Clinical trial NCT02698410
Conditions: Neuroendocrine Tumours
Sponsor: Ipsen
Start date: 2016-07-01; Completion date: 2019-06-18
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the protocol is to evaluate the efficacy and safety of Lanreotide ATG 120 mg in combination with Temozolomide in subjects with unresectable advanced neuroendocrine tumours of the lung or thymus as Disease Control Rate at 9 months.

Detailed description:

Arms: arm 1: Lanreotide ATG 120 mg every 28 days, deep subcutaneous injection for a maximum of 48 weeks, for a total number of 12 injections.

Temozolomide 250 mg hard capsules, for 5 consecutive days every 28 days, oral route, for a maximum of 48 weeks.
Interventions: intervention 1: Lanreotide (Autogel formulation) and Temozolomide
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
IPSEN GROUP 
A-93-52030-325 
 
CONFIDENTIAL 
 
PROTOCOL: FINAL 3.0 (INCLUDING AMENDMENT #2 AND #3) 16 NOVEMBER 2017  PAGE 1/110 
 
EFFICACY AND SAFETY OF LANREOTIDE ATG 120 MG IN COMBINATION WITH 
TEMOZOLOMIDE IN SUBJECTS WITH PROGRESSIVE WELL DIFFERENTIATED 
THORACIC NEUROENDOCRINE TUMORS 
 
A phase II, multicentre, SINGLE ARM, OPEN-LABEL trial 
 
STUDY PROTOCOL 
STUDY number: A-93-52030-325 
  Lanreotide ATG120 mg/52030 
EudraCT number: 2014-005579-10 
 
Final Version 3.0 (including Amendment No. 2 and 3) 16 November 2017 
 
 
Sponsor’s Medically Responsible Person: 
 
 
  
Ipsen SpA   
 
  
Ipsen SpA 
Via del Bosco Rinnovato n. 6 
Milanofiori Nord - Palazzo U7 
20090 Assago (Mi) 
Via del Bosco Rinnovato n. 6 
Milanofiori Nord - Palazzo U7 
20090 Assago (Mi) 
Tel: 
 
Tel: 
 
Fax:     
 
Fax:     
 
 
 
Monitoring Office:   
Co-ordinating Investigator:  
 
  
Via del Bosco Rinnovato n. 6 
Milanofiori Nord - Palazzo U7 
20090 Assago (Mi) 
  
 
  
  
  
 
Tel: 
 
Fax:     
 
 
Pharmacovigilance/Emergency Contact        
 
 
  
 
            
 
 
 
 
  
 
 
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-93-52030-325 entitled “Efficacy and safety of Lanreotide 
ATG 120 mg in combination with Temozolomide in subjects with progressive well 
differentiated thoracic neuroendocrine tumors”. 
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:  
________________________ 
           SIGNATURE: _______ 
 
TITLE: 
PRINCIPAL INVESTIGATOR 
           DATE: ______________ 
 
OFFICE: 
_________________________ 
 
            _________________________ 
 
            _________________________ 
 
            _________________________ 
 
 
 
Sponsor's Representative Signature: 
 
NAME: 
  
 
                       SIGNATURE: ______________ 
 
TITLE: 
   
           DATE: ______________ 
 
  
 
 
OFFICE: 
Ipsen SpA 
 Via del Bosco Rinnovato n. 6 
 Milanofiori Nord - Palazzo U7 
 20090 Assago (Mi) 
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CONFIDENTIAL 
 
PROTOCOL: FINAL 3.0 (INCLUDING AMENDMENT #2 AND #3) 16 NOVEMBER 2017  PAGE 3/110 
 
COORDINATING INVESTIGATOR’S AGREEMENT 
 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol A-93-52030-325 entitled “Efficacy and safety of Lanreotide 
ATG 120 mg in combination with Temozolomide in subjects with progressive well 
differentiated thoracic neuroendocrine tumors”. 
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:   
                                     SIGNATURE: __________________ 
 
 
 
 
 
 
TITLE:    COORDINATING INVESTIGATOR 
           DATE: __________________ 
 
 
 
 
 
OFFICE:  
  
 
     
 
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CONFIDENTIAL 
 
PROTOCOL: FINAL 3.0 (INCLUDING AMENDMENT #2 AND #3) 16 NOVEMBER 2017  PAGE 4/110 
 
SUMMARY OF CHANGES 
 
The current version of the protocol was released on 16 November 2017 and includes 
Amendments 1, 2 and 3. The amendment forms were prepared and is provided in Appendix 4 
and Appendix 5 (Table 1). 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
19 October 2016 
Appendix 4 
2 and 3 
16 November 2017 
Appendix 5 
 


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       SYNOPSIS 
Name of sponsor/company:  Ipsen SpA 
Name of finished product: Ipstyl ATG/ Temozo-cell  
Name of active ingredient(s): Lanreotide Acetate/Temozolomide 
Title of study: Efficacy and safety of Lanreotide ATG 120 mg in combination with 
Temozolomide in subjects with progressive well differentiated thoracic neuroendocrine 
tumors 
Study number: A-93-52030-325 
Number of planned centres: 14 sites in Italy 
Planned study period: 
May 2016 – March 2019 
Phase of development: 
Phase II pilot exploratory trial  
Objectives: 
Primary Objective:  
To evaluate the efficacy of Lanreotide Autogel (ATG) 120 mg in combination with 
Temozolomide (TMZ) in subjects with unresectable advanced neuroendocrine tumours of 
the lung or thymus (typical and atypical carcinoids according to the WHO 2004 criteria) as 
Disease Control Rate (DCR) at 9 months, according to RECIST criteria v 1.1. 
Secondary Objectives: 
 To assess, according to RECIST criteria v 1.1:  
 Progression Free Survival (PFS)  
 Time to Response (TTR) 
 Duration of Response 
 Time to Progression (TTP) 
 Best Overall response:  Complete Response (CR), Partial Response (PR), Stable 
Disease (SD), Progressive Disease (PD) 
 Objective Response Rate (ORR): Complete Response (CR), Partial Response (PR) 
 Disease Control Rate (DCR): Complete Response (CR), Partial Response (PR) 
and Stable Disease (SD) at 12 months 
 The influence of typical carcinoids and atypical carcinoids on the Disease Control 
Rate (DCR) at 9 months. 
 To assess the biochemical response [Chromogranin A (CgA) plasma levels] 
 To assess neuron-specific enolase (NSE) and CgA biomarkers levels prognostic and 
predictive value 
 To assess the prognostic value of biomarkers expression (immunohistochemistry assay 
SSTR2, Ki67 and MGMT status in tissue obtained from paraffin embedded primary 
tumour surgery specimens or biopsies) for PFS, Overall Response Rate (ORR), and 
DCR 
 To assess the agreement of the central assessment of tumor radiological response and the 
local one on the DCR at 9 months 


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 To assess safety profile of Lanreotide ATG 120 mg in combination with TMZ in terms 
of AEs/SAEs, vital signs, physical examination, gallbladder evaluation, laboratory 
abnormalities and concomitant medications.   
Methodology:  
Multicenter, single arm, open label trial.  
Lanreotide ATG 120 mg in combination with TMZ 250 mg for a treatment period of 52 
weeks. 
Number of subjects planned:  
40 subjects with progressive well or moderately differentiated thoracic neuroendocrine 
tumors (lung and thymic carcinoids) 
Diagnosis and criteria for inclusion:  
Inclusion Criteria: 
 
1) Provision of written Informed Consent prior to any study related procedures; 
2) Adult subjects (male or female) ≥ 18 years old; 
3) WHO Performance status ≤ 2; 
4) Histological documented unresectable advanced (locally or metastatic) well or 
moderately differentiated neuroendocrine tumors of the lung or thymus (typical and 
atypical carcinoids according to the WHO 2004 criteria); 
5) Imaging documented progression within 12 months before screening visit (V1), 
according to RECIST criteria v 1.1; 
6) Measurable disease, as defined by RECIST criteria v 1.1, on a CT scan performed at 
screening visit (V1); 
7) Octreoscan or Ga68-DOTA-TATE/TOC/NOC-PET-TC within 12 months before 
screening visit (V1); 
8) Adequate liver, renal and bone marrow function, as defined below: 
a. Adequate bone marrow function  
Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L  
Platelets ≥ 100 × 109/L  
Hemoglobin > 9 g/dL 
b. Adequate liver function 
Total serum bilirubin ≤ 2.0 × ULN (exception for Gilbert disease)  
International Normalized Ratio (INR) < 1.5 
ALT and AST ≤ 2.5 × ULN (≤ 5 × ULN, in subjects with liver metastases) 
c. Adequate renal function 
Serum creatinine ≤ 1.5 × ULN 
9) Willing and able to comply with study restrictions and willing to return to the clinic for 
the required visits during the study period and for the follow up evaluation as specified 
in the protocol.  
10) Female subjects of childbearing potential (not surgically sterile or 2 years 


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postmenopausal) must use a medically accepted method of contraception and must 
agree to continue use of this method for the duration of the study and for 6 months 
after participation in the study. Acceptable methods of contraception include double 
barrier method [i.e. condom and occlusive cap (diaphragm or cervical/vault caps)] with 
spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, 
implanted, and injected) in conjunction with a barrier method. 
11) Male subjects with female partners of childbearing potential must use a medically 
accepted method of contraception and must agree to continue use of this method for 
the duration of the study and for 6 months after participation in the study. 
Exclusion Criteria: 
1) History of hypersensitivity to the IMPs or drugs with a similar chemical structure or 
any excipient used in the formulation. 
2) Any known contraindications to CT scan. 
3) Poorly differentiated neuroendocrine carcinoma and mixed NET tumours, according to 
WHO 2004 criteria. 
4) Neuroendocrine tumours other than lung or thymus. 
5) Non-neuroendocrine thymic neoplasm. 
6) Treated with systemic therapies (chemotherapy, interferon-alpha, somatostatin 
analogues, molecular target therapies) within 28 days prior to screening visit (V1). 
7) Treated with a number of systemic therapy lines > 3 prior to screening visit (V1), and 
any of the following: 
a. for chemotherapy no more than 1 line prior to V1;  
b. for somatostatin analogue no more than 1 line therapy, considered as treatment 
lasting more than 6 months, prior to V1;  
c. no therapy with TMZ prior to V1. 
8) Received a prior therapy with Peptide Receptor Radionuclide Therapy (PRRT) within 
6 months prior to screening visit (V1). 
9) Sign of recurrence of prior malignancies, or concomitant malignancies, or 
malignancies requiring active treatment within the last 3 years, other than the 
investigated disease, with the exception of previous basal cell skin cancer and previous 
cervical carcinoma in situ or neoplasm radically resected within 3 years prior to 
screening visit (V1). 
10) Undergone major surgery/surgical therapy for any cause within 3 months prior to 
screening visit (V1). 
11) Received external palliative radiotherapy within the last 28 days prior to screening visit 
(V1). 
12) Received locoregional therapies (TAE, TACE, TARF) and SIRT within 3 months prior 
to screening visit (V1). 
13) Presence of symptomatic brain metastasis. 
14) Unstable angina pectoris, symptomatic congestive heart failure (NYHA Class III or 
IV), serious uncontrolled cardiac arrhythmia or a history of myocardial infarction ≤ 6 
months prior to screening visit (V1). 
15) Active or uncontrolled severe infection or known history of HIV seropositivity. 
16) Previous Pneumocistis Carini Pneumonitis infection. 
17) Liver cirrhosis, chronic active or persistent hepatitis, HCV and HBV positive test in 
presence of active disease clinical evidence. 
18) Active bleeding diathesis, including abnormal coagulation (PT or APTT greater than 


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30% above ULN). 
19) Uncontrolled diabetes mellitus as defined by HbA1c ≥ 8%, despite adequate therapy. 
Subjects with history of impaired fasting glucose or diabetes mellitus (DM) may be 
included, however blood glucose and antidiabetic treatment must be monitored closely 
throughout the trial and adjusted as necessary. 
20) Subjects with symptomatic cholelithiasis at screening visit (V1). 
21) Any current or prior medical condition that may interfere with the conduct of the 
study. 
22) Hypersensitivity to dacarbazine (DTIC). 
23) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption. 
24) Treated with any other IMP within 28 days prior to screening visit (V1). 
25) Likely to require treatment during the study with drugs that are not permitted by the 
study protocol. 
26) Female subject pregnant or lactating. A pregnancy test will be performed at the start of 
the study for all female subjects of childbearing potential (i.e. not surgically sterile or 
2 years postmenopausal). 
27) Male subject who is planning a sperm donation during the entire study participation 
and at least 6 months after the last study drug administration. 
28) History of, or known current, problems with substance or alcohol abuse. 
29) Any mental condition rendering the subject unable to understand the nature, scope and 
possible consequences of the study, and/or evidence of an uncooperative attitude.  
30) Abnormal baseline findings, any other medical condition(s) or laboratory findings that, 
in the opinion of the investigator, might jeopardise the subject’s safety.  
Test product, dose, mode of administration: 
Lanreotide ATG 120 mg every 28 days, deep subcutaneous injection  
Temozolomide 250 mg, oral route, for 5 consecutive days every 28 days 
Temozolomide 180 mg, oral route, for 5 consecutive days every 28 days, in case dose 
reduction required. 
Duration of treatment: 52 weeks 
Criteria for evaluation: 
Efficacy: 
Primary Endpoint(s) and Evaluation(s):  
Response of subjects to the study combination therapy, 9 months after first treatment 
administration.  Responders are subjects showing disease control rate (DCR) according to 
RECIST criteria v 1.1, defined as objective response or stability of the disease. They 
include: CR (complete response), PR (partial response) or SD (stable disease). 
Secondary Endpoints(s) and Evaluation(s): 
• 
Progression Free Survival (PFS), defined as the time from the first 
treatment administration until progression according to RECIST criteria v 
1.1 or death from any cause 
• 
Time to Response (TTR) defined as the time from the first treatment 
administration to the first objective tumor response (PR or CR) according 
to RECIST criteria v 1.1 
• 
Duration of Response defined as the time from onset of the first objective 


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tumor response (PR or CR) to objective tumor progression (PD, according 
to RECIST criteria v 1.1) or death from any cause 
• 
Time to Progression (TTP) defined as the time from the first treatment 
administration to the first objective tumor progression (PD) observed 
according to RECIST criteria v 1.1 
• 
Best Overall response defined as the best response recorded from the time 
of the first treatment until disease progression/recurrence or the end of 
study, according to RECIST criteria v 1.1 (CR, PR, SD, PD)   
• 
Objective Response Rate (ORR) according to RECIST criteria v 1.1 (CR, 
PR) at 9 and 12 months. 
• 
Disease Control Rate (DCR) according to RECIST criteria v 1.1 (CR, PR, 
SD) at 12 months 
• 
Biochemical Response according to decrease in CgA plasma level in 
subject with baseline CgA level greater than ULN. Biochemical objective 
response is defined as a decrease of CgA ≥ 50%, while stable disease as a 
decrease ≥ 25%  and less than 50%, as their best response to study 
treatments 
• 
Value of NSE and CgA biomarkers at visits 2, 4, 6, 9, 12, 16 (EOS) 
• 
Biomarkers expression (immunohistochemistry assay SSTR2, Ki67 and 
MGMT status in tissue obtained from paraffin embedded primary tumor 
surgery specimens or biopsies) correlated to tumor response for PFS, ORR, 
and DCR at 9 and 12 months to assess their prognostic value 
• 
Central and local assessments of tumor radiological response. 
Safety: 
• 
Occurrence of adverse events (AEs) by CTCAE v 4.03 (June 14, 2010) 
from informed consent and throughout the study.  
• 
Standard haematology and biochemistry test results at each study visit. 
• 
Vital signs (assessment of blood pressure (BP), heart rate (HR) and body 
weight in kg) measurements at each study visit.  
• 
Physical examination at each study visit. 
• 
Concomitant medication usage throughout the study. 
• 
Electrocardiogram (ECG), Echocardiography at visits 1, 9 and 16. 
• 
Gallbladder Echography at Visit 1, 9 and 16. 


