explained to all subject candidates and written informed 
consent was obtained. 
 
 
 Evaluations obtained as part of routine medical care and performed during 
the screening period might be used in place of the study specific evaluations. Subjects 
acknowledged and agreed to the possible use of this information for the study by giving 
informed consent.  
 
After informed consent was obtained, subjects who were screened were allocated a subject 
number. All screened subjects had to be identifiable throughout the study. The investigator 
maintained a list of subject numbers and names to enable records to be found at a later date if 
required. 
 
The screening visit took place between Day 28 and Day -1 of the study; if the screening 
assessments took place within 3 days (72 hours) of Day 1, the results could be accepted as 
Baseline values. The following screening assessments were performed: (Please see footnotes 
under Table 2 for details). 
 
• 
Written informed consent (must be obtained before any screening assessments are 
performed) 
• 
Verify inclusion/exclusion criteria as listed in Sections 4.1 and 4.2: 
• 
Demographics data (year of birth, age, ethnicity and race (as per local regulations) and 
sex)  
• 
Prior surgery, radiotherapy, chemotherapy and medications related to lung NETs 
• 
Medical and surgical history, including ongoing medical history 
• 
Disease history/diagnosis (mitotic count and foci of necrosis, KI67 value if available, 
tumour-node-metastasis (TNM) staging, location of primary tumour, number of 
metastatic organs, presence/absence of hormone related syndrome) 
• 
Clinical evaluation (including physical examination and vital signs) 
• 
ECOG status 
 
• 
NYHA classification 
 and ECG 
• 
Hematology & Biochemistry 
• 
Pregnancy test  
- 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
- 
Female subject who are at risk of becoming pregnant must agree to use an 
effective method of contraception such as double barrier contraception, an 
injectable, combined oral contraceptive or an intra-uterine device (IUD). The 
subject must agree to use the contraception during the whole period of the study 
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and for eight months after the last study drug administration. Non childbearing 
potential is defined as being postmenopausal for at least 1 year, or permanently 
sterilized at least 3 months before study entry,  
• 
CT scans/MRIs performed within 12 months of baseline collected if available (sent for 
analysis by central review as part of an ancillary study) - Refer to Section 5.2.1.2 for 
more details. 
• 
SRI, if not available within the previous 6 months (Octreoscan® ≥ grade 2 Krenning 
scale; Ga-PET scan: uptake greater than liver background),  
• 
Gallbladder echography if biological and/or clinical symptoms of inflammation are 
present. If the gallbladder inflammation is confirmed, the subject failed the screening 
evaluation and should be excluded  
• 
Start collection of AE’s/SAE’s 
• 
Prior and concomitant medications/therapies (see Section 6.2)  
• 
Prior and concomitant non drug therapies  
• 
Concomitant surgical procedures  
• 
Concomitant medication/chemotherapy/molecular targeted therapy related to lung NET 
 
Each investigator also maintained a record of all subjects screened into the study (i.e. who 
signed the informed consent form). Records up to the time of premature termination should 
have been completed. In the event that the subject was not receiving the study drug, the 
primary reason was recorded. 
 
5.2.1.2 
Baseline assessments and procedures on Day 1 
The results of all screening assessments and evaluations had to be completed and reviewed by 
the investigator prior to the Baseline Visit. Baseline assessments should have been performed 
on Day1 prior to study treatment injection; however, screening assessment values could be 
used as Baseline values if done within 72 hours of Day1.  
 
Only those subjects who continued to meet all of the inclusion and none of the exclusion 
criteria on Day1 were eligible to continue in the study. 
 
At the Baseline Visit, the following evaluations were conducted, prior to the administration of 
study treatments: 
 
• 
Verify inclusion/exclusion criteria 
• 
QoL (EORTC QLQ-C30) 
 
• 
Clinical evaluation  
• 
ECOG status 
 
• 
Hematology & Biochemistry  
• 
Pregnancy test  
- 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study 
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medication. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
- 
Female subjects who are at risk of becoming pregnant must agree to use an 
effective method of contraception such as double barrier contraception, an 
injectable, combined oral contraceptive or an intra-uterine device (IUD). The 
subject must agree to use the contraception during the whole period of the study 
and for eight months after the last study drug administration. Non childbearing 
potential is defined as being postmenopausal for at least 1 year, or permanently 
sterilized at least 3 months before study entry,  
• 
CgA and urinary 5-HIAA for all subjects  
• 
CT scan or MRI:  
- 
Perform CT scan of thorax and abdomen, OR MRI of the abdomen with CT scan 
of the thorax 
- 
If available, collect CT scans/MRIs performed within 12 months of Baseline (for 
analysis as part of an ancillary study) 
• 
Baseline value of hepatic and intrathoracic tumour load will be measured by the Central 
Reading CRO 
• 
Gallbladder echography, if biological and/or clinical symptoms of inflammation are 
present 
• 
 
• 
 
 
• 
 
• 
AE’s/SAE’s 
• 
Concomitant medications 
• 
Concomitant non drug therapies  
• 
Concomitant surgical procedures  
• 
Concomitant medication/chemotherapy/molecular targeted therapy related to lung NET 
• 
Randomization 
 
Following 
confirmation 
of 
eligibility 
for 
the 
study, 
subjects 
were 
given 
a 
Randomization/treatment allocation number and allocated to either LAN plus BSC or placebo 
plus BSC (See Section 6.1). Administration of DB study treatment commenced at Baseline 
Visit following completion of the Baseline assessments. DB study treatment was administered 
every 28 days until centrally confirmed disease progression, development of unacceptable 
toxicity, premature withdrawal for any reason or up to approval of Protocol Amendment #5.  
5.2.2 
Double Blind Phase Assessments and Procedures 
Efforts should have been made to conduct study visits at Week 8, Week 12 and then every 12 
weeks, on the day scheduled (± 3 days). Clinical laboratory assessments might be conducted 
anytime within 72 hours prior to the scheduled visit, unless otherwise specified in the 
Schedule of Visits and Procedures. Whenever possible, subjects should have been evaluated 
at approximately the same time of the day (e.g., morning or afternoon) at each visit, and 
reasonable efforts should have been made to conduct all evaluations in the same test order at 
each visit and before the study drug injection. 
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Following the first dose at Baseline Visit, LAN/placebo will be administered every 28 days 
until centrally confirmed disease progression, development of unacceptable toxicity 
withdrawal for any reason or up to 18 months after the last subject randomised. The initial 
planned treatment period is estimated to last 72 weeks; however, after this time, if disease 
progression as assessed centrally or death from any causes have not occurred, subjects may 
continue to receive study drug in a double-blind fashion every 28 days until disease 
progression, development of unacceptable toxicity, withdrawal for any reason, or up to 18 
months after the last subject randomised. 
'Injection only' visits will not be considered as study visits; however, the date and time of 
injection will be recorded in the eCRF. Any AEs reported at these visits will also be recorded 
on the eCRF, reported to the sponsor (if an SAE), and followed up as appropriate by the 
responsible investigational site staff. 
 
The following procedures will be performed every 12 weeks (or earlier if clinically indicated) 
and at the Post Treatment/Early Withdrawal Visit: 
 
• 
QoL (EORTC QLQ-C30) 
 
• 
ECOG status 
 
• 
Hematology & Biochemistry  
• 
Tumour response assessment by CT scan or MRI 
• 
AE’s/SAE’s 
• 
Concomitant medications/therapies 
• 
Concomitant non drug therapies 
• 
Concomitant surgical procedures 
• 
Concomitant medication/chemotherapy/molecular targeted therapy related to lung NET  
 
The following procedures will be performed according to the schedule in Table 2: 
• 
Clinical evaluation at Week 8, Week 12 and every 12 weeks thereafter 
• 
CgA will be measured for all subjects at Week 8, Week 12 and every 12 weeks 
thereafter.  
• 
Urinary 5-HIAA will be measured at Week 8, Week 12 and every 12 weeks thereafter 
only for subjects with elevated urinary 5-HIAA (≥2 x ULN) at the Baseline Visit. 
• 
 
 
• 
  
• 
 
 
• 
ECG and NYHA classification (at Week 24, Week 48 and then every 24 weeks) 
• 
Gallbladder echography will be performed during the DB Study treatment period and at 
the Post Treatment/Early Withdrawal Visit, only if biological and/or clinical 
inflammatory symptoms appear.  
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5.2.2.1 
Post Treatment Visit Assessments and Procedures 
The following assessments should be performed at the Post Treatment/Early Withdrawal 
Visit, within 30 days after subjects have discontinued study treatment for any reason 
(including premature withdrawal please refer to Section 4.3): 
 
• 
QoL (EORTC QLQ-C30) 
• 
Clinical evaluation  
• 
ECOG status,  
• 
NYHA classification and ECG 
• 
Hematology & Biochemistry  
• 
Pregnancy test (urine; if positive with urine, confirm with serum) 
• 
CgA  
• 
Urinary 5-HIAA (only for subjects with elevated urinary 5-HIAA (≥2 x ULN) at 
Baseline Visit) 
• 
CT scan of the thorax and abdomen, OR MRI of the abdomen with a CT scan of the 
thorax  
• 
Gallbladder echography if biological and/or clinical symptoms of inflammation are 
present  
• 
  
• 
 
• 
 
• 
AE’s/SAE’s 
• 
Concomitant medications 
• 
Concomitant non drug therapies 
• 
Concomitant surgical procedures 
• 
Concomitant medication/chemotherapy/molecular targeted therapy related to lung NET 
 
5.2.2.2 
Post Treatment Visit Procedures for Subjects Not Receiving or Do Not Qualify for 
Open Label Lanreotide Autogel/Depot 
For subjects who have discontinued study drug prior to disease progression, tumour 
assessment should be performed at the Post Treatment/Early Withdrawal Visit if not 
performed within the 4 previous weeks (Table 2) or sooner if clinically indicated until 
documentation of disease progression or start of another anticancer therapy. 
 
