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 TUMOR CONTROL IN SUBJECTS WITH WELL DIFFERENTIATED, METASTATIC AND/OR UNRESECTABLE TYPICAL OR ATYPICAL LUNG NEUROENDOCRINE TUMORS

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
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 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* [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).

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

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 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 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.

Secondary Safety Objective
* To evaluate the clinical and biological safety profile.

Exploratory Objectives
* To describe the clinical benefit rate (CBR) of LAN monotherapy plus
BSC every 28 days and placebo plus BSC, as assessed by RECIST v 1.1 criteria
(proportion of subjects with a best overall response of PR, CR or stable
disease (SD)),
* To evaluate the effect on tumour growth rate (TGR), as assessed by
central review prior to and during administration,
* To monitor lanreotide serum concentration in subjects with advanced
lung NET.

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 Period.

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.

N/A

The investigation of Lanreotide in this patient population is justified, based
upon the clinical and nonclinical safety profile, the inadequacy of alternative
treatments available to patients, the limited life expectancy due to malignant
disease, and the strength of the scientific hypothesis under evaluation. Thus
the benefit/risk assessment for this Phase III study supports the
administration of LAN to patients with well differentiated, metastatic and/or
resectable typical or atypical lung neuroendocrine tumours.