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Statistical Methods: 
Sample size 
Sample size and statistical assumption were made according to a Fleming’s Single Stage 
Design with the following assumptions: 
 The proportion of responders should be equal or greater than 30% to be clinically 
relevant (π1), 
 a proportion of responders equal or lower than 10% is considered as not acceptable 
(π0), 
 the 1-sided error probability is set to α = 0.025 and 
 the power is 90% (β = 0.10). 
Assuming a 10% of drop-out rate the total number of subjects to be included in the trial is 
N=40. 
Efficacy Evaluations 
The primary efficacy variable - disease control rate (DCR) according to RECIST criteria v 
1.1 - will be analysed by an exact binomial proportion tests for one-way tables. The 
statistical test on the primary objective will be performed one sided with a type I error rate 
set at 2.5%. 
Secondary endpoints to be evaluated are: 
 Tumor response according to RECIST criteria v 1.1 assessed at Visit 1, Visit 6, 
Visit 9 and Visit 12, EOS analysed using frequency tables; 
 Objective response rate according to RECIST criteria v 1.1 (CR, PR) assessed at 
Visit 1, Visit 6, Visit 9 and Visit 12, EOS analysed using frequency tables; 
 Disease Control rate according to RECIST criteria v 1.1 (CR, PR, SD) analysed 
using frequency tables; 
 
  CgA and NSE levels assessed at Visit 2, Visit 4, Visit 6, visit 9, visit 12  and EOS 
will be presented by mean values, standard deviations, minimum, maximum and 
95%-confidence intervals of the mean at each timepoint and will be analysed by 
ANCOVA for repeated measures, using baseline values as covariates; 
 
 Time to event data derived from tumor response for the endpoints Time to Response 
(TTR), Duration of Response, Time to progression (TTP) and, Progression Free 
Survival will be analysed using survival methods. The results will be presented both 
in summary tables and graphically using Kaplan-Meier plots; 
 The influence of typical carcinoids and atypical carcinoid on the Disease control 
rate (DCR) at 9 months will be analysed using frequency tables; 
 The prognostic value of NSE and CgA biomarkers at baseline on PFS will be 
analysed using a COX-proportional hazard model and the influence on ORR and 
DCR at Visit 12 and 16 will be analysed using a logistic model. 
 The prognostic value of biomarkers expression (immunohistochemistry assay 
SSTR2, Ki67 and MGMT status in tissue obtained from paraffin embedded primary 
tumour surgery specimens or biopsies) for PFS will be analysed using a COX-
proportional hazard model and the influence on DCR and ORR at Visits 12 and 16 
will be analysed using a logistic model; 
 The agreement of the central assessments of radiological response and the local one 


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will be analysed using Cohen’s kappa. 
Safety Evaluations 
Summary statistics (mean, median, SD and range as appropriate) will be presented for vital 
signs, blood pressure, heart rate, ECG parameters, clinical laboratory tests etc. 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 normal or abnormal exams. 
Adverse events reported by investigators using the NCI-CTC classification (version 4.03) 
will be coded using MedDRA dictionary (version 20.0 or higher).  
Summary incidence tables will be provided classified by body system, preferred term and 
associated NCI/CTC worst grade. In the event of multiple occurrences of the same AEs 
being reported by the same subject, the maximum intensity (Grade 5 > Grade 4 > Grade 3 > 
Grade 2 > Grade 1 > missing > not applicable) will be chosen. Dose delays, dose 
interruptions will be listed by cycle. 
Haematological and biochemistry toxicities will be recorded and graded according to the 
NCI-CTC criteria. All haematology and biochemistry parameters by subject will be listed. 
For WBC, neutrophils, platelets and haemoglobin, with associated grade 3 or 4 toxicities, 
nadir and day to nadir will be calculated. In addition, summary tables will be presented by 
maximum intensity, drug relationship and AEs/TEAEs associated with premature 
withdrawal of study medication. 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 17 
1 
BACKGROUND INFORMATION ............................................................................ 20 
1.1 
Introduction ................................................................................................................... 20 
1.2 
Name and Description of Investigational Medicinal Product(s) .............................. 23 
1.3 
Findings from Nonclinical and Clinical Studies ......................................................... 25 
1.4 
Known and potential risks and benefits to human subjects ..................................... 26 
1.5 
Selection of Investigational Medicinal Products and Dosages .................................. 30 
1.6 
Compliance Statement .................................................................................................. 31 
1.7 
Population to be Studied .............................................................................................. 31 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 32 
2.1 
Purpose of the Study ..................................................................................................... 32 
2.2 
Study Objectives ........................................................................................................... 32 
3 
STUDY DESIGN ........................................................................................................... 33 
3.1 
General Design and Study Schema ............................................................................. 33 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 34 
3.2.1 
Primary Efficacy Endpoint and Evaluation .............................................. 34 
3.2.2 
Secondary Efficacy Endpoints and Evaluations ........................................ 34 
3.2.3 
Safety Endpoints and Evaluations ............................................................. 34 
3.3 
Randomisation and Blinding ....................................................................................... 35 
3.4 
Study Treatments and Dosage ..................................................................................... 35 
3.5 
Study Duration .............................................................................................................. 36 
3.6 
Stopping Rules and Discontinuation Criteria ............................................................ 36 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability ......... 37 
3.7.1 
Investigational Medicinal Product Storage and Security .......................... 37 
3.7.2 
Investigational Medicinal Product Preparation ........................................ 37 
3.7.3 
Investigational Medicinal Product Accountability .................................... 37 
3.8 
Maintenance of Randomisation and Blinding ............................................................ 37 
3.9 
Source Data Recorded on the Case Report Form ...................................................... 37 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 39 
4.1 
Inclusion Criteria .......................................................................................................... 39 
4.2 
Exclusion Criteria ......................................................................................................... 40 
4.3 
Subject Withdrawal Criteria and Procedures ........................................................... 41 
5 
STUDY PROCEDURES .............................................................................................. 43 
5.1 
Study Schedule .............................................................................................................. 43 
Blood Biochemistry ........................................................................................................ 43 
5.2 
Study Visits .................................................................................................................... 46 
5.2.1 
Procedures for Screening and Enrolment (Visit 1) ................................... 46 
5.2.2 
Screening Visit (V1) / max -4W .................................................................. 46 


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5.2.3 
Procedures Before Study Treatment - Baseline (V2) / Day 1 .................... 47 
5.2.4 
Procedures During Study Treatment ......................................................... 47 
5.2.5 
Procedures After Study Treatment ............................................................. 51 
5.2.5.1 
End of Study Visit or Early Withdrawal Visit .............................................. 51 
6 
TREATMENT OF SUBJECTS ................................................................................... 52 
6.1 
Study Drugs Administered ........................................................................................... 52 
6.1.1 
Lanreotide ATG ........................................................................................... 52 
6.1.2 
Other Investigation Medicinal Products .................................................... 52 
6.1.3 
Other Study Drugs ...................................................................................... 53 
6.2 
Concomitant Medication/Therapy .............................................................................. 53 
6.3 
Procedures for Monitoring Subject Compliance ....................................................... 54 
7 
ASSESSMENT OF EFFICACY .................................................................................. 55 
7.1 
Primary Efficacy Endpoint and Evaluation ............................................................... 55 
7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 55 
7.3 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 56 
7.3.1 
Responder Subjects ..................................................................................... 56 
7.3.2 
WHO performance score ............................................................................ 58 
7.3.3 
Biomarkers .................................................................................................. 58 
 
 
 
 
 
 
 
 
 
8 
ASSESSMENT OF SAFETY ....................................................................................... 60 
8.1 
Adverse Events .............................................................................................................. 60 
8.1.1 
Definition of an Adverse Event .................................................................. 60 
8.1.2 
Categorisation of Adverse Events ............................................................... 60 
8.1.2.1 
Intensity Classification ................................................................................. 60 
8.1.2.2 
Causality Classification ............................................................................... 61 
8.1.2.3 
Assessment of Expectedness ......................................................................... 61 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 61 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 61 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 61 
8.1.3 
Recording and Follow up of Adverse Events ............................................. 61 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 62 
8.1.5 
Pregnancy .................................................................................................... 63 
8.1.6 
Deaths .......................................................................................................... 64 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 64 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 64 
8.2 
Clinical Laboratory Tests ............................................................................................ 64 
8.2.1 
Haematology ................................................................................................ 65 
8.2.2 
Blood Biochemistry ..................................................................................... 65 
CCI


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8.2.3 
Urinalysis ..................................................................................................... 66 
8.2.4 
Pregnancy Test ............................................................................................ 66 
8.2.5 
Other Clinical Laboratory Tests ................................................................. 66 
8.3 
Physical Examination ................................................................................................... 66 
8.4 
Vital Signs ...................................................................................................................... 66 
8.5 
Electrocardiography ..................................................................................................... 66 
8.6 
Echocardiography ......................................................................................................... 67 
8.7 
Gallbladder echography ............................................................................................... 67 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 68 
10 
STATISTICS ................................................................................................................. 69 
10.1 Analyses Populations .................................................................................................... 69 
10.1.1 
Populations Analysed .................................................................................. 69 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 69 
10.2 Sample Size Determination .......................................................................................... 69 
10.3 Significance Testing and Estimations ......................................................................... 69 
10.4 Statistical/Analytical Methods ..................................................................................... 70 
10.4.1 
Demographic and Other Baseline Characteristics .................................... 70 
10.4.2 
Homogeneity of Treatment Groups ............................................................ 70 
10.4.3 
Subject Disposition and Withdrawals ......................................................... 70 
10.4.4 
Pharmacokinetic Data ................................................................................ 70 
10.4.5 
Efficacy Evaluation ..................................................................................... 70 
10.4.6 
Adjustment for Country/Centre Effect ....................................................... 72 
10.4.7 
Safety Evaluation ........................................................................................ 72 
10.5 Subgroup Analyses ....................................................................................................... 73 
10.6 Interim Analyses ........................................................................................................... 73 
11 
ACCESS TO SOURCE DATA AND DOCUMENTS ............................................... 74 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 75 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................... 75 
12.1.1 
Protocol Amendments ................................................................................. 75 
12.1.2 
Protocol Deviations, Violations, and Exceptions ....................................... 75 
12.2 Information to Study Personnel .................................................................................. 75 
12.3 Study Monitoring .......................................................................................................... 75 
12.4 Audit and Inspection .................................................................................................... 76 
12.5 Data Quality Assurance ................................................................................................ 76 
12.6 Steering Committee ...................................................................................................... 76 
13 
ETHICS ......................................................................................................................... 78 
13.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 78 
13.2 Informed Consent ......................................................................................................... 78 
13.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 79 


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13.4 Confidentiality Regarding Study Subjects ................................................................. 79 
14 
DATA HANDLING AND RECORD KEEPING ....................................................... 80 
14.1 Data Recording of Study Data ..................................................................................... 80 
14.2 Data Management ......................................................................................................... 80 
14.3 Record Archiving and Retention ................................................................................. 81 
15 
FINANCING AND INSURANCE ............................................................................... 82 
15.1 Contractual and Financial Details ............................................................................... 82 
15.2 Insurance, Indemnity and Compensation .................................................................. 82 
16 
REPORTING AND PUBLICATIONS OF RESULTS ............................................. 83 
16.1 Publication Policy ......................................................................................................... 83 
16.2 Clinical Study Report ................................................................................................... 83 
17 
REFERENCES .............................................................................................................. 84 
18 
LIST OF APPENDICES .............................................................................................. 87 
 


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LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Histological classifications of NETs ................................................................... 21 
Table 3 
Summary of undesirable effects reported by subjects treated with 
Lanreotide ............................................................................................................ 28 
Table 4 
Summary of events reported with Temozolomide in the post-marketing 
setting .................................................................................................................... 30 
Table 5 
Blood Volume Calculation .................................................................................. 43 
Table 6 
Study Procedures and Assessments ................................................................... 44 
Table 7 
Dose adaptation of TMZ ..................................................................................... 53 
Table 8 
Secondary Efficacy Endpoints and Evaluations ............................................... 56 
Table 9 
Best Overall Response ......................................................................................... 58 
Table 10 
Censoring Rules for PFS ..................................................................................... 71 
Table 11 
Censoring Rules for TTR .................................................................................... 71 
Table 12 
Censoring Rules for TTP .................................................................................... 72 
 
LIST OF FIGURES 
Figure 1 
Lanreotide structural formula ........................................................................... 24 
Figure 2 
Temozolomide structure ..................................................................................... 25 
Figure 3 
Study Design ........................................................................................................ 33 
Figure 4 
Cockcroft-Gault Equation .................................................................................. 66 
  