The Post Treatment/Early Withdrawal Visit should be then performed within 30 days after the 
last study treatment injection, at which time subjects will enter the Follow-up Period of the 
OL Extension Phase. 
Subjects who withdraw their consent will be asked to perform the Post Treatment/Early 
withdrawal Visit but will not enter the Extension Phase of the study, whatever the treatment 
or the Follow-up Periods.  
 
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The Post Treatment/Early Withdrawal Visit assessments in the DB Phase can be accepted as 
Baseline for the OL Extension Phase.  
Before approval of Protocol Amendment #5, subjects who do not choose to receive or qualify 
for OL LAN plus BSC (those who were on LAN plus BSC during the DB phase) will enter the 
OL Extension Follow-up Period. 
 
5.2.2.3 
Post Treatment Visit Procedures for Subjects Receiving Open Label Lanreotide 
Autogel/Depot plus BSC (Extension Phase OL Lanreotide Autogel/Depot plus BSC 
Treatment Period) 
Before approval of Protocol Amendment #5, subjects with locally documented and centrally 
confirmed disease progression and who were randomized in the placebo arm could choose to 
receive OL LAN. They will enter the OL Treatment Extension Period. 
 
The OL Extension Phase is optional and subjects who qualify for OL LAN and choose to 
progress into this phase of the study will be assessed according to the procedures listed in 
Table 4.  
For subjects treated with placebo plus BSC with confirmed and documented disease 
progression and who choose to receive and qualify for OL LAN,  
• 
Establish new baseline tumour assessments (selection of target and non-target lesions) 
based upon scans taken that showed evidence of disease progression, or on new scans 
performed before beginning OL LAN. 
• 
Assessments should be performed every 12 weeks according to Table 4. 
 
All subjects who enter the OL Extension Phase must first complete the Post Treatment/Early 
Withdrawal Visit of the DB Phase within 30 days of the last study drug injection. The 
assessments from this visit can be accepted as Baseline for the OL Extension Phase if both 
visits are performed the same day. 
After approval of Protocol Amendment #5, all ongoing subjects in DB Phase, who have not 
yet progressed, will enter the OL Treatment Period. 
5.2.3 
Open Label Extension Phase Assessments and Procedures 
Table 4 presents the Schedule of Visits and Procedures for the Optional OL Extension Phase 
of the study. 
 


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Table 4 
Schedule of Visits and Procedures in Open Label Treatment Extension Period 
Period 
OL Extension 
Baseline a, b 
Day 1 
Every 4 Weeks 
Every 12 Weeks 
 
Post-Treatment/ 
Early 
Withdrawal 
Visitn 
Inclusion/Exclusion 
X 
 
 
 
Clinical Evaluatione 
X 
 
X 
X 
ECOG statusc 
X 
 
X 
X 
NYHA classification, ECGd 
X 
 
Xd 
X 
Hematology & Biochemistryf 
X 
 
X 
X 
Pregnancy Testg 
X 
 
 
X 
CgA and urinary 5-HIAAh 
X 
 
X 
X 
CT/MRIi 
X 
 
X 
X 
Gallbladder Echography j 
IF SYMPTOMS 
QoL (EORTC QLQ-C30) 
X 
 
X 
X 
LAN Injection Every 28 days  
X 
X 
X 
 
 
 
 
AEs/SAEsm 
THROUGHOUT THE STUDY 
Concomitant Medications 
THROUGHOUT THE STUDY 
Concomitant non drug therapies 
THROUGHOUT THE STUDY 
Concomitant surgical procedures 
THROUGHOUT THE STUDY 
Concomitant 
medication/chemotherapy/molecular 
targeted therapy related to lung 
NET 
THROUGHOUT THE STUDY 
5-HIAA=5-hydroxyindoleacetic acid; AE=adverse event; CgA=chromogranin A; CT=computed tomography; 
 ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC 
QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30; 
EW=early withdrawal; LAN=lanreotide; MRI=magnetic resonance imaging; NET=neuroendocrine tumour; 
NYHA=New York Heart Association; OL=Open label; PET=positron emission tomography; 
 
QoL=Quality of Life; RECIST=Response Evaluation Criteria in Solid Tumours; SAE=serious adverse event; 
 
  
(a) 
OL Extension Baseline assessments should be performed on Day 1 of the Extension Treatment Period, prior to 
treatment.  Assessments from the Post Treatment Visit in the DB Phase can serve as Baseline values for the OL 
Extension. 
(b) 
Efforts should be made to conduct study visits on the day scheduled (± 3 days). Clinical laboratory assessments may 
be conducted anytime within 72 hours prior to the scheduled visit, unless otherwise specified in the Schedule of 
Visits and Procedures. 
(c) 
ECOG status will be assessed at OL Extension Baseline, and every 12 weeks thereafter and at the Post Treatment / 
Early Withdrawal Visit.  
(d) 
ECGs will be performed at Baseline, Week 24, Week 48, every 24 weeks thereafter and at the Post Treatment/Early 
Withdrawal Visit. The NYHA classification will be performed as per investigator judgement. 
(e) 
A physical examination and vital signs (supine and standing blood pressure and heart rate), and weight will be 
performed at OL Extension Baseline and every 12 weeks thereafter and at the Post-Treatment Extension / Early 
Withdrawal Visit. 
(f) 
Blood samples for hematology and biochemistry (fasting for biochemistry); Refer to Sections 8.2.1 and 8.2.2 for 
details 
(g) 
Urine or serum test: if positive with urine, confirm with serum 
(h) 
CgA will be assessed at Baseline and will be repeated subsequently every 12 weeks. Urinary 5-HIAA will be 
repeated subsequently every 12 weeks only if elevated (≥2xULN) at Baseline of the DB Phase or if clinically 
indicated. 
(i) 
CT/MRI of the thorax and abdomen will be performed at Baseline (if not performed within the previous 4 weeks;  
CT/MRI used for disease progression documentation may be used if performed within the previous 4 weeks), every 12 
weeks. At the Post Treatment/Early Withdrawal Visit, scans will only be conducted if not performed within the previous 
4 weeks. 
(j) 
A gallbladder echography has to be performed if the subject presents biological and/or clinical symptoms of 
gallbladder inflammation.  Gallbladder inflammatory changes are included in the study discontinuation criteria as 
part of AEs leading to study discontinuation.  
 
 
 
 
 
 
 
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(m) 
If a subject presents thyroid function disturbances (identified through thyroid function abnormalities (TSH, FT4) 
considered clinically significant by the investigator) these should be reported as AEs in the e-CRF. 
(n) 
End of Post Treatment Visit assessments of the OL Extension Period have to be performed prior to any 
administration of commercial product (if applicable) 
 
5.2.3.1 
Open Label Extension Treatment Phase Baseline Procedures 
Open label Extension Baseline assessments can be performed either on Day 1 of the OL 
Extension Treatment Phase prior to treatment, or value from the Post Treatment/Early 
Withdrawal Visit in the DB Phase can serve as the OL Extension Baseline values for the OL 
Extension Treatment Phase.   
 
Before approval of Protocol Amendment #5, subjects were qualified for optional OL LAN 
plus BSC if they met the following additional inclusion criteria: 
(14) Subjects have documented disease progression confirmed centrally according to 
RECIST v1.1  
(15) There is a request from the subject to receive OL LAN plus BSC  
(16) Subjects were randomized in the Placebo plus BSC arm  
The following inclusion criteria 9-11 and exclusion criteria 6, 9-15, 17-22 listed in Section 4.1 
and Section 4.2 must continue to be satisfied. 
 
After approval of Protocol Amendment #5, subjects will be offered the option to move to the 
OL Treatment Period. The subjects will receive an addendum to Informed Consent Form 
(ICF) which details in study rationale and explanations about the conduct of the study end. If 
the subjects agree to continue to participate to this study this addendum to ICF will have to be 
signed. 
 
At the OL Extension Baseline Visit, the following evaluations will be conducted: 
 
• 
Reconfirm inclusion/exclusion criteria 9-11 and 6, 9-15, 17-22 eligibility criteria 
• 
QoL (EORTC QLQ-C30) 
• 
Clinical Evaluation (Physical Examination and vital signs) 
• 
ECOG status 
• 
NYHA classification and ECG 
• 
Hematology & biochemistry  
• 
Pregnancy test  
- 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
- 
Female subject who are at risk of becoming pregnant must agree to use an 
effective method of contraception such as double barrier contraception, an 
injectable, combined oral contraceptive or an intra-uterine device (IUD). The 
subject must agree to use the contraception during the whole period of the study 
and for eight months after the last study drug administration. Non childbearing 
potential is defined as being postmenopausal for at least 1 year, or permanently 
sterilized at least 3 months before study entry,  


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• 
CgA will be measured for all the subjects at the OL Extension Baseline.  
• 
Urinary 5-HIAA will be measured only for subjects with elevated urinary 5-HIAA 
(≥2 x ULN) at Baseline of the DB Phase.  
• 
CT/MRI (using the same mode as per baseline, utilizing RECIST 1.1); to be read 
locally by the same person to avoid bias); establish new baseline tumour assessments 
(selection of target and non-target lesions) based upon scans taken that showed 
evidence of disease progression according to central review, or on new scans performed 
before beginning OL LAN 
• 
Gallbladder echography if biological and/or clinical symptoms of inflammation are 
present 
• 
 