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LIST OF ABBREVIATIONS 
βHCG 
Beta human chorionic gonadotropin 
AC 
AE 
Atypical Carcinoids 
Adverse Event/Experience 
ALT 
Alanine aminotransferase 
ANC 
ANCOVA 
Absolute Neutrophil Count 
Analysis of covariance 
aPTT 
AST 
activated partial thromboplastin time  
Aspartate aminotransferase 
ATC  
ATG 
Anatomical Therapeutic Chemical 
Autogel 
BMI 
Body mass index 
bpm 
Beats per minute 
CA 
Competent Authorities 
CgA  
Chromogranin A 
CR 
CrCl 
Complete Response 
Creatinine Clearance 
CRF 
Case Report Form 
CRO 
CSR 
Contract research organisation 
Clinical Study Report 
CT 
Computed tomography 
CTSU 
Clinical Trial Supplies Unit (relates to sponsor) 
DCR 
DEA 
Disease Control Rate 
Drug Enforcement Administration 
ECG 
ED 
Electrocardiogram 
Early death 
EDC 
Electronic data capture 
eCRF 
EOS 
Electronic case report form 
End of Study 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
EW 
Early Withdrawal 
FDA 
Food and Drug Administration 
GCP 
GEP_NET 
GH 
Good Clinical Practice 
GastroEnteroPancreatic Neuroendocrine Tumors 
Growth Hormone 


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GMP 
Good Manufacturing Practice 
HbA1c 
Glycated Haemoglobin 
HBV 
HCV 
HIV 
HR 
hepatitis B virus 
hepatitis C virus 
Human immunodeficiency virus 
Heart Rate 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational Medicinal Product 
IND 
INR 
Investigational New Drug 
International Normalized Ratio  
IRB 
Institutional review board 
ITT 
Intent to treat 
IUD 
Intrauterine device 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
O6-methylguanine-DNA methyltransferase 
MRI 
Magnetic resonance imaging 
NANETS 
NCI-CTC 
NSE 
North America Neuro Endocrine Tumors Society 
National Cancer Institute – Common Toxicity Criteria 
Neuron-Specific Enolase  
ORR  
Objective Response Rate 
PCP 
Pneumocystis jirovecii pneumonia  
PD 
PDD 
PFS 
Partial Disease 
Protocol Deviation Document 
Progression Free Survival 
PI  
PP  
PR 
PRRT 
PT 
Package Insert  
Per Protocol 
Partial Response 
Peptide Receptor Radionuclide Therapy 
Prothrombin Time  
RBC 
Red Blood Cell(s) 
RT 
Radio Therapy 
SAE 
SAP 
Serious adverse event 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System® 


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s.c. 
SCLC 
Subcutaneous 
Small cell lung carcinoma 
SD 
Std 
Stable Disease 
Standard deviation 
SDV 
Source document verification 
SEER 
SIRT 
Surveillance Epidemiology and End Results 
Selective internal radiotherapy   
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SSA 
SST 
SSTR 
T3 
T4 
TACE 
TAE 
TARF 
TC 
somatostatin analogues 
somatostatin  
human somatostatin receptors  
Triiodothyronine  
Thyroxine 
Transcatheter arterial chemoembolization 
Transcarterial emoembolization 
thermo-ablation with radio-frequency 
Typical Carcinoids 
TEAE 
TFLs 
Treatment emergent adverse event 
Tables, Figures and Listings  
TMF 
TMZ 
TNM 
T-NET 
TSH 
TTP 
TTR 
Trial master file 
Temozolomide 
Tumor Node Metastasis 
Thoracic Neuroendocrine Tumors 
Thyroid Stimulating Hormone 
Time To Progression 
Time To Response 
UDS 
US 
Urine drug screen 
United States 
VEGF 
Vascular endothelial factor 
WBC 
White blood cell(s) 
WHO 
World Health Organisation 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
In the Western World, thoracic neuroendocrine tumours are one of the most frequent type of 
neoplasm of neuroendocrine origin.  
Well differentiated thoracic neuroendocrine (T-NET) tumours (bronchial and thymic 
carcinoid, according to the WHO 2004 Classification) represent the 25-30% of NETs, with 
the remaining part of 75% represented by NETs from the gastroenteropancreatic tract.   
Furthermore according to all the published data [1, 2, 3], they constitute the subgroup of 
NETs with the most relevant increase of incidence in the last 2 decades. 
NETs incidence and prevalence increase may be partly due to the improved understanding 
and recognition of these tumours, but maybe also to an actual rise in the number of cases. 
Data from the US Surveillance Epidemiology and End Results (SEER) database, shows an 
estimated incidence of thoracic NETs of 1.37/100,000 inhabitants per year, where 1.35 is the 
contribute of bronchial NETs and 0.02 of thymic NETs, compared to about 2.5-5 cases per 
100,000 reported for gastroenteropancreatic neuroendocrine tumors (GEP NETs) [4]. Among 
lung NETs, the epidemiology varies greatly between well-differentiated and poorly 
differentiated forms. The well differentiated forms, typical carcinoids (TC) and atypical 
carcinoids (AC), which represent a very small proportion of lung cancers, show a prevalence 
of about 1-2% and the atypical forms have a prevalence of 0.1-0.2% [5, 6]. Thymic NETs 
show an incidence < 1 case /100,000 inhabitants per year and represent 2-5% of all thymic 
tumors and 2% of mediastinic tumors [2, 7, 8]. 
Median age of subjects affected by bronchial NET and thymic NET is 64 and 59 years, 
respectively. 
The increased incidence has not been matched by an improvement in outcome, in fact data 
from the US SEER database reported no substantial change in 5-year survival for the period 
1973-2002. NETs Survival rates vary according to disease stages, and even grade 1 and grade 
2 NETs have the potential to metastasize to distant sites, negatively impacting subject 
prognosis. Long term data from NCI SEER database (1973-2004) show that the median 
survival for subjects with well differentiated NETs with metastases is 33 months and 65% of 
these subjects die within 5 years [5].  
The current classification of lung NET is based on WHO 2004 classification, with the 
distinction of four different histological subtypes: TC, AC, large-cell neuroendocrine 
carcinoma (LCNEC) and small-cell lung carcinoma (SCLC). This classification is based on 
the morphological characteristics of the tumour combined with the mitotic rate and the 
presence or absence of necrosis [4]. Recently it has been proposed a grading of NETs based 
on the information given by Ki-67 and necrosis  and mitotic counts with the identification of 
three different grades of disease (G1, G2, G3) with different prognosis, as a result of 
combining the WHO 2004, ENETS/WHO 2010 (GI NET) [9], ESMO 2012 [6] and ENETS 
2015 [10] (see Table 2). According to WHO 2004, in Europe the current classification for 
thoracic NET differentiate three categories: well-differentiated and poorly differentiated 
(either low and intermediate grade or carcinoids tumours respectively TC and AC) and high 
grade NEC (LCNEC and SCLC). 
In the latest review of Pelosi et al 2014 [11], the Ki-67 was detected as an interesting marker 
in lung NE tumours as prognostic criteria and the publication of Rindi et al 2013 [12] shows 
that the Ki-67 index has a prognostic significance and it is useful in grading of lung 
neuroendocrine tumours, in lung NETs, to be used in combination with mitotic count and 


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necrosis. To make the three-tiers grading system effective, they were identified site specific 
cut-offs of Ki-67 and mitotic count for lung NETs, since more large studies have to be 
conduct to validate it. 
The staging of T-NETs follows the TNM (Tumor-Node-Metastasis) staging system and 
biochemical evaluation include Chromogranin A, plasma NSE and other biomarkers specific 
for symptoms of carcinoids syndrome.  
Among the well differentiated T-NETs, the TCs show a good prognosis with a 5-years 
survival of 87-90%, but the ESMO guidelines recommend a follow up to 15 years, in fact it 
has been observed that distant metastases may develop from TCs many years after radical 
resection of primary tumour. ACs are associated with a poorer prognosis and the 5-year 
survival rate is of 44-78% [4]. 
Due to the aggressive behaviour of thymic NETs, which show a high incidence of recurrence 
after surgery, the prognosis for subjects affected by primary thymic NETs is poor: while low-
grade thymic NETs present a 5-year survival of 50%, the high grade thymic NETs have a 5-
years survival of about 0% [4]. 
NETs are tumours that develop from glands, islets or endocrine cells of various origin present 
in several districts of the organism. By their nature, NETs are sensitive to the action of 
somatostatin (SST) hormone present in all districts of the human body and which binds to 
specific receptors (SSTRs) present in the outer membrane of the endocrine cells. Its action is 
expressed by inhibiting some cellular functions, such as motility, proliferation and secretion 
of various hormones, including growth hormone and other hormones in the gastrointestinal 
tract. Somatostatin analogues (SSA) have a cytostatic and cytotoxic (pro-apoptotic) effect on 
tumour cells and they have been used in the treatment of NETs for many years, with the aim 
of inhibit tumour progression in advanced disease [13, 14].  
 
Table 2 
Histological classifications of NETs 
Differentiation 
Traditional 
Nomenclature 
Grade 
Mitotic 
Counta 
Mitotic 
Countb 
(10 
HPF)c 
Necrosisd 
Necrosisb 
(%) 
Ki-67 
index 
(%) (P-
NET)d 
Ki-67 
index 
(%)  
T-NETb 
Well 
differentiated 
Typical 
Carcinoids 
Low Grade 
(G1) 
<2/10 
HPF 
2 
Absent 
Absent 
≤2 
<4 
Moderately 
differentiated 
Atypical 
Carcinoids 
Intermediate 
Grade (G2) 
2-9/10 
HPF 
>2-47 
Present 
(focal) 
Focal 
(<10% of 
sample) 
3-20 
4<25 
Poorly 
differentiatied 
SCLC 
LCNEC 
High Grade 
(G3) 
>9/10 
HPF 
>47 
Present    
(extensive) 
Diffuse 
(>10% of 
sample) 
>20 
≥25 
a 
    ESMO Guidelines 2012  
b 
Rindi et al 2013 
c 
10 HPF, ten high-power field=2 mm2, to be assessed in at least 50 fields at 40x I areas of highest mitotic density 
d 
ENETS 2015  
 
Lanreotide ATG, a somatostatin analogue (SSA), in Italy is currently approved for the 
treatment of symptoms associated with neuroendocrine tumours; recently it has been 
approved in the United States (US) for antitumor effect (for unresectable, well-or moderately-
differentiated, locally advanced or metastatic GEP-NETs to improve progession-free survival, 
and submitted in European Union (EU) for the treatment of NETs including tumour control 
[for both grade 1 and grade 2 (Ki67 up to 10%) GEP-NETs in adult patients with unresectable 
locally advanced or metastatic disease], but the implementation of the indication at country 


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level in EU is ongoing. This new indication was approved in the US and EU based on the 
results from the CLARINET [15] study, a 96-week, randomised, double-blind, placebo-
controlled, parallel group, multicountry study of Lanreotide ATG at a dose of 120 mg 
compared with placebo. The study demonstrated that Lanreotide ATG 120 mg produces a risk 
reduction of 53% for progression or death in 204 subjects with Ki-67 <10% and well- or 
moderately-differentiated GEP-NETs. Thus Lanreotide ATG has an anti-tumour effect in 
G1/low G2 GEP-NET, significantly prolonging progression-free survival (PFS) over 2 years 
months compared with placebo (HR 0.47; p=0.0002). 
Despite CLARINET data and despite the most recent ENETS guidelines pointed out that the 
primary aims of the medical therapy of T-NET are the control of hormone related symptoms 
and the tumour growth, data currently available on the application of SSA in T-NETs comes 
from subgroup analysis of  larger controlled randomized trials, such as RADIANT-2 [16], and 
from small groups of subjects evaluated in retrospective analysis and single centers 
experiences [17, 18, 19].  
Temozolomide (TMZ) is an alkylating agent and by methylating DNA inhibites DNA and 
cellular replication. It’s approved for use in the first-line treatment of glioblastoma 
multiforme.  In Italy according to 648 law for the extension of the indication, TMZ can be 
used in endocrine advanced carcinoma.  
The latest ENETS Guidelines indicated TMZ as palliative treatments in pulmonary 
carcinomas because the acceptable safety profile and as it is the most studied in the lung NET. 
To date, only few retrospective studies evaluating the efficacy of therapy with TMZ in NETs 
have been published. TMZ in monotherapy has been proved to be efficacious in a series of 36 
subjects leading to a tumor regression in 31% of bronchial carcinoid tumors and in 8% of 
pancreatic neuroendocrine tumors [20]. The association of TMZ with capecitabine seems to 
increase the percentage of responders in pancreatic NETs [21]. On the other hand, the 
combination of TMZ with thalidomide or bevacizumab seems to add significant toxicities, 
with some increase of response in pancreatic NETs, but not impacting in carcinoids [22, 23, 
24].The overall response (stable disease plus partial response) ranged in the published series 
between 40 and 70%. 
According to literature TMZ has been used alone or in combination with capecitabine or 
bevacizumab in well-differentiated neuroendocrine carcinoma, resulting in high response 
rates [20, 24]. In a previous paper a subject with poorly differentiated endocrine carcinoma 
(PDEC) has been described to be responder to TMZ treatment [25]. 
In a recent published study [26] the median of the progression free survival, in 31 subjects 
with bronchial carcinoid treated with TMZ, was 5.3 months.  
A recent study evaluating the combination of TMZ with bevacizumab and octreotide 
demonstrated a good activity in advanced G2 NETs [27].  
Some studies investigating SSAs treatment in T-NETs are currently ongoing: LUNA [28] and 
COOPERATE-II trials [29]. 
ESMO, NANETS and the most recent AIOM guidelines have underlined how the role of SSA 
and TMZ in T-NETs may be similar to GEP NET both in functioning and non-functioning 
carcinoids [4, 6, 7, 9]. 
Combining the properties of Lanreotide and of TMZ can be a rational treatment strategy to 
inhibit the tumour growth by multiple pathways. Furthermore the safety profile of both drugs 
is well known and the combination should not worsen the safety profile of the individual 
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The SONNET study is a German multicentre open-label study evaluating the efficacy of the 
combination of Lanreotide ATG 120 mg and TMZ in subjects with progressive GEP-NET 
G1/G2. It is on-going and no data are yet available [30]. 
To reinforce the SONNET objective and to investigate further Lanreotide ATG 120 mg plus 
TMZ combination, the ATLANT study will evaluate the efficacy of the combination of 
Lanreotide ATG 120 mg and TMZ in subjects with progressive thoracic neuroendocrine 
tumors, typical and atypical carcinoids and thymus, according to WHO 2004 classification. 
The primary objective of the ATLANT study is the evaluation of efficacy of Lanreotide ATG 
120 mg plus TMZ combination in patients with T-NETs (typical and atypical carcinoids and 
thymus) as DCR at 9 months, according to RECIST criteria vs 1.1. There is not enough data 
on both SSA and TMZ in monotherapy to estimate the time to progression (progression-free 
survival) for the combination treatment.  
The only data for SSA in Midgut and Bronchopulmonary-NET comes from RADIANT-2 
trial, where patients with advanced carcinoid tumor Received Octreotide Depot and 
Everolimus 10 mg/Day or Octreotide Depot and Placebo [16].  Limitation from this trial are 
the differences between central and local radiological review and the huge differences in the 
subgroups, thus not providing reliable PFS values (Total population: Central review 11 
months, Local review 8.6 months; subgroup analysis: Midgut NET 14 months).  
Available data on monotherapy with TMZ comes only from one retrospective trial in 
advanced neuroendocrine tumors (pNET n=12; CR=0, PR=8%, SD=67%, PD=25%) [20].  
Other available data for TMZ comes from combination studies (TMZ + Thalidomide [22]: 
pNET ORR 45%, Carcinoids ORR 7%; TMZ + Bevacizumab [27]: pNET 33%, Carcinoids 
0%; TMZ + Capecitabine [21]: pNET PR 70%, SD 27%). 
The primary endpoint to assess the efficacy of the combination treatment is the Disease 
Control Rate (DCR), according to statistic methodology for a single arm phase II trial [31], 
such as ATLANT study. 
According to those evidences it is suggested to choose “Disease Control Rate” (CR+PR+SD) 
as primary endpoint to evaluate the efficacy of the combination of Lanreotide ATG 120 mg 
and TMZ. Progression free survival and additional response parameters are addressed in this 
pilot exploratory study as secondary endpoints, and could be possible primary endpoints for a 
consecutive trial.  
The sensitivity of tumor cells to alkylating agents, including TMZ, has been associated with 
decreased levels of the DNA repair enzyme, O6-methylguanine DNA methyltransferase 
(MGMT), which, through its ability to restore DNA to its normal form, can prevent 
chemotherapy-induced cell death. Among subjects with either advanced melanoma or 
glioblastoma treated with TMZ, loss of tumoral MGMT expression was associated with an 
improvement in survival. The correlation was not confirmed in all the tumor models, 
including pituitary aggressive tumors treated with TMZ [32, 33, 34, 35]. So since 
O6-methylguanine DNA methyltransferase (MGMT) expression in NETs could be helpful to 
select responders to TMZ treatment, in this study one of the secondary objectives is the 
assessment of the prognostic value of this biomarker expression. 
1.2 
 Name and Description of Investigational Medicinal Product(s) 
The Study Protocol foresees the combination of two Investigational Medicinal Product(s) 
(IMPs), Lanreotide ATG and Temozolomide. 
Lanreotide is an octapeptide analogue of natural somatostatin. Its structural formula is shown 
in Figure 1. 


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Figure 1 Lanreotide structural formula 
 
The mechanism of action of Lanreotide is believed to be similar to that of natural 
somatostatin. Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 
and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR 2 and 5 is 
the primary mechanism believed responsible for GH (Growth Hormone) inhibition. Like 
somatostatin, Lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and 
paracrine functions. 
Lanreotide is approved for the long term treatment of subjects with acromegaly when the 
circulating levels of GH and /or Insulin-like Growth Factor remain abnormal after surgery 
and/or radiotherapy, or in subjects who otherwise required medical treatment.  
Lanreotide ATG in Italy is currently approved for the treatment of symptoms associated with 
neuroendocrine tumours; based on the results from CLARINET study [15] it has been 
recently approved in US and EU for the treatment of NETs including tumour control, but the 
implementation of the indication at a country level in EU is ongoing. 
The chemical name of Temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-
tetrazine-8-carboxamide. The structural formula is shown in Figure 2.  


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Figure 2 Temozolomide structure 
 
 
TMZ is not directly active but undergoes rapid non-enzymatic conversion at physiologic pH 
to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The 
cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation 
(methylation) occurs mainly at the O6 and N7 positions of guanine.  
TMZ is indicated for the treatment of adult subjects with newly-diagnosed glioblastoma 
multiforme concomitantly with radiotherapy (RT) and subsequently as monotherapy 
treatment; children from the age of three years, adolescents and adult subjects with malignant 
glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or 
progression after standard therapy. 
A more detailed description of the products is given in Section 3.4. 
1.3 
Findings from Nonclinical and Clinical Studies 
NETs are highly vascularized tumours which overexpress angiogenic factors.  
Angiogenesis is a topic mechanism on the tumour growth and its inhibition is a common anti-
tumour process targeted by most of chemotherapeutic drugs, such as TMZ, methotrexate, 
paclitaxel, vinblastine, bevacizumab and doxorubicin, either directly or indirectly by the 
inhibition of cell proliferation, migration and blood vessel formation.  
SST and SSA seem to inhibit the production and secretion of several angiogenic factors, such 
as the vascular endothelial growth factor (VEGF), with the result of tumours growth reduction 
[13]. 
Studies on TMZ, administered at metronomic doses, enhances the inhibition of angiogenesis 
accompanied by the down-regulation of MGMT expression in endothelial cells [36, 37]. 
Combine the properties of Lanreotide to decrease levels of angiogenic factors and enhanced 
apoptosis, and of TMZ, an alkylating agent, can be a rational treatment strategy to inhibit by 
multiple pathways, the angiogenesis [14].  
It is estimated that the combination of these different mechanisms of anti-tumour activity 
could be supportive or even additive given the high expression of SSTR on NET. 
A paper with the practical clinical recommendation from the principal European expert, 
collected during a meeting held in Perugia, recommended the association of TMZ or 
everolimus, according to the availability in the country, in subjects with T-NETs who develop 
progressive disease in the course of SSA [9]. The latest ENETS recommendations reinforce 
the use of SSA and TMZ in T-NETs [10, 38].  
Current data available on the application of SSA in T-NETs comes from subgroup analysis of 
larger controlled randomized trials, such as RADIANT-2 [16], and from small groups of 
subjects evaluated in retrospective analysis and single centers experiences [17, 18, 19].  
TMZ has been used alone or in combination with capecitabine or bevacizumab in well-
differentiated neuroendocrine carcinoma, resulting in high response rates [20, 24]. In a 


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previous paper a subject with poorly differentiated endocrine carcinoma (PDEC) has been 
described to be responder to TMZ treatment [25]. 
The sensitivity of tumor cells to alkylating agents, including TMZ, has been associated with 
decreased levels of the DNA repair enzyme, O6-methylguanine DNA methyltransferase 
(MGMT), which, through its ability to restore DNA to its normal form, can prevent 
chemotherapy-induced cell death. Among subjects with either advanced melanoma or 
glioblastoma treated with TMZ, loss of tumoral MGMT expression was associated with an 
improvement in survival. The correlation was not confirmed in all the tumor models, 
including pituitary aggressive tumors treated with TMZ. These discrepancies ingenerated 
discussion on the ideal method to evaluate the activity of the enzyme, so at the moment 
appear more appropriate to evaluate the correlation with the enzymatic activity in “a 
posteriori” subgroup analysis [32, 33, 34, 35]. 
To date, only few retrospective studies evaluating the efficacy of therapy with TMZ in NETs 
have been published. TMZ in monotherapy has been proved to be efficacious in a series of 36 
subjects leading to a tumor regression in 31% of bronchial carcinoid tumors and in 8% of 
pancreatic neuroendocrine tumors [20]. The association of TMZ with capecitabine seems to 
increase the percentage of responders in pancreatic NETs [21]. On the other hand, the 
association with thalidomide or bevacizumab seems to add significant toxicities, with some 
increase of response in pancreatic NETs, but not impacting in carcinoids [22, 23, 24]. 
The overall response (stable disease plus partial response) ranged in the published series 
between 40 and 70%. 
To date, no studies have been published on the association with SSA alone. A recent study 
evaluating the combination of TMZ with bevacizumab and octreotide demonstrated a good 
activity in advanced G2 NETs [27].  
In a recent published study [26] the median of the progression free survival, in 31 subjects 
with bronchial carcinoid treated with TMZ, was 5.3 months.  
Other international studies investigating SSAs in thoracic NETs populations are ongoing. 
LUNA trial is a prospective, multicenter, randomized, open-label, 3-arm, phase II study with 
a single-stage design in each arm. The purpose of this study is to test the effectiveness and 
safety of Everolimus or Pasireotide LAR alone or in combination in adult subjects with 
advanced (unresectable or metastatic) neuroendocrine carcinoma (typical and atypical) of the 
lung and thymus [28].  
COOPERATE-1 is a phase I trial with the purpose to assess the safety and tolerability of 
pasireotide 
LAR 
in 
combination 
with 
everolimus 
in 
advanced 
metastatic 
gastroenteropancreatic or pulmonary neuroendocrine Tumors (NET). Two arms are planned 
with Pasireotide LAR followed by Pasireotide LAR + Everolimus versus Everolimus 
followed by Pasireotide LAR + Everolimus [29]. 
1.4 
Known and potential risks and benefits to human subjects 
During clinical studies in subjects affected by NET, Lanreotide ATG was well tolerated. 
Lanreotide ATG may reduce gallbladder motility and lead gallstone formation, therefore 
subjects may need to be monitored periodically. 
Lanreotide, like somatostatin and other somatostatin analogues, inhibits secretion of insulin 
and glucagon. Hence, patients treated with Lanreotide may experience hypoglycaemia or 
hyperglycaemia. Blood glucose levels should be monitored when Lanreotide treatment is 
initiated, or when the dose is altered and any anti-diabetic treatment should be adjusted 
accordingly. 


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Slight decreases in thyroid function have been seen during treatment with Lanreotide in 
patients with acromegaly, although clinical hypothyroidism is rare (<1%). Tests of thyroid 
function should be done where clinically indicated. 
In patients without underlying cardiac problems, Lanreotide may lead to a decrease of heart 
rate without necessarily reaching the threshold of bradycardia. In patients suffering from 
cardiac disorders prior to Lanreotide treatment, sinus bradycardia may occur. Care should be 
taken when initiating treatment with Lanreotide in patients with bradycardia. 
The pharmacological gastrointestinal effects of Lanreotide ATG may reduce the intestinal 
absorption of co-administered drugs including ciclosporin and therefore may necessitate the 
adjustment of its dose to maintain therapeutic levels. 
Interactions with highly plasma bound drugs are unlikely in view of the moderate binding of 
Lanreotide ATG to serum proteins. Limited published data indicate that concomitant 
administration of somatostatin analogues and bromocriptine may increase the availability of 
bromocriptine. 
Concomitant administration of bradycardia-inducing drugs (e.g. beta blockers) may have an 
additive effect on the slight reduction of heart rate associated with Lanreotide ATG. Dose 
adjustments of such concomitant medications may be necessary. 
The limited published data available indicate that somatostatin analogues may decrease the 
metabolic clearance of compounds known to be metabolised by Cytochrome P450 enzymes, 
which may be due to the suppression of growth hormone. Since it cannot be excluded that 
Lanreotide ATG may have this effect, other drugs mainly metabolized by CYP3A4 and which 
have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with 
caution. 
The most commonly expected AE reactions following treatment with Lanreotide are: 
gastrointestinal disorders (most commonly reported are diarrhoea and abdominal pain, usually 
mild or moderate and transient), cholelitiasis (often asymptomatic) and injection site reactions 
(pain, nodules and indurations).  
The following adverse reactions occurred in subjects suffering from acromegaly and treated in 
clinical trials with Lanreotide are listed in (see Table 3). 
Safety profile is similar for other indication. 
Post-marketing Adverse Drug Reactions include pancreatitis and allergic reactions (including 
angioedema, anaphylaxis, hypersensitivity). 
Additional information regarding risks and benefits to human subjects may be found in the 
SmPC (version updated on February 2015). 


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  Table 3 Summary of undesirable effects reported by subjects treated with Lanreotide 
Blood system disorders  
Common (> 1/100-> 1/10) ALAT 
increased/abnormal, 
ASAT 
abnormal, 
blood 
bilirubin 
increased, blood glucose increased, Glycosylated Haemoglobin 
increased, weight decreased 
Uncommon (> 1/1000-> 1/100) ASAT increased, Blood alkaline phosphatase increased, blood 
bilirubin abnormal, blood sodium decreased 
Cardiac Disorders 
Common (> 1/100-> 1/10) Sinus Bradycardia 
Nervous System Disorders  
Common (> 1/100-> 1/10) Dizziness, headache  
Gastrointestinal disorders  
Very Common (> 1/10) Diarrhoea, loose stools, abdominal pain 
Common (> 1/100-> 1/10) Nausea, vomiting, constipation, flatulence, abdominal distension, 
abdominal discomfort, dyspepsia 
Uncommon (> 1/1000-> 1/100) Faeces discoloured 
Skin and subcutaneous tissue disorders 
Common (> 1/100-> 1/10) Alopecia, hypotrichosis 
Metabolism and nutrition disorders 
Common (> 1/100-> 1/10) Hypoglycaemia 
Uncommon (> 1/1000-> 1/100) Diabetes Mellitus, hyperglycaemia 
Vascular disorders 
Uncommon (> 1/1000-> 1/100) Hot flush 
General disorders and administration site conditions 
Common (> 1/100-> 1/10) Fatigue, injection site reactions (pain, mass, induration, 
nodule, pruritus) 
Uncommon (> 1/1000-> 1/100) Asthenia 
Hepatobiliary system disorders 
Very Common (> 1/10) Cholelithiasis 
Common (> 1/100-> 1/10) Biliary dilatation 
Psychiatric disorders 
 
Uncommon (> 1/1000-> 1/100) Insomnia 
 
Regarding TMZ, when is administered during a longer dosing regimen there may be a higher 
occurrence of Pneumocystis jirovecii pneumonia (PCP). However, all subjects receiving 
TMZ, particularly subjects receiving steroids, should be observed closely for the development 
of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in 
subjects using TMZ, in particular in combination with dexamethasone or other steroids. 
Hepatic injury, including fatal hepatic failure, has been reported in subjects treated with TMZ. 
Baseline liver function tests should be performed prior to treatment initiation. For all subjects, 
liver function tests should be checked after each treatment cycle. For subjects with significant 
liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. 
Liver toxicity may occur several weeks or more after the last treatment with TMZ. 