• 
AE’s/SAE’s 
• 
Concomitant medications 
• 
Concomitant non drug therapies 
• 
Concomitant surgical procedures 
• 
Concomitant medication/chemotherapy/molecular targeted therapy related to lung NET 
• 
 
 
5.2.3.2 
Open Label Extension Treatment Phase Assessments and Procedures 
 
The OL Extension Treatment Phase Visit assessments should be performed according to 
Table 4: 
 
• 
QoL (EORTC QLQ-C30) 
• 
Clinical Evaluation  
• 
ECOG status,  
• 
NYHA classification and ECG (every 6 months) 
• 
Hematology and biochemistry  
• 
CgA will be measured for all the subjects at OL Extension Baseline, and every 12 
weeks thereafter and at the Post Treatment/Early Withdrawal Visit.  
• 
Urinary 5-HIAA will be measured at the OL Extension Baseline and every 12 weeks 
thereafter and at the Post Treatment/Early Withdrawal Visit only for subjects with 
elevated urinary 5-HIAA (≥2 x ULN) at the OL Extension Baseline Visit, or if 
clinically indicated. 
• 
CT/MRI: CT scan of thorax and abdomen, OR MRI of the abdomen with CT scan of 
the thorax  
• 
Gallbladder echography if biological and/or clinical symptoms of inflammation are 
present 
• 
 
• 
 
 
• 
AE’s/SAE’s reporting for the treatment part of this period only 
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• 
Concomitant medications 
• 
Concomitant non drug therapies 
• 
Concomitant surgical procedures 
• 
Concomitant medication/chemotherapy/molecular targeted therapy related to lung NET 
 
5.2.3.3 
Post Treatment/Early Withdrawal Visit Procedures of OL Extension Treatment 
Phase 
All subjects will be asked to return to the sites for discontinuation or off-treatment 
assessments, if possible. If a subject fails to appear for a scheduled study visit, the investigator 
will make every attempt to contact the subject and determine the reason(s) for the missed visit 
as completely and accurately as possible. Subjects will only be judged as lost to follow-up if 
they cannot be reached following three documented attempts by the site to contact them (1 
week apart). 
 
The Post Treatment/Early Withdrawal Visit assessments in the OL Extension Treatment 
Phase should be performed within 30 days after subjects have discontinued study treatment 
for any reason: 
 
• 
QoL (EORTC QLQ-C30) 
• 
Clinical Evaluation 
• 
ECOG status  
• 
NYHA classification and ECG 
• 
Hematology and biochemistry  
• 
Pregnancy test 
- 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
- 
Female subject who are at risk of becoming pregnant must agree to use an 
effective method of contraception such as double barrier contraception, an 
injectable, combined oral contraceptive or an intra-uterine device (IUD). The 
subject must agree to use the contraception for eight months after the last study 
drug administration. Non childbearing potential is defined as being 
postmenopausal for at least 1 year, or permanently sterilized at least 3 months 
before study entry  
• 
CgA 
• 
Urinary 5-HIAA (only for subjects with elevated urinary 5-HIAA (≥2 x ULN) at the 
OL Extension Baseline Visit) 
• 
CT/MRI: CT scan of the thorax and abdomen, OR MRI of the abdomen with a CT scan 
of the thorax  
• 
Gallbladder echography if biological and/or clinical symptoms of inflammation are 
present 
• 
 
• 
 
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• 
AE’s/SAE’s 
• 
Concomitant medications 
• 
Concomitant non drug therapies 
• 
Concomitant surgical procedures 
• 
Concomitant medication/chemotherapy/molecular targeted therapy related to lung NET 
 
At the end of the OL Extension Treatment period, if subjects are still benefiting from 
treatment (i.e. not progressing) and there is sufficient evidence of the safety and efficacy of it, 
the subjects will have the option, to continue to receive lanreotide 120 mg every 28 days up to 
disease progression or unacceptable toxicity. In such a situation, if authorized by local 
regulations, lanreotide 120 mg will be provided free of charge by the sponsor to the sites 
under its commercial packaging. During this period, the physician will report immediately to 
Ipsen Pharmacovigilance Contact any safety concerns arising from the use of the product. 
 
5.2.3.4 
Open Label Extension Follow-Up Phase Baseline Procedures  
After study drug discontinuation, subjects will be followed for survival, QoL and all 
subsequent anticancer treatments during the OL Extension Follow-up Phase (Table 5). 
Survival data and other cancer treatments received will be collected every 12 weeks. The 
sponsor may elect to discontinue survival follow-up during the Extension Phase before the 18-
month period. 
Table 5 
Schedule of Visits and Procedures in the Open Label Extension Follow-up Phase 
Period 
OL 
Extension 
Follow-up 
Baseline a 
Day 1 
Every 12 Weeks 
 
Post-Extension 
Follow-up 
Visit 
/Early Withdrawal 
Within 30 days from 
last 
injection/When 
applicable 
Clinical Evaluationb 
X 
X 
X 
Survival status form 
THROUGHOUT THE STUDY 
Concomitant 
medication/chemotherapy/molecular 
targeted therapy related to lung 
NET 
THROUGHOUT THE STUDY 
QoL (EORTC QLQ-C30)c 
X 
X 
X 
 
 
 
 
EORTC QLQ C30=European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
Core 30; OL=Open label; QoL=Quality of Life  
(a) 
OL Extension Follow-up Baseline assessments should be performed on Day 1 of the Extension Follow-up Phase, 
prior to any other treatment.  The values from the Post Treatment/Early Withdrawal Visit assessments in the DB 
Phase or OL Extension Treatment Period can serve as the Baseline for OL Extension Follow-up Period. 
(b) 
A physical examination and vital signs will be performed at OL Extension Follow-up Baseline and every 12 weeks 
thereafter and at the Post-Extension Follow-up Period/ Early Withdrawal Visit. 
(c) 
Subjects will complete the EORTC QLQ-C30 at Baseline and every 12 weeks thereafter and at the Post-Extension 
Follow-up/Early Withdrawal Visit. As it is preferable to reduce all sources of potential bias it is recommended that 
the questionnaire is completed prior to seeing the physician [23]. 
 
At the OL Extension Follow-up Baseline Visit, the following evaluations will be conducted: 
• 
QoL (EORTC QLQ-C30) 
• 
Clinical evaluation 
• 
Survival status form 


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• 
Concomitant medication/chemotherapy/molecular targeted therapy related to lung NET 
 
5.2.3.5 
Open Label Extension Follow-Up Phase and Post-Extension Follow-up Phase Visit 
Procedures  
At the OL Extension Follow-up Visits and at the Post-Extension Follow-up Phase/Early 
Withdrawal Visit, the following evaluations will be conducted: 
• 
QoL (EORTC QLQ-C30) 
• 
Clinical evaluation 
• 
Survival status form 
• 
Concomitant medication/chemotherapy/molecular targeted therapy related to lung NET 
 


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6 
TREATMENT OF SUBJECTS 
6.1 
Study drugs Administered 
At Screening, subjects were allocated a subject number. Following confirmation of eligibility 
for the study, subjects were allocated to one of the following treatment groups: 
 
• 
LAN, deep subcutaneous, every 28 days plus BSC 
or 
 
• 
Placebo, deep subcutaneous, every 28 days plus BSC 
 
Subjects will receive injections of the study drug to which they are allocated by deep 
subcutaneous injection (in the superior external quadrant of the buttock) every 28 days 
thereafter. The first injection was administered during the baseline visit after randomization.  
Subjects will receive study drug according to this schedule until locally documented and 
centrally confirmed disease progression, development of unacceptable toxicity, withdrawal 
for any reason or up to 18 months after the last subject randomised.  
Because LAN and the placebo were not similar in colour and appearance, an independent 
qualified and unblinded person appointed by the investigator prepared and administered the 
injections, in order to maintain the blinded conditions of the study. All study drugs were 
administered at the study centres by these qualified persons. 'Injection only' visits were not 
considered as study visits; however, the date and time of injection were recorded in the eCRF. 
 
There will be no dose modification as LAN administered at 120mg is well-tolerated, effective 
and has a safe AE profile.  Based on our experience in subjects with Acromegaly, and in 
subjects with NETs in the CLARINET study, we do not anticipate toxicities that would 
require either discontinuation or dose modification (for more details, see Sections 6.2 and 
8.1.7). 
 
It is forbidden to use study drug for purposes other than as defined in this protocol. 
 
6.1.1 
Lanreotide Autogel/Depot  
Lanreotide Autogel/Depot 120 mg will be administered by deep s.c. injection in the superior, 
external quadrant of the buttock at a dose of 120 mg, every 28 days. 
Lanreotide Autogel/Depot 120 mg 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. 
 
It will be provided by the Sponsor (CMC SC (CMC Supply Chain), 
 
).  
 
Lanreotide Autogel/Depot 120 mg will be stored at the recommended temperature (between 
+2°C and +8°C). 
 
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The procedures for drug administration are provided in the drug instructions leaflet and in the 
Study Manual. 
 
6.1.2 
Placebo 
The placebo injection consisted of saline solution 0.9% and was provided as a vial with an 
empty syringe fitted with a 20 mm needle of 19 gauge external diameter, sealed in a laminated 
bag. 
 
Placebo was provided by the sponsor and had to be stored under recommended temperature 
(between +2°C and +8°C). 
 
An independent, non-blinded qualified person had to fill the empty syringe with the NaCl 
provided in order to administer the same volume as the active treatment.   
 
The procedures for study drug administration are provided in the Study Manual.  
 