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Cases of myelodysplastic syndrome and secondary malignancies, including myeloid 
leukaemia, have also been reported very rarely. 
Nausea and vomiting are very commonly associated with TMZ. Anti-emetic therapy may be 
administered prior to or following administration of TMZ. 
Subjects treated with TMZ may experience myelosuppression, including prolonged 
pancytopenia, which may result in aplastic anaemia, which in some cases has resulted in a 
fatal outcome. In some cases, exposure to concomitant medicinal products associated with 
aplastic anaemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, 
complicates assessment.  
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor 
antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with 
valproic acid was associated with a small but statistically significant decrease in clearance of 
TMZ. 
No studies have been conducted to determine the effect of TMZ on the metabolism or 
elimination of other medicinal products. However, since TMZ does not undergo hepatic 
metabolism and exhibits low protein binding, it is unlikely that it would affect the 
pharmacokinetics of other medicinal products. 
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood 
of myelosuppression. 
In patients treated with TMZ in a clinical study setting, whether used in combination with RT 
or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as 
monotherapy in patients with recurrent or progressive glioma, the reported very common 
adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and 
fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma 
multiforme patients receiving monotherapy, and rash was reported very commonly in newly-
diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as 
monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions 
(including neutropenia, lymphopenia, thrombocytopenia, leucopenia, anaemia) were reported 
commonly or very commonly in both indications.  
Additional serious adverse reactions, that have been identified during post-marketing 
exposure, are reported in Table 4.  
Additional information regarding risks and benefits to human subjects may be found in the 
SmPC (version updated on February 2015). 


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Table 4 
Summary of events reported with Temozolomide in the post-marketing setting 
Blood and lymphatic system disorders 
Very rare: prolonged pancytopenia, aplastic anaemia[a] 
Neoplasm benign, malignant and unspecified  
Very rare: myelodysplastic syndrome (MDS), secondary malignancies, including myeloid 
leukaemia  
Respiratory, thoracic and mediastinal disorders  
Very rare: interstitial pneumonitis/pneumonitis, pulmonary fibrosis, respiratory failure[a] 
Hepatobiliary disorders[b] 
Common: liver enzymes elevations  
Uncommon: hyperbilirubinemia, cholestasis, hepatitis, hepatic injury, hepatic failure† 
Skin and subcutaneous tissue disorders  
Very rare: toxic epidermal necrolysis, Stevens-Johnson syndrome  
a 
Including cases with fatal outcome 
b 
Frequencies estimated based on relevant clinical trials 
 
The safety profile of Lanreotide ATG and TMZ is well established; an increase in AEs due to 
the combination of both substances is not expected. Combining the properties of Lanreotide 
and of TMZ can be a rational treatment strategy to inhibit the tumour growth by multiple 
pathways.  
For this reason, ATLANT study will evaluate the efficacy of the combination of Lanreotide 
ATG 120 mg and TMZ in subjects with progressive thoracic neuroendocrine tumors, typical 
and atypical carcinoids and thymus, according to WHO 2004 classification. 
1.5 
 Selection of Investigational Medicinal Products and Dosages 
The Study will evaluate the combination of two IMPs, Lanreotide ATG and TMZ.  
Lanreotide dosage to be evaluated in this open label study was selected on the basis of the 
usual dosage in NET treatment: the usual clinical dosing regimen of Lanreotide ATG in NETs 
is 120 mg, deep s.c. injection every 28 days. In the recently published CLARINET clinical 
trial [15], it has been demonstrated the safety and efficacy of this dosing regimen in the 
control of tumour growth in gastroenteropancreatic NETs. 
Lanreotide ATG is a controlled release preparation of Lanreotide acetate and water for 
injection which together form  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.  
For what regards TMZ, according to the monotherapy administration of the drug as described 
in the SmPC, starting dose should be 150 mg/m2/day for 5 consecutive days followed by 23 
days free of treatment. At the beginning of the second cycle of therapy, dosage can be 
increased to 200 mg/m2/day, if non-haematological toxicity in the first cycle of therapy was 
Grade ≤ 2 (with the exception for alopecia, nausea and vomiting), ANC ≥ 1.5 x 109/L and 
thrombocyte count is ≥ 100 x 109/L. Dosage after second cycle remains fix apart for toxicity 
which can require dose reduction to 100 mg/m2/day (same schedule) due to Grade 3 non-
haematological toxicity or ANC < 1.0 x 109/L and/or platelets count < 50 x 109/L. TMZ 
administration should stop if persistent haematological toxicity, or Grade 4 non-
haematological, is registered. 


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In our protocol, based on clinical trials and experts clinical experience [20, 26] a starting dose 
of 250 mg x day for 5 consecutive days followed by 23 days free of treatment (corresponding 
to SmPC starting dosage of 150 mg/m2, but considering a total adult body surface of 1.73 m2, 
man of about 70 kg weight) is considered well tolerated and efficacious. The first intake will 
start the same day of the administration of Lanreotide ATG 120 mg and will continue for the 
next 4 days (5 days of treatment in total). This treatment schedule will be administered for a 
maximum of 12 months. This initial dose can be continued until disease progression/death or 
toxicity. In case of toxicity TMZ dose reduction must be considered, when ANC falls to < 1.0 
x 109/L or platelet count is < 50 x 109/L during any cycle. In this case TMZ dose will be 
reduced  to 180 mg per day, equivalent to 100 mg/m2, considering the total standard adult 
body surface of 1.73 m2 (man of about 70 kg of weight). If dose is reduced subject should 
remain on the reduced dose level for the rest of the study. Up titration dose is not allowed. If 
at any study visit, at dosing before treatment cycle administration, haematology results 1.0 < 
ANC < 1.5 x 109/L and/or 50<platelet count<100 x 109/L therapy must be postponed by 1 
week and haematological test repeated. If  the repeated test show ANC ≥ 1.5 x 109/L and 
platelets count ≥ 100 x 109/L therapy may recommends, if not weekly testing must be 
performed up to the third week after last TMZ administration. If haematological levels remain 
low, the subject must be withdrawn. 
There are no dietary restrictions with TMZ. To reduce nausea and vomiting, TMZ should be 
taken on an empty stomach. Bedtime administration may be advised. Antiemetic therapy may 
be administered prior to and/or following administration of TMZ. Capsules should not be 
opened or chewed. They should be swallowed whole with a glass of water. If capsules are 
accidentally opened or damaged, precautions should be taken to avoid inhalation or contact 
with the skin or mucous membranes. 
A more detailed description of administration procedures is given in Section 6.1.  
1.6 
Compliance Statement 
The study will be conducted in compliance with independent ethics committees/institutional 
review boards (IECs/IRBs), informed consent regulations, the Declaration of Helsinki and 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines 
[39]. Any episode of noncompliance will be documented. 
Considering that Electronic Data Capture (EDC) will be used, the study will be in compliance 
with the following regulations: Food and Drug Administration (FDA), 21 CFR Part 11, 
Electronic Records, Electronic Signatures, and FDA, Guidance for Industry: Computerized 
Systems Used in Clinical Trials requirements [40, 41]. 
In addition, the study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent 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 IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
1.7 
Population to be Studied 
The study will enrol 40 adult subjects, males or females afferent to 14 Italian clinical sites, 
diagnosed with progressive well or moderately differentiated thoracic NETs (typical and 
atypical carcinoids and thymus) and with at least one measurable tumour lesion.  


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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
The aim of this study is to explore the efficacy and safety of the combination of Lanreotide 
ATG 120 mg and TMZ in progressive T-NETs. 
2.2 
Study Objectives 
The primary objective of the study is to evaluate the efficacy of Lanreotide ATG 120 mg in 
combination with TMZ in subjects with unresectable advanced neuroendocrine tumours of the 
lung or thymus (typical and atypical carcinoids according to the WHO 2004 criteria), as 
disease control rate (DCR) at 9 months, according to RECIST criteria v 1.1. 
The secondary objectives of the study are: 
• 
To assess, according to RECIST criteria v 1.1:  
- 
Progression Free Survival (PFS)  
- 
Time to Response (TTR) 
- 
Duration of Response 
- 
Time to Progression (TTP) 
- 
Best Overall Response:  Complete Response (CR), Partial Response (PR), Stable 
Disease (SD), Progressive Disease (PD)  
- 
Objective Response Rate (ORR): Complete Response (CR), Partial Response 
(PR) at 9 and 12 months 
- 
Disease Control Rate (DCR): Complete Response (CR), Partial Response (PR) 
and Stable Disease (SD) at 12 months 
- 
The influence of typical carcinoids and atypical carcinoid on the Disease Control 
Rate (DCR) at 9 months 
• 
To assess the Biochemical Response (CgA plasma levels)  
• 
To assess NSE and CgA biomarkers levels prognostic and predictive value 
• 
To assess the prognostic value of biomarkers expression (immunohistochemistry assay 
SSTR2, Ki67 and MGMT status in tissue obtained from paraffin embedded primary 
tumour surgery specimens  or biopsies) for PFS, ORR and DCR 
• 
To assess the agreement of the central assessment of tumor radiological response and 
the local one, on the DCR at 9 months 
• 
To evaluate the safety of study treatments as assessed by the following:  
- 
occurrence of adverse events (AEs) throughout the study 
- 
clinical laboratory test results (haematology, biochemistry at each study visit, 
and urinalysis at visits 1, 6, 9, 12, End of Study (EOS) 
- 
vital signs (blood pressure, heart  rate and body weight) measurements at each 
study visit 
- 
electrocardiogram (ECG), echocardiography at visits 1, 9 and EOS 
- 
physical examination at each study visit 
- 
concomitant medication usage throughout the study 
- 
Gallbladder echography at visits 1, 9 and EOS. 


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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a phase II, open label, single arm, prospective, multicenter, non-comparative, pilot 
study to evaluate the efficacy and safety of Lanreotide ATG 120 mg /28 days in combination 
with TMZ 250 mg/day for 5 consecutive days/28 days on Disease Control Rate (DCR), in 
adult subjects with a histologically documented unresectable advanced (locally or metastatic) 
well or moderately differentiated neuroendocrine tumor of the lung or thymus (typical and 
atypical carcinoids), according to the WHO 2004 criteria. The study consists of a screening 
period (maximum 4 weeks), followed by a 52 week open label phase. 
At Screening visit (V1), after informed consent for the study has been obtained, an eligibility 
CT scan must be performed.  
At Baseline visit (V2), performed  after a maximum of 4 weeks after V1, subjects fulfilling 
the inclusion and exclusion criteria will be treated with Lanreotide ATG 120 mg every 28 
days and TMZ 250 mg daily for 5 consecutive days every 28th days (in case of bone marrow 
toxicity the dose may subsequently be reduced to 180 mg daily for 5 consecutive days of each 
month)  for a maximum treatment period of 52 weeks (about 12 months) or until disease 
progression, death or unacceptable toxicity, subject/physician decision, whichever comes first. 
Specific details of the dosage groups are given in Section 6. 
Subjects who complete all scheduled visits will be considered to have completed the study. 
Subjects who progress or die are considered to have completed the study. Subjects who 
complete all scheduled visits until Visit 12 (36 weeks of treatment) will be considered to be 
evaluable for primary objective of the study. 
Subjects who complete the study will have final procedures and assessments performed at the 
final visit (EOS – Visit 16). Subjects who withdraw from the study before the completion of 
the evaluation period will have an Early Withdrawal Visit within 4 weeks after last IMP 
intake either one has been administered (i.e. lanreotide ATG or TMZ) and should perform all 
assessments provided at final visit (EOS).  
At their last study visit (EOS- V16-Week52), subjects still benefiting from treatment 
(according to the investigator judgment) will have the option, to continue to receive the 
combination of Lanreotide ATG 120 mg and TMZ 250 mg. In such a situation, Lanreotide 
120 mg  and TMZ 250 mg will be provided free of charge by the Sponsor to the 
investigational sites under its commercial packaging, for a maximum of 12 months. During 
this post-trial treatment, the Investigator will report immediately to Ipsen Pharmacovigilance 
Contact any safety concerns arising from the use of the product. 
 
Figure 3 Study Design 
 
 


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3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Efficacy Endpoint and Evaluation 
The primary endpoint is the percentage of responders (DCR according to RECIST criteria v 
1.1) at 9 months (V12) after first treatment administration, defined as objective response or 
stability of the disease. They include: CR (complete response), PR (partial response) or SD 
(stable disease). 
3.2.2 
Secondary Efficacy Endpoints and Evaluations 
Secondary endpoints are: 
• 
Progression Free Survival (PFS) from first treatment administration; Progression, 
according to RECIST criteria v 1.1 
• 
Time to Response (TTR) defined as the time from first treatment administration to the 
first objective tumor response (PR or CR according to RECIST criteria v 1.1) 
• 
Duration of Response defined as the time from onset of the first objective tumor 
response (PR or CR) to objective tumor progression (PD,  according to RECIST criteria 
v 1.1) or death from any cause 
• 
Time to Progression (TTP) defined as the time from first treatment administration to 
the first objective tumor progression (PD) observed according to RECIST criteria v 1.1 
• 
Best Overall Response defined as the best response recorded from the time from the 
first treatment until disease progression/recurrence or the end of study, according to 
RECIST criteria v 1.1 (CR, PR, SD, PD) Objective Response Rate (ORR): Complete 
Response (CR), Partial Response (PR) at 9 and 12 months 
• 
Disease Control Rate (DCR): Complete Response (CR), Partial Response (PR) and 
Stable Disease (SD) at 12 months 
• 
The influence of typical carcinoids and atypical carcinoid on the Disease control rate 
(DCR) at 9 months  
• 
Biochemical Response according to decrease in CgA plasma level in subjects with 
baseline CgA level greater than ULN. Biochemical objective response is defined as a 
decrease of CgA ≥ 50%, while stable disease as a decrease ≥ 25% and less than 50%, as 
their best response to study treatment 
• 
Value of NSE and CgA biomarkers levels (Centrally assessed) at baseline (V2),  1 
month (V4), 3 months (V6), 6 months (V9), 9 months (V12) and End of study (V16), to 
assess their predictive and prognostic value  
• 
Biomarkers expression (Centrally assessed)  (immunohistochemistry assay SSTR2, 
Ki67 and MGMT status in tissue obtained from paraffin embedded primary tumour 
surgery specimens  or biopsies) correlated to tumor response for PFS, ORR, DCR at 9 
(V12) and 12 months (V15), to assess their prognostic value 
• 
Agreement between central and local assessment of tumor radiological response. 
3.2.3 
Safety Endpoints and Evaluations 
The safety and tolerability of Lanreotide in combination with TMZ will be assessed 
throughout the study by evaluating AEs/SAEs, changes from baseline in physical 
examination, vital signs (blood pressure, heart rate and body weight), laboratory tests 
(haematology, biochemistry, urinalysis), diagnostic tests (ECG, Echocardiography, 
Gallbladder Echography) and concomitant medication usage.  