6.2 
Prior and Concomitant Medication/Therapy 
Any medication and/or other therapy that the subject takes, other than the study 
investigational drug, is considered concomitant medication, whether or not it is targeting the 
studied tumour (Lung NET). Concomitant treatments are prescribed, modified or discontinued 
at the discretion of the investigator. 
6.2.1 
Prior Medication/Therapy 
Any prior therapy or medication given to a subject within 6 months before entry into the study 
(Screening) will be indicated on the eCRF. 
Forbidden prior therapies include: 
• 
Surgery within 6 weeks prior to randomization,  
• 
SSAs for more than 15 days (e.g. peri-operatively) of short acting SSA or one dose of 
long acting SSA and the treatment was received within 6 weeks prior to randomization,  
• 
Cytotoxic chemotherapy, molecular targeted therapy, or interferon within 4 weeks prior 
to randomization   
• 
More than one line of cytotoxic chemotherapy, molecular targeted therapy, and 
interferon 
• 
Previous local therapy (e.g. chemo-embolization, bland, or radio-embolization) within 
6 weeks prior to randomization 
• 
Treatment with PRRT at any time prior to randomization 
 
Dose and generic name or tradename will be indicated. 
 
6.2.2 
Concomitant Medication/Therapy 
Any concomitant therapy or medication given to a subject during study drug administration 
will be indicated on the eCRF. Dose and generic name or tradename will be indicated. 


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The following concomitant medications, therapy and procedures are not permitted during this 
study: 
- 
Cyclosporine,  
- 
GH antagonists, 
- 
Any SSAs (other than LAN used as study treatment), including rescue octreotide and/or 
LAR SSA, 
- 
Bromocriptine 
- 
Chemotherapy, molecular targeted therapy, chemoembolization, PRRT and interferon. 
 
Radiation (radiotherapy) is allowed for lesions other than target lesions according to the 
RECIST analysis. 
Rescue antidiarrheal medications (e.g., loperamide 2 mg tablets, and/or tincture of opium 
and/or pancreatic enzyme) are authorized. 
 
If any of the medications/therapies prohibited by the study protocol are taken/performed 
during treatment with study drug, subjects must be withdrawn from the study and, when 
possible, followed up for further data collection. 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 blockers) please refer to the current IB (Summary of 
Data and Guidance for the Investigator, Section 6.5.4 and Section 6.5.7). 
 
6.3 
Procedures for Monitoring Subject Compliance 
Study treatment will be administered by an independent non-blinded representative assigned 
by the Investigator at the study center, thus subject compliance is not expected to be an issue.  
Drug accountability records will be maintained by the Investigator documenting that subject 
received allocated study drug.  Any study drug administration issue should be explained on 
the eCRF. 
'Injection only' visits will not be considered as study visits; however, the date and time of 
injection will be recorded in the eCRF. 
A check system is included in the syringe to indicate that the whole dose has been 
administered.  
Where a subject is consistently noncompliant with study drug intake they should be 
discontinued from study drug and entered into the OL Extension Follow-up Period. 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 and Table 4, for 
the DB Phase and the OL Extension Treatment Period, respectively. 
 
7.1 
Primary Efficacy Endpoint and Evaluation 
The primary endpoint will be the PFS for subjects randomized in LAN group, assessed by 
central review using the RECIST v1.1 criteria, every 12 weeks, defined as the time from 
randomization to disease progression or death from any causes in either the double-blind 
phase, or in the OL period. 
 
Images centrally reviewed will be CT scan of thorax and abdomen, OR MRI of the abdomen 
with CT scan of thorax (using the same mode as per baseline). 
 
7.2 
Secondary Efficacy Endpoints and Evaluations 
• 
Progression-free survival (PFS), assessed by central review using RECIST v1.1 criteria 
every 12 weeks, defined as the time from randomization to disease progression or death 
from any causes during the double-blind phase.  
• 
Progression-free survival (PFS), assessed by local review using RECIST v1.1 criteria 
every 12 weeks, defined as the time from randomization to disease progression or death 
from any causes during the double-blind phase.  
• 
ORR: objective response rate of CR or PR measured by RECIST v1.1 criteria every 12 
weeks until the Post Treatment/Early Withdrawal Visit during the double blind phase. 
• 
Time to treatment failure during the double blind phase, defined as the time from 
randomization to disease progression [defined as the minimum (time to event according 
to central review, time to event according to local review)] using RECIST v1.1, death,  
consent withdrawn, an AE, protocol deviations, lost to follow-up, the appearance of 
carcinoid syndrome or other hormone related syndrome necessitating the initiation of 
SSAs (rescue octreotide and/or LAR SSA), or initiation of anticancer treatment 
• 
Mean changes from Baseline in biomarker CgA at Week 8, Week 12 and every 12 
weeks thereafter until the Post DB and in the OL Extension Treatment Phase 
• 
Proportion of subjects with decrease in CgA ≥30% at Week 8, in the population of 
subjects with an elevated CgA (≥2 x ULN) at Baseline during the double blind and the 
OL treatment phases. 
• 
Change in QoL, as assessed by EORTC QLQ-C30 questionnaire from Baseline to 
Week 12, every 12 weeks and at the Post Treatment/Early Withdrawal Visit and in OL 
Extension Treatment and Follow-up Phases. 
• 
Time to QoL deterioration, defined by a decrease from baseline in EORTC QLQ-C30 
score of at least 10 points during the double blind, the OL treatment and the follow-up 
phases.  
• 
Mean changes from Baseline in urinary 5-HIAA levels at Week 8, every 12 weeks 
thereafter, and at the Post Treatment/Early Withdrawal Visit and in OL Extension 
Treatment in subjects with elevated urinary 5-HIAA (≥2 x ULN) at Baseline, 
 


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Primary, secondary 
 efficacy endpoints and evaluations are summarized in 
Table 6. 
 
Table 6 
Primary, Secondary 
 Efficacy Endpoints and Evaluations 
Measure 
Time point 
Variable  
Endpoint 
PFS assessed by central 
review using RECIST 
v1.1 criteria 
Baseline and every 12 weeks 
or death date 
PFS (central) 
PFS 
PFS assessed by local 
review using RECIST 
v1.1 criteria (sensitivity 
analysis of the primary 
endpoint) 
Baseline and every 12 weeks 
or death date 
PFS (local) 
PFS 
ORR: 
objective 
response rate of CR or 
PR, 
using 
RECIST 
v1.1 criteria 
Baseline,  and every 12 weeks 
until the Post treatment/Early 
Withdrawal Visit 
Best Overall Response 
ORR assessed by local 
and central review using 
RECIST v1.1 criteria 
Time 
to 
treatment 
failure 
Baseline, every 12 weeks, or 
death date, or date of consent 
withdrawn, 
date 
of 
withdrawal due to an AE, date 
of lost to follow-up, date of 
appearance 
of 
carcinoid 
syndrome or other hormone 
related 
syndrome 
necessitating 
initiation 
of 
SSAs 
(rescue 
octreotide 
and/or LAR SSA) or date of 
initiation 
of 
anticancer 
treatment. 
Time 
to 
treatment 
failure  
Time to treatment failure  
Biomarker CgA level  
Baseline, Week 8, Week 12 
and every 12 weeks until the 
Post 
treatment/Early 
Withdrawal Visit 
Biomarker 
CgA 
changes from Baseline 
 
 
 
Mean change from 
Baseline values at 
each post baseline 
time point 
 
Proportion 
of 
subjects 
with 
decrease in CgA of 
≥30% at Week 8 
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Measure 
Time point 
Variable  
Endpoint 
Change in QoL, as 
assessed 
by 
the 
EORTC 
QLQ-C30 
questionnaire  
Baseline, and every 12 weeks 
until the Post treatment/Early 
Withdrawal Visit 
QoL 
change 
from 
Baseline 
 
Mean change from 
Baseline values at 
each post baseline 
time point. 
 
Time 
to 
QoL 
deterioration 
Mean 
change 
from 
Baseline 
in 
urinary 
5-HIAA 
levels 
in 
subjects with elevated 
5-HIAA (≥2xULN) at 
Baseline  
Baseline, Week 8 and every 
12 until 
the 
Post 
treatment/Early 
Withdrawal 
Visit 
Urinary 5-HIAA levels 
change from Baseline 
Mean 
change 
from 
Baseline values at each 
post baseline time point 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5-HIAA=5-hydroxyindoleacetic acid; AE=adverse event; CgA=chromogranin A; CR=complete response, 
 
 EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
Core-30; LAR=long acting release; OS=overall survival; PFS=progression free survival; PR=partial response, QoL= quality 
of life; RECIST=Response Evaluation Criteria in Solid Tumours; SD=stable disease; SRI=somatostatin receptor imaging; 
SSA=somatostatin analogue; 
 ULN=upper limit of normal. 
  
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 
PFS defined as time from randomization to the first documentation of progression according 
to RECIST v1.1 or death from any cause whichever occurs first, will be presented.  
7.4.2 
Tumour Response 
All tumour assessments will be performed using the RECIST v1.1 criteria every 12 weeks 
throughout the study (Table 2 and Table 4). The same imaging technique will be used for each 
subject throughout the study, in order to ensure comparability between tumour assessments. 
Subjects will receive either CT scan of the thorax and abdomen, or an MRI of the abdomen 
with CT scan of the thorax. Routine use of MRI with early arterial phase is strongly 
recommended, especially to assess liver and bone metastasis. At the Post Treatment/Early 
Withdrawal Visit, scans will only be conducted if not performed within the previous 4 weeks.  
For a given subject, it is recommended: 
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- 
to use the same scanner(s) and imaging parameters across all time points throughout the 
study to ensure comparability between tumour assessments, 
- 
that all scans will undergo a local review by the same reader designated for the study at 
each site, according to the study schedule.  
 
An independent central review of all scans will be performed in an ongoing manner and will 
be used for the analysis of the primary endpoint. Details of the procedure to handle the central 
reading of the CT scans/MRI are provided in the central reading site manual.  
A Best Overall Response of SD can only be made after the subject is on study for a minimum 
of seven (7) weeks (49 days). If the subject is on study less than seven (7) weeks (49 days), 
any tumour assessment indicating stable disease before this time period will have a Best 
Response of “non evaluable” unless PD is identified.  
In addition, at Baseline, the Central Reading CRO will measure the hepatic and intrathoracic 
tumour load. From the imaging data, PFS (see Section 7.4.1), ORR, time to treatment failure 
. 
Should CT scans/MRIs, performed within 12 months of Baseline, be available, they should be 
sent for analysis by central review, as part of an ancillary study.  
7.4.3 
Biomarkers (Chromogranin A and 5-Hydroxyindoleacetic Acid) 
7.4.3.1 
Chromogranin A 
Plasma CgA will be assessed according to the schedules in Table 2 and Table 4. At each time 
point a 5 mL blood sample for analysis of CgA will be taken, prepared and shipped as 
specified in the Central Laboratory Services Manual.  
In the DB Phase, blood samples for CgA will be collected at Baseline and will be repeated, at 
Week 8, Week 12 and every 12 weeks thereafter and at the Post Treatment/Early Withdrawal 
Visit. 
Blood samples for CgA will also be collected at the OL Treatment Extension Baseline and 
will be repeated every 12 weeks thereafter and at the Post Treatment/Early Withdrawal Visit 
of the OL Treatment Extension. 
 
7.4.3.2 
5-Hydroxyindoleacetic Acid 
Urinary 5-HIAA will be assessed according to the schedules in Table 2 and Table 4.  
At Baseline (Visit 2), urinary 5-HIAA levels will be assessed for all subjects. Urinary 
5-HIAA levels will be assessed at Week 8, Week 12 and every 12 weeks thereafter and at the 
Post Treatment/Early Withdrawal Visit, only for subjects with elevated urinary 5-HIAA 
(≥2 x ULN) at Baseline of the DB Phase, or if clinically indicated.  
The 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 
instructed not to eat bananas, pineapple, plums, walnuts, eggplant, tomatoes, chocolate or 
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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. Intake of 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 analyzed in order to assess compliance with the 24 hour 
collection period.  
7.4.4 
Somatostatin Receptor Imaging 
The following type of imaging can be used for SRI: 
1. 
Octreoscan® 
(a) 
Synonym: Indium In 111-Pentetreotide, Indium In-111 Pentetreotide, Indium-
111 Octreotide DTPA, Indium-111-DTPA-D-Phe-1-octreotide, Indium-In 111 
Pentetreotide, Indium-In-111-Pentetreotide 
(b) 
Method: Planar or SPECT 
(c) 
Evaluation: Krenning scale 
0 = no uptake by tumour. 
1 = uptake by tumour but < background liver. 
2 = uptake by tumour equal to background liver. 
3 = uptake by tumour greater than background liver. 
4 = very intense uptake by tumour. 
(d) 
Result: SRI by Octreoscan® is positive if Krenning scale is equal or greater than 
grade 2 (Krenning scale 2) 
2. 
Ga-PET-Scan 
(a) 
Synonym: Ga-68 DOTATATE PET/CT, Gallium-68 DOTA-DPhe1, (68)Ga-
DOTA-TATE, 68Ga-DOTATATE, Ga-68 DOTA0-Tyr3-octreotide, Ga-68 
DOTATOC 
(b) 
Method: CT + PET 
(c) 
Evaluation: Krenning scale does not “fully” apply to Ga-PET-scan 
(d) 
Result: SRI by Ga-PET-scan is positive if “uptake is greater than background 
liver” 
 
Somatostatin receptor imaging by Octreoscan or Ga-PET-scan performed within the last 6 
months will be collected if available in the subject file and SRI positivity can be confirmed 
according to the rules described above. If not available in the subject file, a new SRI is 
required before inclusion. 
 
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7.4.5 
Time to Treatment Failure 
Treatment failure is defined as progression [defined as the minimum (time to event according 
to central review, time to event according to local review)] using RECIST v1.1, death, 
consent withdrawn, an AE, protocol deviations, lost to follow-up, the appearance of carcinoid 
syndrome or other hormone related syndrome necessitating the initiation of SSAs (rescue 
octreotide and/or LAR SSA), or initiation of anticancer treatment. Time to treatment failure 
will be defined as the time from randomization to treatment failure.  
7.4.6 
Quality of Life  
Quality of life will be assessed using the EORTC QLQ-C30 v3.0 questionnaire. The 
questionnaire will be completed at Baseline (Visit 2), every 12 weeks (throughout the DB and 
both OL phases), at the Post treatment/Early Withdrawal Visit at the end of the DB and both 
OL Phases. If necessary, the investigator or delegated personnel will explain the questions, 
which will be provided in a paper format, to the subject. The subject will complete the 
questionnaire in the same conditions throughout the study (i.e. prior to study medication 
administration) and the investigator or delegated personnel will check that all questions have 
been answered. 
 
7.4.7 
Subsequent Therapies 
Details of all new cancer therapies during the OL Extension Follow-up phase will be 
collected. 
8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study and up to 30 days after the last study drug administration. They will be 
elicited by direct, non-leading questioning or by spontaneous reports. Further details for AE 
reporting can be found in Section 8.1.2. 
 
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, electrocardiogram). In clinical studies an 
AE can include an undesirable medical condition occurring at any time, including run in or 
washout periods, even if no study drug has been administered.  
 
This definition includes events occurring from the time of the subject giving informed consent 
up to 30 days after last study drug administration. 
 
Natural progression or deterioration of the malignancy under study will be recorded as part of 
the efficacy evaluation and should not be recorded as an AE/SAE. 
 
Death due to disease progression will be recorded as part of the efficacy evaluation and will 
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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 baseline malignancy. 
 
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 symptoms 
or 
• 
If the investigator considers the deterioration of signs and symptoms to be caused 
directly by the study drug. 
 
If there is any uncertainty about an AE being due solely to the malignancy under study, it 
should be reported as an AE/SAE as appropriate. 
 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
Adverse events will be recorded and graded according to the current version of the 
NCI-CTCAE v4.03, 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, 
• 
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 well-being, 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: 
 


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• 
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. electrocardiogram changes, thyroid function disturbances) that result in a change in study 
drug dosage or administration schedule, or in discontinuation of the 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 visit (during the DB and OL phase), the subject should be asked a non-leading 
question such as: “How have you felt since the last visit?” 
 
'Injection only' visits will not be considered as study visits; however, any AEs reported at 
these visits will 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 treatment group or 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 


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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 a SAE 
requiring immediate notification to the sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the investigator to determine 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 level 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 treatment group or suspected relationship to study 
drug must be reported immediately (within 24 hours of the investigator’s knowledge of the 
event) via an SAE report form and sent immediately (within 24 hours of the treating 
physician’s knowledge of the event) to the fax number specified at the beginning of this 
protocol.  
 
A 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 in-subject hospitalization or prolongation of existing hospitalization, 
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 
the  study drug, 
(6) 
Is an important medical event that may not result in death, be life threatening, or 
require hospitalization 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 in-subject hospitalization, or the 
development of drug dependency or drug abuse. 
 
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 
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• 
Hospitalization is defined as any in-subject admission (even if less than 24 hours). For 
chronic or long term in-subjects, in-subject admission also includes transfer within the 
hospital to an acute/intensive care in-subject unit. 
• 
Prolongation of hospitalization is defined as any extension of an in-subject 
hospitalization 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 hospitalization 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.  
• 
Pre-planned or elective treatments/surgical procedures should be noted in the subject’s 
screening 
documentation. 
Hospitalization 
for 
a 
pre-planned 
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 
• 
Subject sex 
• 
Nature and seriousness of the event 
• 
Reason for the serious classification 
• 
Causality (related, not related) 
• 
Event Onset date 
• 
Outcome of the event (if available) and any action taken 
 
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 


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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 the study drug has 
interfered with a contraceptive method. If pregnancy occurs during the study, the subject will 
be immediately withdrawn from the study treatment.  The outcome of the pregnancy will then 
need to be collected post study. Prior to withdrawal from the study, the pregnant subject will 
undergo either Post Treatment /Early Withdrawal Visit for the DB Phase or the OL Extension 
Phase, as applicable, within 30 days of last study drug administration. 
 
Information regarding pregnancies must be collected on the AE page of the eCRF and 
reported to the sponsor using the Standard Pregnancy Outcome Report Form. 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. 
8.1.6 
Deaths 
All AEs resulting in death, except death due to disease progression, either during the study 
period or within 30 days after the last dose of study drug, must be reported within 24 hours of 
the investigator’s knowledge of the event. 
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. 
 


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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 the study drug (see Section 4.3). 
 
If the study drug is discontinued due to a 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).  
 
The investigator should assess the ongoing benefit risk for each subject during their 
participation in the study, in consideration of any AEs 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 (>2x ULN) or lipase (>2x 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. 
• 
Hepatic impairment: NCI CTCAE grade ≥3 ALT (>5xULN) or AST (>5xULN) or 
Bilirubin (>2xULN). 
• 
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. 
 
8.1.8 
Reporting to Competent Authorities/IRBs/IECs/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’s, 
IRBs/IECs and other investigators concerned by the study drug. Reporting will be done in 
accordance with the applicable regulatory requirements. 
 