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Assessments of adverse events will be evaluated for timing, seriousness and relatedness and 
graded for type, incidence and severity according to the National Cancer Institute (NIC) using 
the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03-14 June 2010 
(refer to Appendix 3). 
3.3 
Randomisation and Blinding 
This is a non-randomised, open label study. 
3.4 
Study Treatments and Dosage 
Each subject eligible and enrolled in the Study will be treated with the combination of 
Lanreotide ATG 120 mg and TMZ 250 mg, as specified in the following paragraphs. 
Lanreotide ATG 120 mg, will be administered, at study site, to the subjects at baseline and 
every 28 days until 48 weeks of treatment (12 injections) through deep subcutaneous 
injection. 
Lanreotide will be packaged and delivered to investigational sites by CREAPHARM, ZA Air 
Space, Av de Magudas CS2007, 33187 Le Haillan, France. 
The treatment will be provided in a pre-filled syringe, sealed in a laminated bag.  
A more detailed description of administration procedures is given in Section 6.1.1.  
TMZ will be administered at starting dose of 250 mg per day for 5 consecutive days of each 
month for a maximum of 48 weeks (5 hard capsules dispensed at 12 visits). In case of bone 
marrow toxicity the dose may subsequently be reduced to 180 mg per day for 5 consecutive 
days of each month. The first intake will start the same day of the administration of 
Lanreotide ATG 120 mg and will continue for the next 4 days (5 days of treatment in total).  
TMZ will be provided in glass bottles or blisters containing 5 hard capsules of 
Temozolomide, at two different dosages: 250 mg and 180 mg, to allow a dose reduction in 
case of bone marrow toxicity.  
TMZ will be packaged and delivered to investigational sites by CREAPHARM, ZA Air 
Space, Av de Magudas CS2007, 33187 Le Haillan, France. 
A more detailed description of administration procedures is given in Section 6.1.2.  
A sufficient quantity of IMP 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 IMP has 
been used under their study, Material Data Safety Sheet for both active IMPs, Packaging 
Order which reflects the product release statement.  
The core label texts for all packaging units will be translated or adjusted, to be in compliance 
with applicable regulatory requirements [Good Manufacturing Practice (GMP) Annex 13 
[42], national laws in force and in accordance with the local languages. A description of the 
core text of the IMP labels is displayed below: 
• 
Study Number, 
• 
Pharmaceutical dosage form, 
• 
Route of administration, 
• 
Quantity of dose units, 
• 
Batch number, 
• 
“Keep out of reach of children”, 
• 
a treatment number  
• 
a specific blank space to enter the subject ID 


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• 
“For clinical study use only” 
• 
Name, address and telephone number of the sponsor (the main contact for information 
on the product and clinical study) 
• 
Name of Investigator 
• 
Storage conditions 
• 
Expiry date 
The investigator, or designee, will only dispense IMPs to subjects included in this study. Each 
subject will only be given the IMP carrying his/her number. The dispensing for each subject 
will be documented in the eCRF. 
3.5 
Study Duration 
Subjects are expected to participate in this study for a minimum of 53 weeks and up to 56 
weeks, considering that the study will consist of a four week (maximum) screening period, 
and a 52 week open label phase. 
The subject’s participation in the study will be considered to have ended at the time of the last 
visit (EOS – V16), 4 weeks after last IMP intake, either one has been administered (i.e. 
lanreotide ATG or TMZ).  
For subjects who prematurely withdraw from the study, every effort should be done to 
perform Early Withdrawal Visit within 4 weeks after last IMP intake, either one has been 
administered (i.e. lanreotide ATG or TMZ). Subjects enrolment will last 20 months and the 
overall duration of the study will be approximately 3 years. The study will be considered to 
have started when the first subject has provided his/her signed informed consent.  
The study will be considered to have ended after the last subject last visit has been performed. 
At their last study visit (EOS- V16-Week52), subjects still benefiting from treatment 
(according to the investigator judgment) will have the option, to continue to receive the 
combination of Lanreotide ATG 120 mg and TMZ 250 mg. In such a situation, Lanreotide 
120 mg and TMZ 250 mg will be provided free of charge by the Sponsor to the 
investigational sites under its commercial packaging, for a maximum of 12 months. During 
this post-trial treatment, the Investigator will report immediately to Ipsen Pharmacovigilance 
Contact any safety concerns arising from the use of the product. 
3.6 
Stopping Rules and Discontinuation Criteria 
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events (SAEs) will be reviewed (see Section 8.1.4) as they are reported from 
the study centre to identify safety concerns.  
A subject may discontinue participation in the study at any time for any reason (e.g. lack of 
efficacy, withdrawal of consent, AE). The investigator and/or sponsor can withdraw a subject 
from the study at any time for any reason (e.g. protocol violation or deviation as defined in 
Section 12.1.2, non-compliance with the protocol conditions or AE). 
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 points 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. 


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• 
Investigator’s decision according to clinical judgment. 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability 
3.7.1 
Investigational Medicinal Product Storage and Security 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all IMP and 
any other study related material is stored in a secured area, under recommended temperature 
monitored storage conditions, in accordance with applicable regulatory requirements. 
• 
Lanreotide ATG 120 mg will be stored under the recommended temperature (between 
+2°C and +8°C) and will be administered to the subjects through deep subcutaneous 
injection, at study sites. 
• 
TMZ capsules should not be stored above 30°C. Procedures for drug administration are 
provided in the drug instructions leaflet and more details provided in the study manual.    
3.7.2 
Investigational Medicinal Product Preparation 
The investigator, or an approved representative (e.g. pharmacist), will ensure that all IMP is 
dispensed by qualified staff members.  
3.7.3 
Investigational Medicinal Product Accountability 
All IMP and any other study related material is to be accounted for on the IMP accountability 
log provided by the sponsor. 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 IMP accountability log. 
The procedure for either return of unused clinical study supplies to the sponsor or destruction 
of these unused clinical study supplies at site are detailed in the Study Manual. 
3.8 
Maintenance of Randomisation and Blinding 
Not applicable. 
3.9 
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), IMP 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). 
• 
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, 


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microfiches, photographic negatives, microfilm or magnetic media, x rays, subject files, 
and records kept at the pharmacy, at the laboratories and at medico-technical 
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, CAs. This information is included in 
the informed consent. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
All subjects must fulfil all of the following criteria to be included in the study: 
(1) 
Provision of written Informed Consent prior to any study related procedures; 
(2) 
Adult subjects (male or female)  18 years old; 
(3) 
WHO Performance status  2; 
(4) 
Histological documented unresectable advanced (locally or metastatic) well or 
moderately differentiated neuroendocrine tumors of the lung or thymus (typical and 
atypical carcinoids according to the WHO 2004 criteria); 
(5) 
Imaging documented progression within 12 months before screening visit (V1), 
according to RECIST criteria v.1.1; 
(6) 
Measurable disease, as defined by RECIST criteria v 1.1, on a CT scan performed at 
screening visit (V1); 
(7) 
Octreoscan or Ga68-DOTA-TATE/TOC/NOC-PET-TC within 12 months before 
screening visit (V1); 
(8) 
Adequate liver, renal and bone marrow function, as defined below: 
• 
Adequate bone marrow function  
- 
ANC  1.5 × 109/L  
- 
Platelets  100 × 109/L  
- 
Hemoglobin > 9 g/dL 
• 
Adequate liver function 
- 
Total serum bilirubin  2.0 × ULN (exception for Gilbert disease)  
- 
INR < 1.5   
- 
ALT and AST  2.5 × ULN (  5 × ULN, in subjects with liver 
metastases) 
• 
Adequate renal function 
- 
Serum creatinine  1.5 × ULN 
(9) 
Willing and able to comply with study restrictions and willing to return at the clinic for 
the required visits during the study period and for the follow up evaluations as specified 
in the protocol. 
(10) Female subjects of childbearing potential (not surgically sterile or 2 years 
postmenopausal) must use a medically accepted method of contraception and must 
agree to continue use of this method for the duration of the study and for 6 months after 
participation in the study. Acceptable methods of contraception include double barrier 
method [i.e. condom and occlusive cap (diaphragm or cervical/vault caps)] spermicide, 
intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and 
injected) in conjunction with a barrier method. 
(11) Male subjects with female partners of childbearing potential must use a medically 
accepted method of contraception and must agree to continue use of this method for the 
duration of the study and for 6 months after participation in the study. 


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4.2 
Exclusion Criteria 
Subject will not be included in the study if: 
(1) 
History of hypersensitivity to the IMP or drugs with a similar chemical structure or any 
excipient used in the formulation. 
(2) 
Any known contraindications to CT scan. 
(3) 
Poorly differentiated neuroendocrine carcinoma and mixed NET tumours, according to 
WHO 2004 criteria. 
(4) 
Neuroendocrine tumours other than lung or thymus. 
(5) 
Non-neuroendocrine thymic neoplasm. 
(6) 
Treated with Systemic therapies (chemotherapy, interferon-alpha, somatostatin 
analogues, molecular target therapies) within 28 days prior to screening visit (V1). 
(7) 
Treated with a Number of systemic therapy lines > 3 prior to screening visit (V1), and 
any of the following: 
(a) 
for chemotherapy no more than 1 line prior to V1;  
(b) 
for somatostatin analogues no more than 1 line therapy, considered as treatment 
lasting more than 6 months, prior to V1;  
(c) 
no therapy with TMZ prior to V1. 
(8) 
Received a prior therapy with Peptide Receptor Radionuclide Therapy (PRRT) within 6 
months prior to screening visit (V1). 
(9) 
Sign of recurrence of prior malignancies, or concomitant malignancies, or malignancies 
requiring active treatment within the last 3 years, other than the investigated disease, 
with the exception of previous basal cell skin cancer and previous cervical carcinoma in 
situ or neoplasm radically resected within 3 years prior to screening visit (V1). 
(10) Undergone major surgery/surgical therapy for any cause within 3 month prior to 
screening visit (V1). 
(11) Received external palliative radiotherapy within the last 28 days prior to screening visit 
(V1). 
(12) Received locoregional therapies (TAE, TACE, TARF) and SIRT within 3 months prior 
to screening visit (V1). 
(13) Presence symptomatic brain metastasis. 
(14) Unstable angina pectoris, symptomatic congestive heart failure (NYHA Class III or 
IV), serious uncontrolled cardiac arrhythmia or a history of myocardial infarction ≤ 6 
months prior to screening visit (V1). 
(15) Active or uncontrolled severe infection or known history of HIV seropositivity. 
(16) Previous Pneumocistis Carini Pneumonitis infection. 
(17) Liver cirrhosis, chronic active or persistent hepatitis, HCV and HBV positive test in 
presence of active disease clinical evidence. 
(18) Active bleeding diathesis, including abnormal coagulation (PT or APTT greater than 
30% above ULN). 
(19) Uncontrolled diabetes mellitus as defined by HbA1c  8%, despite adequate therapy. 
Subject with known history of impaired fasting glucose or diabetes mellitus (DM) may 
be included, however blood glucose and antidiabetic treatment must be monitored 
closely throughout the trial and adjusted as necessary. 


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(20) Subjects with symptomatic cholelithiasis at screening visit (V1). 
(21) Any current or prior medical condition that may interfere with the conduct of the study. 
(22) Hypersensitivity to dacarbazine (DTIC). 
(23) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption. 
(24) Treated with any other IMP within 28 days prior to screening visit (V1). 
(25) Likely to require treatment during the study with drugs that are not permitted by the 
study protocol. 
(26) Female subject pregnant or lactating. A pregnancy test will be performed at the start of 
the study for all female subjects of childbearing potential (i.e. not surgically sterile or 
2 years postmenopausal). 
(27) Male subject who is planning a sperm donation during the entire study participation and 
at least 6 months after the last study drug administration. 
(28) History of, or known current, problems with substance or alcohol abuse. 
(29) Any mental condition rendering the subject unable to understand the nature, scope and 
possible consequences of the study, and/or evidence of an uncooperative attitude. 
(30) Abnormal baseline findings, any other medical condition(s) or laboratory findings that, 
in the opinion of the investigator, might jeopardise the subject’s safety. 
4.3 
Subject Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, 
pregnancy (see section 8.1.5), or other reasons concerning the health or wellbeing of the 
subject, or in the case of lack of cooperation. In addition, a subject may be withdrawn from 
the study as described in Sections 3.6, 5.2.5.1, 6.2 and 8.1.7.  
If one or more of the following occurs, the subject will be discontinued from study 
medication: 
• 
In case of disease progression as defined in the RECIST criteria version 1.1 (refer to 
Appendix 1);  
• 
In case of AEs, SAEs, serious and unexpected worsening of clinical conditions, or any 
other reasons that, in the Investigator's judgement, may jeopardize the subject safety; 
If one or more of the following occurs the subject will be withdrawn from the study: 
(1) 
Informed consent withdrawal / Subject's request; 
(2) 
Occurrence of disease(s) which can interfere with subject's final evaluation; 
(3) 
Administration of prohibited drugs; 
(4) 
If TMZ is not tolerated and unacceptable toxicity persists even after TMZ dose 
reduction or delay (see Table 7 Dose Adaptation of TMZ); 
(5) 
According to clinical judgement of the investigator or to their own request; 
(6) 
Substantial non-compliance with the requirements of the study; 
(7) 
Development of a situation which would, in the Judgment of the investigator, affect 
clinical study endpoint measurements with a significant degree; 
(8) 
Subjects lost to follow- up; 
(9) 
Subject death. 


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Discontinued subjects will not be replaced.  
Should a subject decide to withdraw from the study after administration of IMP, 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 5.2.5.1) and an 
explanation given of why the subject is withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the CRF. The 
Investigator will provide or arrange for appropriate follow-up (if required) for subjects 
withdrawing from the study, and will document the course of the subject’s condition.  
If a subject withdraws consent, every attempt will be made to determine the reason. 
If the reason for withdrawal is an AE or a clinically significant laboratory test abnormality, 
monitoring will continue until the event has resolved or stabilised, until the subject is referred 
to the care of a local health care professional, or until a determination of a cause unrelated to 
the IMP or study procedure is made. The specific AE or test result(s) must be recorded on the 
CRF. All evaluations should be performed, according to the protocol, on the last day the 
subject receives IMP, or as soon as possible thereafter.  
In case of subject discontinuation due to SAE or AE, the evolution of the SAE or AE will be 
followed up and recorded by the Investigator till the outcome definition. If possible, subjects 
removed from the Study should perform the Early withdraw visit (see Section 5.2.5.1.) 
concomitantly with the Study Drug discontinuation decision, and in any case within 4 weeks 
after last dose of drug administered (i.e. lanreotide ATG or TMZ). 
 