It is the investigators’ responsibility to notify their IRB/IEC in a timely manner. 
 


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8.2 
Clinical Laboratory Tests 
During the DB Phase and OL Extension Treatment Period, blood samples will be collected at 
Screening, Baseline, Week 12 and then every 12 weeks until the Post Treatment/Early 
Withdrawal Visit (see Table 2 and Table 4). 
 
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). Laboratory test results reported as AEs will be graded according to NCI CTCAE 
criteria (see Section 8.1.2.1).  
 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to Baseline or to a level 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 
Hematology 
Blood samples (3 mL+3 mL) will be collected in a potassium ethylenediaminetetraacetic acid 
(EDTA) tube to assess the following parameters: red blood cell (RBC) count, hemoglobin, 
haematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), white blood cell (WBC) count with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils, and others) and 
platelet count. 
 
8.2.2 
Blood Biochemistry 
Blood samples (5mL) will be collected in an activator gel tube to assess the following 
parameters: 
 
• 
urea, creatinine, total bilirubin, conjugated bilirubin 
• 
chloride, bicarbonate, sodium, potassium, calcium, phosphate 
• 
alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), gamma glutamyl transferase, lipase, amylase. 
• 
albumin total protein, total cholesterol, triglycerides, fasting glucose 
• 
glycated haemoglobin (HbA1c) 
 
Blood samples will be collected at Screening in a citrated tube to assess the following 
coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT) 
and its derived measures of prothrombin ratio (PR) and international normalised ratio (INR). 
 
Detailed requirements for blood collection will be provided in the laboratory manual. 
 


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8.2.3 
Pregnancy Test 
Female subject of childbearing potential should have a negative urine or serum pregnancy test 
within 72 hours; if positive with urine, confirm with serum prior to receiving the first dose of 
study medication and at Baseline of the Post OL Extension Treatment Phase. A urinary test 
should also be performed at the Post Treatment/Early Withdrawal Visit and confirm with 
serum if positive with urine. 
 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
 
Female subjects who are at risk of becoming pregnant must agree to use an effective method 
of contraception such as double barrier contraception, an injectable, combined oral 
contraceptive or an intra-uterine device (IUD). The subject must agree to use the 
contraception during the whole period of the study and for eight months after the last study 
drug administration. Non childbearing potential is defined as being postmenopausal for at 
least 1 year, or permanently sterilized at least 3 months before study entry. 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.3 
Physical Examination 
Physical examinations will be assessed at Screening, Baseline, and every 12 weeks thereafter 
until the last study Visit.  Please see Table 2, Table 4 and Table 5 for details.   
 
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 treatment will be followed by the investigator until resolution or until 
reaching a clinically stable endpoint. 
 
8.4 
Vital Signs 
Vital signs will be assessed at Screening, Baseline, and every 12 weeks thereafter until the last 
study Visit. Please see Table 2, Table 4 and Table 5. 
Blood pressure (SBP/DBP) and heart rate will be assessed with an automated device so that 
measurements are independent of the observer. Blood pressure and heart rate will be recorded 
after five minutes rest in supine and standing position and after 1 minute of standing. 
Absolute values and change from Baseline will be analyzed. 
Weight will be recorded, and height will be measured at Screening (Visit 1) only. 
 
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9 
ASSESSMENTS OF 
PHARMACODYNAMICS 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1.2 
Analytical Procedures 
The concentrations of lanreotide in serum will be analyzed by COVANCE (Harrogate, UK) 
using a validated LC-MS/MS method. 
A detailed description of the analytical procedures and validation methods will be provided in 
the Trial Master File (TMF). 
 
At the end of the study when all serum samples are analysed, the bioanalytical report will be 
appended to the clinical study report. 
 
Details of sample handling will be provided in the laboratory manual. 
 
9.2 
Pharmacodynamics 
For subjects participating in the optional research programme, serum and whole blood 
samples will be taken for further potential analyses, aimed at: 
• 
Exploring the association of biomarkers with drug activity (clinical benefit and 
mechanisms of action). 
• 
Exploring the association of biomarkers with AEs, or other effects associated with 
LAN treatment. 
• 
Exploring biomarkers of diagnostic assays and establishing the performance 
characteristics of these assays. 
 
 
 
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Samples will be archived in a central biorepository designated by the sponsor and according 
to local administration regulations, and/or the European Medicines Agency and will not carry 
personal identification (e.g. Social Security number or name). The samples will be destroyed 
no more than 15 years after the end of the main study or at the subject’s request. 
 
 
 
 
  
Only people designated by the sponsor will be allowed access to the samples. All information 
collected will be kept strictly confidential and all clinical information will be anonymous. 
 
 
 
  
 
 
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10 
STATISTICS 
10.1 
Analyses Populations 
The following populations will be used for the statistical analyses: 
• 
Screened population:  All subjects screened (i.e. who signed informed consent). 
• 
Intention to treat (ITT) population: All randomized subjects. Subjects will be 
analyzed as randomized, regardless of the treatment received. 
• 
Per protocol (PP) population: All subjects in the ITT population with no major 
protocol violations/deviations. 
• 
Safety population: All subjects in the ITT population who received at least one 
injection of study treatment. Subjects will be analyzed as treated. 
• 
Open Label Intention to Treat (OLITT) population: All subjects entering the LAN 
OL Extension Treatment Phase who have signed an informed consent.  
• 
Follow-up population: All OLITT subjects entering the Follow-up Extension Phase. 
 
10.1.1 
Populations Analyzed 
The primary analysis of efficacy will be performed on the ITT population. The PP population 
will be used for secondary efficacy analyses of the primary endpoints as well as all PFS 
derived endpoints. All other secondary endpoints will be analyzed only on the ITT. All safety 
data related to the DB phase will be analyzed on the safety population according to the 
treatment received. All safety data related to the OL extension treatment period will be 
analyzed on the OLITT population. All safety data related to the OL extension follow-up 
period will be analyzed on the Follow-up population. 
 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses 
Any major protocol deviation will be described in the Protocol-Deviation Specification 
Document.  The final list of protocol deviations impacting inclusion in all populations will be 
reviewed during the data review meeting held prior to database lock. 
 
10.2 
Sample Size Determination 
Eligible subjects are stratified by 
 
 Typical versus atypical tumour characteristics, and  
 Prior chemotherapy (cytotoxic chemotherapy or molecular targeted therapy or interferon) 
versus no prior chemotherapy 
 
and randomly assigned 2:1 (two subjects in the LAN plus BSC group for each subject in the 
placebo plus BSC group). The limited published data on PFS in subjects with typical and 
atypical, well differentiated metastatic lung NETs provide a range of median PFS from 
5.6 months, up to 24 months according to the typical or atypical characteristics of the disease. 
It is considered that an overall difference of 4 months in median PFS between the two groups 
is clinically meaningful.  
 


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The following assumptions are used to derive the sample size for the study:  
 
• 
Exponential distribution of survival on both treatment groups with constant event rate  
• 
Expected median PFS times of 6 and 10 months in the control and experimental arms, 
respectively (expected hazard ratio of 0.6)  
• 
Type 1 error α = 0.05 using a 2-sided log-rank test for the primary endpoint of PFS in 
the ITT population  
• 
Type 2 error β = 0.10 (90% power)  
• 
A uniform accrual time of 18 months  
• 
An additional follow-up period of 18 months after the last subject is randomized  
• 
A 2:1 random assignment ratio  
 
Under these assumptions, using SAS procedure POWER, a total of 201 randomized subjects 
were initially necessary to observe an estimated 175 disease progression as assessed centrally 
or death events in both treatment groups, and detect a statistically significant treatment effect. 
Taking into account 5% of subjects lost to follow up, and the stratification factors, 
216 subjects had to be randomized initially (144 subjects in the LAN plus BSC group and 
72 subjects in the placebo plus BSC group). 
A blinded sample size reassessment was planned to be performed prior to the end of the 
recruitment period. Sample size was planned to be increased should the rate of censored 
subjects be higher than anticipated. 
 
Due to the premature stop of the recruitment, the sample size as originally calculated will not 
be achieved. Study results will be underpowered and hence, statistical analyses will only be 
descriptive. Results should therefore be interpreted with caution. 
 
At the time of the premature stop, 77 subjects were included in this study. Assuming a 
theoretical 2:1 randomization, 52 subjects are included in experimental arm and 25 in placebo 
arm. It will ensure an estimation accuracy of 13% for an expected median PFS of 10 months. 
 
 
10.3 
Significance Testing and Estimations 
All statistical analyses will be descriptive.  
 
10.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external Contract Research Organization (CRO), 
managed by the sponsor’s Specialty Franchise Clinical Operations Biometry 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. 
 


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Statistical analyses will be performed using Statistical Analysis System® (SAS)® 
(version 9.3 or higher). 
10.4.1 
Demographic and Other Baseline Characteristics 
In order to evaluate balance of treatment groups, descriptive summary statistics (n, mean, 
standard deviation (StD), 95% CI of the mean, median, minimum, maximum) or frequency 
counts of demographic (age, ethnicity and race (as per local regulations) and sex) and baseline 
data (medical and surgical history, concomitant disease (predosing AEs and ongoing medical 
history), disease history/diagnosis (mitotic count and foci of necrosis, Ki67 value if available, 
TNM staging, location of primary tumour, number of metastatic organs, hepatic and 
intrathoracic tumour load, presence/absence of hormone related syndrome), ECOG status and 
subject status in terms of somatostatin receptors (Krenning scale) will be presented by 
treatment group and overall for the ITT. Data will also be presented for the PP population 
should there be a difference of more than 10% between the number of subjects in the ITT and 
the PP population. 
 