 
 
 If a subject wishes to withdraw his consent, the investigator 
must inform the study monitor in writing of the subject’s decision. Within the sponsor, the 
request for sample withdrawal will be forwarded to the repository leader. If the samples are in 
the sponsor’s repository (or at the central laboratory prior to shipping to the repository), the 
repository leader will ensure destruction of the samples and all corresponding aliquots and 
issue confirmation of the withdrawal, which will be forwarded to the investigator. If the 
samples are still at the investigator site at the time the subject withdraws his consent, the 
investigator must inform the study monitor and destroy the samples. The study monitor will 
forward confirmation of the destruction to the repository leader. 
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5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in Table 6. 
The total volume of blood drawn for all evaluations throughout this study is approximately 
286 mL for each subject.  
 
 
 
 
 
 
 
 
Table 5 
Blood Volume Calculation 
Description 
Number of Samples 
Volume (mL) 
Total Volume (mL) 
Haematology 
17 
8 
136 
Blood Biochemistry 
16 
5 
80 
CgA and NSE  
6 
10 
60 
Serology 
1 
10 
10 
 
 
 
 
Total Volume (mL)/subject 
 
 
301 
 
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Table 6 
Study Procedures and Assessments 
 
Pretreatment 
Treatment period 
End of Study 
(or Early 
Withdrawal) 
 
V1 
V2 
V3 
V3 
bis[a] 
V4 
V5 
V6 
 
V7 
V8 
V9 
 
V10 
V11 
V12 
 
V13 
V14 
 
V15 
V16 
 
Allowed 
visit 
schedule 
deviation 
(days) 
 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
±2 
±2 
±2 
 
 
 
 
±2 
±2 
±2 
 
 
 
 
±2 
±2 
 
 
 
 
±2 
±2 
Procedures and assessments 
Screening 
Maximum 
-4W 
Baseline 
Day 1 
 
W2 
W 
3 
W 
4 
W 
8 
W 
12 
 
 
W 
16 
W 
20 
W 
24 
 
 
W 
28 
W 
32 
W 
36 
 
 
W 
40 
W 
44 
 
 
W 
48 
W52 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Therapies for T-NETs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Octreoscan or Ga68-
DOTA/TATE/TOC/NOC-PET 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical and Physical examination 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO performance score 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Prior / concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sample tissue for centralized SSTR2, 
MGMT, Ki-67 evaluation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gallbladder echography  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 


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V1 
 
V2 
 
V3 
V3 
bis[a] 
V4 
V5 
V6 
 
V7 
V8 
V9 
 
V10 
V11 
V12 
 
V13 
V14 
 
V15 
V16 
 
Allowed 
visit 
schedule 
deviation 
(days) 
 
±2 
±2 
±2 
±2 
±2 
 
 
 
 
±2 
±2 
±2 
 
 
 
 
±2 
±2 
±2 
 
 
 
 
±2 
±2 
 
 
 
 
±2 
±2 
Procedures and assessments 
Screening 
Maximum 
-4W 
Baseline 
Day 1 
 
W2 
W 
3 
W 
4 
W 
8 
W 
12 
 
W 
16 
W 
20 
W 
24 
 
W 
28 
W 
32 
W 
36 
 
W 
40 
W 
44 
 
W 
48 
W 
52 
Urinalysis 
X 
 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
Blood sample collection to assess 
Haematology 
 
X[b] 
X[b] 
X 
X[a] 
X[b] 
X[b] 
X[b] 
X[b] 
X[b] 
X[b] 
X[b] 
X[b] 
X[b] 
X[b] 
X[b] 
X[b] 
X 
Blood sample collection to assess 
Biochemistry 
 
X[c] 
X[c] 
X[c] 
 
X[c] 
X[c] 
X[c] 
X[c] 
X[c] 
X[c] 
X[c] 
X[c] 
X[c] 
X[c] 
X[c] 
X[c] 
X[c] 
Blood sample collection to assess 
Serology (HCV, HBV) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (Serum) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample collection for 
CgA and NSE dosage 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
ECG and Echocardiography 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
CT scan e 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
LAN ATG 120 mg 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TMZ 250 mg  (or 180 mg if dose 
down titrated) x 5days 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
a Haematology will be reconfirmed at day 21, to assess the TMZ bone marrow tardive toxicity (only WBC, ANC, Hemoglobin, Platelets). 
 
b Please refer to section 5.2 for completed list of parameters to be assessed at each visit. Tests to be assessed BEFORE STUDY INTAKE. 
 
c Please refer to section 5.2 for completed list of parameters to be assessed at each visit. Tests to be assessed BEFORE STUDY INTAKE. 
  
e The CT scan report must be available at the time of scheduled visits; the exam could be performed within maximum 10 days before the visit 
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5.2 
Study Visits 
5.2.1 
Procedures for Screening and Enrolment (Visit 1) 
A signed and dated Informed Consent Form will be obtained 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. Subjects will acknowledge and 
agree to the possible use of this information for the study by giving informed consent. 
 
 
 Subjects who agree to participate will be requested to sign a separate informed 
consent. After informed consent is obtained, subjects who are screened will be allocated a 
subject number. All screened subjects must be identifiable throughout the study. The 
investigator will maintain a list of subject numbers and names to enable records to be found at 
a later date if required. The screening visit (Visit 1) will take place between Day –28 and Day 
-1 of the study. The following assessments will be performed: 
5.2.2 
Screening Visit (V1) / max -4W 
• 
Demography (sex, age, ethnic origin)  
• 
Medical/surgical history in the past year  
• 
Documented histology of typical/atypical carcinoid of lung or thymus according to 
WHO 2004 criteria 
• 
Disease history (date of diagnosis, tumour localization and  tumour staging according 
to UICC/AJCC 7th Edition TNM System 
• 
WHO performance score 
• 
Prior and concomitant medications/therapies 
• 
Prior Chemotherapy, Radiotherapy, Target Therapies, Locoregional Therapies (TAE, 
TACE, TARF, SIRT), PRRT for T-NETs in the past year  
• 
Clinical and physical examination  
• 
Vital signs: assessment of blood pressure (BP), heart  rate, height and body weight (kg) 
• 
Blood sample collection to assess Haematology: RBC count, haemoglobin, 
haematocrit, MCV, MCH, MCHC, WBC count, ANC, Platelets, Glycated 
Haemoglobin (HbA1c), coagulation indexes: aPTT, PT and INR. 
• 
Blood sample collection to assess Biochemistry: urea, serum creatinine (Cr), total 
serum bilirubin (direct bilirubin only if total serum bilirubin is out of range), 
electrolytes (chloride, sodium, potassium, calcium, phosphate), lactate dehydrogenase 
(LDH), ALT, AST, gamma glutamyl transferase (γGT), albumin, total protein, total 
cholesterol, triglycerides, fasting glucose, insulin, C-peptide, vitamin B12, TSH, FT3, 
FT4. 
• 
Blood sample collection to assess serology: hepatitis C virus (HCV) and hepatitis B 
virus (HBV)  
• 
Urinalysis 
• 
Serum pregnancy test 
• 
Tissue sample for SSTR2, MGMT, Ki-67: check if available 
• 
CT scan (chest, abdomen and pelvis). If a CT scan was already performed in the last 28 
days it would be considered suitable for the screening tumour evaluation. 
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• 
ECG, Echocardiography  
• 
Gallbladder Echography  
• 
Octreoscan or GA68-DOTA/TATE/TOC/NOC-PET (within 12 months) 
• 
Eligibility check (starting verify inclusion/exclusion criteria) 
Each Investigator has to check the patient safety (AE reporting) starting from the signature of 
Informed Consent. The subjects under no circumstances will be screened more than once. 
Following confirmation of eligibility for the study, subjects will start the study treatments, 
specified in Section 6.1. Each investigator will also maintain 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 be completed. In the event that the subject was not receiving 
IMP, the primary reason will be recorded. 
5.2.3 
Procedures Before Study Treatment - Baseline (V2) / Day 1 
The following procedures will be performed at Baseline on Day 1 of the study, prior to the 
administration of study treatments: 
• 
Eligibility check (final evaluation of inclusion/exclusion criteria) 
• 
Review of pre-treatment AEs  
• 
New or changed concomitant medications 
• 
Clinical and physical examination  
• 
Vital signs: assessment of blood pressure (BP), heart rate and body weight (kg) 
• 
Blood sample collection to assess Haematology: RBC count, haemoglobin, 
haematocrit, MCV, MCH, MCHC, WBC count, ANC, Platelets, Glycated 
Haemoglobin (HbA1c), aPTT, PT and INR. Do not repeat if V1 haematology has been 
performed less than 7 days before.  
• 
Blood sample collection to assess Biochemistry: urea, serum creatinine (Cr), total 
serum bilirubin (direct bilirubin only if total serum bilirubin is out of range), 
electrolytes (chloride, sodium, potassium, calcium, phosphate), lactate dehydrogenase 
(LDH), ALT, AST, gamma glutamyl transferase (γGT), albumin, total protein, total 
cholesterol, triglycerides, fasting glucose, insulin, C-peptide, vitamin B12, TSH, FT3, 
FT4. Do not repeat if V1 biochemistry has been performed less than 7 days before. 
• 
Blood sample collection for centralized dosage of CgA and NSE 
• 
 
 
 
 
 
 
 
 
 
 
   After above check performed,  
• 
Lanreotide ATG 120 mg 
• 
TMZ 250 mg for the first consecutive 5 days  
 
5.2.4 
Procedures During Study Treatment 
The following procedures will be performed at Visit 3 (W2 ± 2 days): 
• 
Clinical and physical examination  
• 
Vital signs: assessment of blood pressure (BP), heart rate and body weight (kg) 
• 
Blood sample collection to assess bone marrow, liver and renal function: WBC count, 
ANC, Haemoglobin, Platelets, total serum bilirubin (direct bilirubin only if total serum 
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bilirubin is out of range), γGT, ALT, AST, serum Cr, Urea, LDH, aPTT, PT, INR, 
electrolytes (chloride, sodium, potassium, calcium, phosphate) 
• 
Review of AEs 
• 
New or changed concomitant medications 
The following procedures will be performed at Visit 3 bis (W3 ± 2 days): 
• 
Blood sample collection to assess TMZ tardive bone marrow toxicity: WBC count, 
ANC, Haemoglobin, Platelets 
• 
Review of AEs 
• 
New or changed concomitant medications 
The following procedures will be performed at Visit 4 (W4 ± 2 days) 
• 
Clinical and physical examination 
• 
Vital signs: assessment of blood pressure (BP), heart  rate and body weight (kg) 
• 
Blood sample collection to assess Haematology: RBC count, haemoglobin, 
haematocrit, MCV, MCH, MCHC, WBC count, ANC, Platelets, Glycated 
Haemoglobin (HbA1c), aPTT, PT and INR. 
• 
Blood sample collection to assess Biochemistry: urea, serum creatinine (Cr), total 
serum bilirubin (direct bilirubin only if total serum bilirubin is out of range), 
electrolytes (chloride, sodium, potassium, calcium, phosphate), lactate dehydrogenase 
(LDH), ALT, AST, gamma glutamyl transferase (γGT), albumin, total protein, total 
cholesterol, triglycerides, fasting glucose, insulin, C-peptide, vitamin B12, TSH, FT3, 
FT4 
• 
Urinalysis 
• 
Blood sample collection for centralized dosage of CgA and NSE 
• 
Review of AEs 
• 
New or changed concomitant medications 
After above check performed, 
• 
Lanreotide ATG 120 mg 
• 
TMZ 250 mg for the first consecutive 5 days, or dose reduction if appropriate– see 
Section 6.1.2. 
The following procedures will be performed at Visit 5 (W8 ± 2 days) 
• 
Clinical and physical examination 
• 
Vital signs: assessment of blood pressure (BP), heart  rate and body weight (kg) 
• 
Blood sample collection to assess Haematology: RBC count, haemoglobin, 
haematocrit, MCV, MCH, MCHC, WBC count, ANC, Platelets, Glycated 
Haemoglobin (HbA1c), aPTT, PT and INR. 
• 
Blood sample collection to assess Biochemistry: urea, serum creatinine (Cr), total 
serum bilirubin (direct bilirubin  only if total serum bilirubin is out of range), 
electrolytes (chloride, sodium, potassium, calcium, phosphate), lactate dehydrogenase 
(LDH), ALT, AST, gamma glutamyl transferase (γGT), albumin, total protein, total 
cholesterol, triglycerides, fasting glucose, insulin, C-peptide, vitamin B12, TSH, FT3, 
FT4) 
• 
Urinalysis 
• 
Review of AEs 


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• 
New or changed concomitant medications  
After above check performed, 
• 
Lanreotide ATG 120 mg 
• 
TMZ 250 mg for the first consecutive 5 days, or dose reduction if appropriate– see 
Section 6.1.2. 
The following procedures will be performed at Visit 6 (W12 ± 2 days) and Visit 12 (W36 
± 2 days):  
• 
Clinical and physical examination 
• 
WHO performance score 
• 
Vital signs: assessment of blood pressure (BP), heart  rate and body weight (kg) 
• 
Blood sample collection to assess Haematology: RBC count, haemoglobin, 
haematocrit, MCV, MCH, MCHC, WBC count, ANC, Platelets, Glycated 
Haemoglobin (HbA1c), aPTT, PT and INR. 
• 
Blood sample collection to assess Biochemistry: urea, serum creatinine (Cr), total 
serum bilirubin (direct bilirubin only if total serum bilirubin is out of range), 
electrolytes (chloride, sodium, potassium, calcium, phosphate), lactate dehydrogenase 
(LDH), ALT, AST, gamma glutamyl transferase (γGT), albumin, total protein, total 
cholesterol, triglycerides, fasting glucose, insulin, C-peptide, vitamin B12, TSH, FT3, 
FT4) 
• 
CT scan (chest, abdomen and pelvis) 
• 
Review of AEs 
• 
New or changed concomitant medications  
• 
 