10.4.2 
Homogeneity of Treatment Groups 
Homogeneity of treatment groups at Baseline will be explored for selected parameters such as 
age, sex, performance status, and other known risk factors using 95% CI. 
 
10.4.3 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in each population will be 
summarized. The reasons for subject exclusions from each of the populations will be 
tabulated. In addition, the number of subjects who were randomized, treated, discontinued and 
completed at each of the study periods will be summarized by treatment group for the DB 
phase (as randomized), the OL Treatment Period (per status at the end of the DB phase), the 
OL Extension Follow-up Period and overall. Primary reasons for discontinuation of study 
treatment will be tabulated for each study phase. 
 
 
 
 
 
 
 
 
 
 
10.4.5 
Efficacy Evaluation 
10.4.5.1 Primary Efficacy Variable 
As indicated in Section 7.1, the primary efficacy endpoint is PFS for subjects randomized in 
LAN group assessed by central review using RECIST v1.1 criteria every 12 weeks. PFS is 
defined as the time from randomization to the first documentation of progression according to 
RECIST v1.1 in assessments every 12 weeks, or death from any cause, whichever occurs first 
in either the double-blind phase or in the OL period.  
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Table 7 summarizes the rules for determination of the date and assignment of the outcome 
[26]. 
 
Table 7 
Progression Free Survival Rules (Centrally Assessed Using RECIST v1.1 Criteria) 
Situation 
Date of progression or censoring 
Outcome 
No baseline tumour assessment 
Randomization  
Censored 
Progression documented (centrally) 
Date of radiological assessment of 
measured 
lesions 
showing 
progression 
Event 
Progression 
documented 
(locally) 
and 
withdrawal from DB phase  
Date of radiological assessment of 
measured 
lesions 
showing 
progression 
Censored 
No progression 
Date of last radiological assessment 
of measured lesions 
Censored 
Treatment discontinuation for undocumented 
progression  
Date of last radiological assessment 
of measured lesions 
Censored 
Treatment discontinuation for toxicity or other 
reason 
Date of last radiological assessment 
of measured lesions 
Censored 
New anticancer treatment started 
Date of last radiological assessment 
of measured lesions prior to initiation 
of an anti-cancer treatment 
Censored 
Death before first PD assessment 
Date of death 
Event 
Death between adequate assessment visits 
Date of death 
Event 
Death or progression after more than one 
missed visit 
Date of last radiological assessment 
of measured lesions 
Censored 
Prohibited medication/therapy 
Date of last evaluable assessment 
prior to initiation of prohibited 
medication/therapy 
Censored 
PD=progressive disease; RECIST=Response Evaluation Criteria in Solid Tumours. 
 
The distribution of PFS times in the LAN plus BSC group will be estimated using the Kaplan 
Meier product limit method. The median PFS times with 2-sided 95% confidence intervals 
will be estimated in the LAN plus BSC group, together with the estimates of PFS rates at 6, 
12, 18, and 24 months interval after randomization. The results of the analyses will be 
presented both in summary tables and graphically in Kaplan Meier plots.  
 
As a sensitivity analysis to the primary endpoint, the analysis of PFS according to local 
review will include investigator assessed PD and deaths. Other data will be censored.   
Clinical progression (i.e., locally assessed documented progression when the subject is 
withdrawn from the study due to clinical judgement of progression, however the progression 
is not confirmed by independent centralized review) is considered as progression in this 
analysis. 
Table 8 summarizes the rules for determination of the date and assignment of the outcome 
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Table 8 
Censoring Rules for PFS via Local Review 
Situation 
Date of progression or censoring 
Outcome 
No baseline tumor assessment 
Randomization for subjects randomized in 
LAN group 
Censored 
Progression documented (locally)  
Date of radiological assessment of measured 
lesions showing progression 
Event 
No progression 
Date of last radiological assessment of 
measured lesions 
Censored 
Treatment 
discontinuation 
for 
undocumented progression  
Date of last radiological assessment of 
measured lesions 
Censored 
Treatment 
discontinuation 
for 
toxicity or other reason 
Date of last radiological assessment of 
measured lesions 
Censored 
New anticancer treatment started 
Date of last radiological assessment of 
measured lesions prior to initiation of an 
anti-cancer treatment 
Censored 
Death before first PD assessment 
Date of death 
Event 
Death 
between 
adequate 
assessment visits 
Date of death 
Event 
Death or progression after more 
than one missed visit 
Date of last radiological assessment of 
measured lesions 
Censored 
Prohibited medication/therapy 
Date of last evaluable assessment prior to 
initiation of prohibited medication/therapy 
Censored 
PD=progressive disease. 
Similar analyses to those employed for the primary efficacy endpoint will be performed.   
 
10.4.5.2 Secondary Efficacy Variables 
As indicated in Section 7.2, the secondary efficacy endpoints are: 
Progression-free survival (PFS) assessed by central review using RECIST v1.1 criteria every 
12 weeks during the double-blind phase: 
PFS is defined as the time from randomization to the first documentation of progression 
according to RECIST v1.1 in assessments every 12 weeks, or death from any cause during the 
double-blind phase, whichever occurs first. The rules for determination of the date and 
assignment of the outcome will be described in the SAP. 
 
The distribution of PFS times for each treatment group will be estimated using the Kaplan 
Meier product limit method. The median PFS times with 2-sided 95% confidence intervals 
will be estimated for each treatment group, together with the estimates of PFS rates at 6, 12, 
18, and 24 months interval after randomization. The results of the analyses will be presented 
both in summary tables and graphically in Kaplan Meier plots. A stratified Cox proportional 
hazards model will be used to estimate the HR, and its two sided 95% CI. If the assumption of 
the proportionality of hazards is not satisfied, an appropriate model will be used (with time 
varying covariate or by using a parametric model).   
 
Progression-free survival (PFS) assessed by local review using RECIST v1.1 criteria every 12 
weeks during the double-blind phase: 
PFS is defined as the time from randomization to the first documentation of progression 
according to RECIST v1.1 in assessments every 12 weeks, or death from any cause during the 
double-blind phase, whichever occurs first. The rules for determination of the date and 
assignment of the outcome will be described in the SAP. 
 


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The distribution of PFS times for each treatment group will be estimated using the Kaplan 
Meier product limit method. The median PFS times with 2-sided 95% confidence intervals 
will be estimated for each treatment group, together with the estimates of PFS rates at 6, 12, 
18, and 24 months interval after randomization. The results of the analyses will be presented 
both in summary tables and graphically in Kaplan Meier plots. A stratified Cox proportional 
hazards model will be used to estimate the HR, and its two sided 95% CI. If the assumption of 
the proportionality of hazards is not satisfied, an appropriate model will be used (with time 
varying covariate or by using a parametric model).   
 
 
ORR: Proportion of subjects with the best overall response of CR or PR using RECIST v1.1 
criteria. 
The ORR in each treatment arm, with the corresponding exact 95% CIs, will be estimated. In 
addition, the difference in rates, together with a 95% CI, will be calculated. ORR will be 
performed for the DB phase.  
 
Time to treatment failure, defined as the time from randomization to disease progression 
[defined as the minimum (time to event according to central review, time to event according 
to local review)] using RECIST v1.1, death, consent withdrawn, an AE, protocol deviations, 
lost to follow-up, the appearance of carcinoid syndrome or other hormone related syndrome 
necessitating the initiation of SSAs (rescue octreotide and/or LAR SSA), or initiation of 
anticancer treatment 
Treatment failure is defined as progression [defined as the minimum (time to event according 
to central review, time to event according to local review)] using RECIST v1.1, death, 
consent withdrawn, an AE, protocol deviations, lost to follow-up, the appearance of carcinoid 
syndrome or other hormone related syndrome necessitating the initiation of SSAs (rescue 
octreotide and/or LAR SSA), or initiation of anticancer treatment. Time to treatment failure 
(TTF) will be performed for the DB phase. The distribution of times to treatment failure for 
each treatment arm will be estimated using the Kaplan Meier method. The median time to 
treatment failure and associated 95% CI will be computed for each treatment arm. The results 
will be presented both in summary tables and graphically in Kaplan Meier plots.  
 
Mean changes from Baseline in biomarker CgA at Week 8, Week 12 and every 12 weeks 
thereafter until the Post Treatment/Early Withdrawal visit 
Mean changes from Baseline in biomarker CgA will be presented descriptively by time point 
and treatment group in the DB phase and in OL treatment phase, using summary statistics. 
Raw values and change from Baseline will be presented. 
 
Proportion of subjects with decrease in CgA ≥30% at Week 8 in the population of subjects 
with an elevated CgA (≥2 x ULN) at Baseline  
The proportion of subjects with a 30% or more decrease in CgA from Baseline to Week 8 
during the double-blind phase and the OL treatment phase will be estimated (in the population 
of subjects with an elevated CgA (≥2 x ULN) at Baseline), with the corresponding 95% CI in 
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Change in QoL, as assessed by the EORTC QLQ-C30 questionnaire from Baseline to Weeks 
12, every 12 weeks and at the Post Treatment/Early withdrawal Visit and in OL Extension 
Treatment and Follow-up Phases 
EORTC QLQ-30 will be described at each time point, by treatment arm. Both raw values and 
change from Baseline will be presented in the DB phase, in the OL treatment phase and in the 
follow-up treatment phase.  
 
Time to QoL deterioration, defined by a decrease from baseline in EORTC QLQ-30 score of 
at least 10 points.  
Time to QoL deterioration will be analyzed in a similar fashion to time to treatment failure 
during the double-blind phase, during the OL treatment phase and during the follow-up 
treatment phase. 
 
Mean changes from Baseline in urinary 5-HIAA levels at Week 8, every 12 weeks and at the 
Post Treatment/Early Withdrawal visit in subjects with elevated urinary 5-HIAA (≥2 x ULN) 
at Baseline 
Mean changes from Baseline in 5-HIAA urinary levels will be presented descriptively for 
subjects with elevated urinary 5-HIAA (≥2 x ULN) at Baseline, by time point and treatment 
group in the DB phase and in the OL treatment phase, using summary statistics. 
 
For all RECIST 1.1 based efficacy endpoints, the analyses will be performed using data from 
local and central review. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
10.4.6 
Adjustment for Country/Center Effect 
No adjustment for country/center effect is planned. 
 
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10.4.7 
Safety Evaluation 
All safety data will be included in the subject data listings.  
All safety data related to the DB phase will be analyzed on the Safety Population according to 
the treatment received. 
All safety data related to the OL extension treatment period will be analyzed on the OLITT 
Population. 
All safety data related to the OL extension follow-up period will be analyzed on the Follow-
up Population. 
 
All treatment emergent adverse events (TEAEs) will be reported and graded by investigators 
using the NCI CTCAE classification (Version 4.03, dated 14 June 2010). All AEs will also be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) (version 18.1or 
later). 
Summary incidence tables will be provided, classified by body system, System Organ Class 
(SOC), Preferred Term (PT) and associated NCI CTCAE worst grade. 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) will 
be chosen. AEs resulting in dose delays, dose interruptions and study drug withdrawal will be 
listed and presented in summary tables.  
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 
by subject and by visit will be listed.  
Incidence of all reported TEAEs and SAEs will be tabulated by treatment group and overall. 
In addition, summary tables will be presented by maximum intensity, drug relationship and 
TEAEs associated with premature withdrawal of study medication. 
A TEAE is defined as any AE that occurs from receiving the first dose of study drug to End of 
Study/withdrawal if:  
• 
it was not present prior to receiving the first dose of study drug, or  
• 
it was present prior to receiving the first dose of study drug but the intensity 
increased at or after receiving the first dose of study drug.  
All TEAEs will be flagged in the AEs listings. 
Prior and concomitant medication will be coded by using the WHO Drug Dictionary 
(version 2 (June 2015) or later) and will be summarized by treatment group and overall with 
the number and percentage of subjects receiving concomitant medication by drug class and 
preferred drug name. Concomitant therapies and surgical procedures will be summarized 
separately. Prior medications/therapies are all those stopped at the Screening visit (Visit 1) 
and concomitant medications/therapies are defined as all those ongoing or started within 28 
days before the study drug administration/after the first dose of study drug. 
For the DB phase, summary statistics (mean, 95% CI of the mean, median, StD and range as 
appropriate) by treatment group and overall will be presented for vital signs, clinical 
laboratory tests, physical exam, NYHA, ECG, ECOG, and gallbladder at each assessment 
with change from Baseline. 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 


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normal or abnormal physical examinations between Baseline and the Post Treatment/Early 
Withdrawal Visit in the DB Phase. 
For the OL Extension Treatment phase, similar analyses will be performed on the OLITT 
population according to the status at the end of the DB phase. 
 
 
 
 
 
 
 
10.5 
Subgroup Analyses 
No subgroup analyses will be performed. 
 
10.6 
Interim Analyses 
No interim analyses are planned. 
 
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11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
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 
inspection. 
 


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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 IRB/IEC, 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 non-adherence 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 significant divergence from the protocol, i.e. non-adherence 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. In addition, protocol 
violations will be reported by the monitor in the monitoring reports and any other related 
study documents, as detailed in the monitoring manual. 
 
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 
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12.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
 
The sponsor is responsible for monitoring these 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 
requirements. Monitoring will be conducted by a CRO, directed by the sponsor's Specialty 
Franchise Clinical Operations department. 
 
Contracted CRO assigned monitors will conduct regular site visits. As the active treatment 
and placebo are not similar in appearance (see Section 6.1) two monitors will be assigned to 
each site. One monitor will be dedicated to conducting study treatment checks and 
accountability and will have no access to the subject's data, files or assessments. The other 
monitor will be responsible for all other monitoring activities. 
 
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. 
 
Electronic data capture (EDC) will be utilized for collecting subject data. The site must 
complete the eCRFs according to the subject’s visit and on an ongoing basis to allow regular 
review by the study monitor, both remotely by the internet and during site visits. The central 
study monitor at the sponsor and/or at the assigned CRO(s) 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. 
 
A Steering Committee will be composed of investigator and sponsor representatives to govern 
the overall scientific and operational management of the study. A specific charter may be 
developed to define roles and responsibilities. 
 
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. 


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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/data manager 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 IRBs/IECs, informed consent regulations, 
the Declaration of Helsinki and ICH GCP Guidelines (Section 1.4). 
 
For electronic data capture (EDC) studies the following regulations must be included: Food 
and Drug Administration (FDA), 21 CFR Part 11, Electronic Records, Electronic Signatures, 
and FDA, Guidance for Industry: Computerized 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 IRB/IEC for the study protocol/amendment(s), written 
informed consent form, 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 IRB/IEC that they comply with GCP requirements. The 
IRB/IEC approval must identify the protocol version as well as the documents reviewed. 
 
After IRB/IEC 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 IRB/IEC must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IRB/IEC. 
 
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 the study drug). Sufficient time will be allowed to discuss 
any questions raised by the subject. 
 
 
 
 
The sponsor will provide sample informed consent form. The final version controlled form 
must be agreed to by the sponsor, and the IRB/IEC and must contain all elements included in 
the sample form, 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. 
 
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The consent forms 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 IRB/IEC. 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. 
 
 
 
 
 
 
 
 
13.3 
Health Authorities and Institutional Review Boards/Independent Ethics 
Committees 
As required by local regulations, the sponsor’s or designated CRO’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 not be identified by their 
names, but by an identification code (e.g. 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, study drug 
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.  
QoL questionnaires will be presented to the subjects in paper format. Once completed, the 
original copy will be sent to the designated CRO in charge of data management. 
 
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 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 (EDC) 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 sponsor’s Specialty Franchise 
Clinical Operation Biometry department. All data management procedures will be completed in 
accordance with the sponsor and the contracted CRO SOPs. Prior to data being received in-house 
at the assigned CRO, it will be monitored at the investigator site, (for further details please see 
Section 12.3 Study Monitoring). The paper subject questionnaires and other data documentation 
removed from the investigator site(s) will be tracked by the CRO and the monitor. A hard copy 
should be retained at site in the subject file. 
 
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 
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Any queries generated during the data management process will also be tracked by the 
contracted data management CRO 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 
AE, 
medical 
and 
surgical 
history, 
prior/concomitant 
medication/chemotherapy/molecular targeted therapy/radiotherapy related to lung NETs and 
general prior/concomitant medication/non drug therapies/surgical procedures will be performed 
by the Sponsor’s specialised Medical Coding Group.  
Coding will be performed with WHODRUG and MedDRA dictionaries as appropriate. 
 
14.3 
Record Archiving and Retention 
During the pre-study 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. 
Selection of authors for scientific publications will follow the International Committee of 
Medical Journal Editors (ICMJE) guidelines [26]. In particular, those named as authors, 
whether employed by an Ipsen Affiliate or sponsor, or external investigators, ‘should have 
participated sufficiently in the work to take public responsibility for the content’. 
Authorship credit should be based on: 
• 
Substantial contributions to the conception and design, or acquisition of data, or 
analysis and interpretation of data. 
• 
Drafting the article or revising it critically for important intellectual content. 
• 
Final approval of the version to be published. 
• 
Agreement to be accountable for all aspects for the work, thereby ensuring that 
questions related to the accuracy or integrity of any part of the work were appropriately 
investigated and resolved. 
All authors of a manuscript should meet all four criteria. Each author must agree to their 
inclusion in the list of authors. 
Resolution of scientific differences in the presentation or interpretation of study findings will 
be conducted along principles of honest scientific debate. The sponsor shall be promptly 
notified of any amendments subsequently requested by referees or journal editors. 
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. 


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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. 
 
 
 
 
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17 
REFERENCES 
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2. 
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, 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 Jun 20;26(18):3063-72. 
3. 
Hauso O, Gustafsson BI, Kidd M, et al. Neuroendocrine tumor epidemiology: 
contrasting Norway and North America. Cancer 2008; 113:2655. 
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NCCN NET Guidelines; V1.2015 [available at www.nccn.org].  
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Phan AT, Oberg K, Choi J, et al. NANETS consensus guideline for the diagnosis and 
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Krug LM, Kris MG, Rosenzweig K, Travis WD. Small cell and other neuroendocrine 
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Wilkins; 2008:946-971. 
7. 
Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with 
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immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 
1991;15:529 53. 
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Oberg K , Akerström G , Rindi G , Jelic S ; ESMO GuidelinesWorking Group . 
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Marquez-Medina D, Popat S. Systemic therapy for pulmonary carcinoids. Lung 
Cancer. 2015 Nov;90(2):139-47. 
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Walter T et al. Characterization and Prognosis of Patients with Metastatic Lung 
Carcinoid Tumors. ENETS 2015 
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Forde PM, Hooker CM, Boikos SA, Petrini I et al. Systemic therapy, clinical outcomes, 
and overall survival in locally advanced or metastatic pulmonary carcinoid: a brief 
report. J Thorac Oncol. 2014 Mar;9(3):414-8. 
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Filosso PL, Ferolla P, Guerrera F, Ruffini E, Travis WD, Rossi G, et al. 
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