 
• 
 
After above check performed, 
• 
Lanreotide ATG 120 mg 
• 
TMZ 250 mg for consecutive 5 days, or dose adjustment if appropriate – see Section 
6.1.2. 
The following procedures will be performed at Visit 7 (W16 ± 2 days), Visit 8 (W20 ± 2 
days), Visit 10 (W28 ± 2 days), Visit 11 (W32 ± 2 days), Visit 13 (W40 ± 2 days), and 
Visit 14 (W44 ± 2 days): 
• 
Blood sample collection to assess bone marrow, liver and renal function: WBC count 
ANC, Haemoglobin, Platelets, total serum bilirubin (direct bilirubin only if total serum 
bilirubin is out of range), γGT, ALT, AST, serum Cr, Urea, LDH, aPTT, PT, INR 
electrolytes (chloride, sodium, potassium, calcium, phosphate) 
• 
Clinical and physical examination  
• 
Vital signs: assessment of blood pressure (BP), heart  rate and body weight (Kg) 
• 
Review of AEs 
• 
New or changed concomitant medications  
After above check performed, 
• 
Lanreotide ATG 120 mg at monthly schedule 
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• 
TMZ 250 mg for consecutive 5 days, or dose adjustment if appropriate – see Section 
6.1.2. 
The following procedures will be performed at Visit 9 (W24 ± 2 days): 
• 
Clinical and physical examination 
• 
WHO performance score 
• 
Vital signs: assessment of blood pressure (BP), heart  rate and body weight (kg) 
• 
Blood sample collection to assess Haematology: RBC count, haemoglobin, 
haematocrit, MCV, MCH, MCHC, WBC count, ANC, Platelets, Glycated 
Haemoglobin (HbA1c), aPTT, PT and INR. 
• 
Blood sample collection to assess Biochemistry: urea, serum creatinine (Cr), total 
serum bilirubin (direct bilirubin only if total serum bilirubin is out of range), 
electrolytes (chloride, sodium, potassium, calcium, phosphate), lactate dehydrogenase 
(LDH), ALT, AST, gamma glutamyl transferase (γGT), albumin, total protein, total 
cholesterol, triglycerides, fasting glucose, insulin, C-peptide, vitamin B12, TSH, FT3, 
FT4 
• 
Urinalysis 
• 
Blood sample collection for Centralized dosage of CgA and NSE 
• 
CT scan (chest, abdomen and pelvis) 
• 
ECG and Echocardiography  
• 
Gallbladder Echography  
• 
Review of AEs 
• 
New or changed concomitant medications   
After above check performed, 
• 
Lanreotide ATG 120 mg 
• 
TMZ 250 mg for consecutive 5 days every 28 days, or dose adjustment if appropriate – 
see Section 6.1.2. 
The following procedures will be performed at Visit 15 (W48 ± 2 days): 
• 
Clinical and physical examination  
• 
Vital signs: assessment of blood pressure (BP), heart  rate and body weight (Kg)  
• 
Blood sample collection to assess bone marrow, liver and renal function: WBC count, 
ANC, Haemoglobin, Platelets, total serum bilirubin (direct bilirubin  only if total serum 
bilirubin is out of range), γGT, ALT, AST, serum Cr, Urea, LDH, aPTT, PT, INR, 
electrolytes (chloride, sodium, potassium, calcium, phosphate) 
• 
Review of AEs 
• 
New or changed concomitant medications  
After above check performed, 
• 
Lanreotide ATG 120 mg at monthly schedule 
• 
TMZ 250 mg for consecutive 5 days, or dose adjustment if appropriate – see Section 
6.1.2 


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5.2.5 
Procedures After Study Treatment 
5.2.5.1 
End of Study Visit or Early Withdrawal Visit 
Subjects who participate in the study in compliance with the protocol for at least 48 weeks of 
IMP administration will be considered to have completed the study and will be evaluated at 
52 weeks (Visit 16 – EOS).  
For subjects who withdraw prematurely from the study, final evaluations should be performed 
concomitantly with the Study Drug discontinuation decision, and in any case within 4 weeks 
after last dose of drug administered, either one has been administered (i.e. lanreotide ATG or 
TMZ). 
 
Data from any efficacy evaluations performed after this time will not be collected on the CRF. 
Subjects with ongoing AEs or clinically significant laboratory test abnormalities (as 
determined by the investigator) will be monitored as described in Section 8.1.3 and Section 
8.1.2.4, respectively. 
 
The following procedures will be performed at the End of Study Visit (Visit 16, W52 ± 2 
days), or Early Withdrawal visit: 
• 
Clinical and physical examination  
• 
Vital signs: assessment of blood pressure (BP), heart  rate and body weight (kg)  
• 
WHO performance score  
• 
Blood sample collection to assess Haematology: RBC count, haemoglobin, 
haematocrit, MCV, MCH, MCHC, WBC count, ANC, Platelets, Glycated 
Haemoglobin (HbA1c), aPTT, PT and INR. 
• 
Blood sample collection to assess Biochemistry: urea, serum creatinine (Cr), total 
serum bilirubin (direct bilirubin only if total serum bilirubin is out of range), 
electrolytes (chloride, sodium, potassium, calcium, phosphate), lactate dehydrogenase 
(LDH), ALT, AST, gamma glutamyl transferase (γGT), albumin, total protein, total 
cholesterol, triglycerides, fasting glucose, insulin, C-peptide, vitamin B12, TSH, FT3, 
FT4 
• 
Urinalysis  
• 
Blood sample collection for Centralized dosage of CgA and NSE 
• 
 
 
• 
CT scan (chest, abdomen and pelvis) 
• 
ECG and Echocardiography 
• 
Gallbladder Echography  
• 
Review of AEs 
• 
New or changed concomitant medications 
 
At their last study visit (EOS- V16-Week52), subjects still benefiting from treatment 
(according to the investigator judgment) will have the option, to continue to receive the 
combination of Lanreotide ATG 120 mg and TMZ 250 mg. In such a situation, Lanreotide 
120 mg and TMZ 250 mg will be provided free of charge by the Sponsor to the 
investigational sites under its commercial packaging, for a maximum of 12 months. During 
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this post-trial treatment, the Investigator will report immediately to Ipsen Pharmacovigilance 
Contact any safety concerns arising from the use of the product. 
 
6 
TREATMENT OF SUBJECTS 
6.1 
Study Drugs Administered 
At Screening, subjects will be allocated a subject number. Following confirmation of 
eligibility for the study, subjects will be treated as follow: 
• 
Lanreotide ATG 120 mg every 28 days, deep subcutaneous injection for a maximum of 
48 weeks, for a total number of 13 injections. 
• 
TMZ 250 mg hard capsules, for 5 consecutive days every 28 days, oral route, for a 
maximum of 48 weeks. 
6.1.1 
Lanreotide ATG 
Lanreotide ATG will be provided in a pre-filled syringe, and will be administered to the 
subjects at baseline and every 28 days, for 48 weeks of treatment through deep subcutaneous 
injection (total number of 13 injections), at the investigational site. 
If strictly required and after discussion with Sponsor, a maximum delay of four weeks in 
lanreotide administration is allowed.  
 
6.1.2 
Other Investigation Medicinal Products 
TMZ will be provided in glass bottles or blisters containing 5 hard capsules of TMZ. Capsules 
are presented as dose strength 180 mg or 250 mg. 
Starting dose of TMZ will be 250 mg /day. The first cycle intake will start the same day of the 
administration of Lanreotide ATG 120 mg and will continue for the next 4 days (5 days of 
treatment in total). A cycle treatment includes the first 5 days of each month. 250 mg of TMZ 
are equivalent to 150 mg/m2, considering the total standard adult body surface of 1.73 m2 
(man of about 70 kg of weight); this treatment schedule will be administered for a maximum 
of 48 weeks (about 12 months) or until progression/death or toxicity.  
TMZ hard capsules should be administered in the fasting state. Capsules must be swallowed 
whole with a glass of water and must not be opened or chewed. Anti-emetic therapy may be 
administered prior to or following administration of TMZ. 
Prior to dosing the following laboratory parameters must be met: ANC ≥ 1.5 x 109/L and 
platelet count ≥ 100 x 109/L. 
If at any study visit, at dosing before treatment cycle administration, haematology results 1.0 
< ANC < 1.5 x 109/L and/or 50<platelet count<100 x 109/L therapy must be postponed by 1 
week and haematological test repeated. If next dosing is ANC ≥ 1.5 x 109/L and platelets 
count ≥ 100 x 109/L therapy is assigned; if not, weekly re-dosing must be performed up to the 
third week after last TMZ administration. If haematological levels remain low, subject must 
be withdrawn. 
A TMZ dose reduction must be considered if ANC falls to < 1.0 x 109/L or platelet count is < 
50 x 109/L during any cycle (see Table 7). In this case therapy must be postponed by 1 week 
and haematological test repeated weekly until recovery (ANC ≥ 1.5 x 109/L and platelet count 
≥ 100 x 109/L), up to the fourth week after last TMZ administration. After recovery, TMZ 
dose will be reduced to 180 mg / day. This cycle treatment reduction is equivalent to 


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100 mg/m2, considering the total standard adult body surface of 1.73 m2 (man of about 70 kg 
of weight).  
If no recovery occurred within four weeks after last TMZ administration, subject should be 
discontinued from the study. 
If dose is reduced subject should remain on the reduced dose level for the rest of the study. Up 
titration dose is not allowed. 
Table 7 
Dose adaptation of TMZ 
TMZ (TMZ) dose levels 
Dose level 
TMZ dose (mg/day) 
Remarks 
0 
250 
Initiation dose 
-1 
180 
Reduction 
for 
prior 
toxicity 
TMZ dose reduction or discontinuation during monotherapy treatment 
Toxicity 
Reduced TMZ by 1 dose 
level (a) 
Discontinue TMZ 
Absolute 
neutrophil 
count (ANC) 
< 1.0 x 109/L 
See footnote  (b) 
Thrombocyte count 
<50x109/L 
See footnote  (b) 
CTC non-haematological 
toxicity  
CTC Grade 3 
CTC Grade 4 (b) 
a – TMZ dose levels are listed above 
b – TMZ is to be discontinued if 
 
Dose level -1 (180 mg/day) still results in unacceptable toxicity 
 
The same Grade 3 non-haematological toxicity recurs after dose reduction 
6.1.3 
Other Study Drugs 
Anti-emetic therapy may be administered prior to or following administration of TMZ. 
6.2 
Concomitant Medication/Therapy  
Any prior or concomitant medication given to a subject during the course of the study will be 
indicated on the CRF.  
Dose and generic name or trade name will be indicated. 
The following concomitant medications are not permitted during this study: 
• 
Cytotoxic therapies 
• 
Immunotherapies 
• 
Herbal medicine for anticancer treatment  
• 
Other Anti-cancer chemotherapy 
• 
Molecular target therapy  
• 
PRRT 
• 
Locoregional Therapies (TAE, TACE, SIRT, TARF) 
• 
Tumor Surgery 
• 
Radiotherapy (with the exception of external radiotherapy for bone metastasis) 
• 
Other Investigational therapies 
• 
Any somatostatin analogues other than study drug  
• 
Cyclosporin 
• 
GH (Growth Hormone) antagonist 
• 
Dacarbazine 


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6.3 
Procedures for Monitoring Subject Compliance 
The investigator will be responsible for monitoring subject compliance.  
Subjects can be withdrawn from the study at any time if the investigator or the sponsor 
decides that the subject is not in compliance with the study protocol. 
Compliance will be assessed only for TMZ by returned capsule count, because Lanreotide 
ATG will be administered as deep subcutaneous injection at the investigational site, so its 
compliance is ensured. Appropriate number of TMZ capsules will be given to the subject 
during visits. Deviations of 80 % of the scheduled amount of TMZ intake will be regarded as 
a major protocol violation 
Where a subject is consistently noncompliant with IMP intake they should be discontinued 
from IMP/withdrawn from the study. Please refer to Section 4.3 for the criteria for 
discontinuing the subject from IMP. 
 
 
 


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7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedule in Table 6. 
7.1 
Primary Efficacy Endpoint and Evaluation 
The primary efficacy endpoint is the response of subjects to the study combination therapy, 9 
months (Visit 12) after first treatment administration.  Responders are subjects showing 
disease control according to RECIST criteria v 1.1, defined as objective response or stability 
of the disease. They include: CR (complete response), PR (partial response) or SD (stable 
disease). 
7.2 
Secondary Efficacy Endpoints and Evaluations 
Secondary endpoints are: 
• 
Progression Free Survival (PFS), defined as the time from first treatment administration 
to disease progression according to RECIST criteria v 1.1 or death 
• 
Time to Response (TTR), defined as the time from first treatment administration to the 
first objective tumor response (PR or CR) according to RECIST criteria v 1.1 
• 
Duration of Response, defined as the time from onset of the first objective tumor 
response (PR or CR) to objective tumor progression (PD, according to RECIST criteria 
v 1.1) or death from any cause 
• 
Time to Progression (TTP) defined as the time from first treatment administration to 
the first objective tumor progression (PD) observed according to RECIST criteria v 1.1 
• 
Best Overall Response defined as the best response recorded from the time of the first 
treatment until disease progression/recurrence, or the end of study, according to 
RECIST criteria v 1.1 (CR, PR, SD, PD)  
• 
Objective Response Rate (ORR): Complete Response (CR), Partial Response (PR) at 9 
and 12 months 
• 
Disease Control Rate (DCR): Complete Response (CR), Partial Response (PR) and 
Stable Disease (SD) at 12 months 
• 
The influence of typical carcinoids and atypical carcinoid on the Disease control rate 
(DCR) at 9 months 
• 
Biochemical Response according to decrease in CgA plasma level in subject with 
baseline CgA level greater than ULN. Biochemical objective response is defined as a 
decreases of CgA ≥ 50%, while stable disease as a decrease ≥ 25%  and less than 50%, 
as their best response to study treatment 
• 
Value of NSE and CgA biomarkers levels at visits 2, 4, 6, 9, 12, 16 to assess their 
prognostic and predictive value 
• 
Biomarkers expression (immunohistochemistry assay SSTR2, Ki67 and MGMT status 
in tissue obtained from paraffin embedded primary tumour surgery specimens  or 
biopsies) correlated to tumor response (PFS and ORR and DCR) at 9 months and 12 
months (V 12 and V 16), to assess their prognostic value 
• 
The agreement of the central assessments of tumor radiological response and the local 
one, on the DCR at 9 months 
 
Secondary efficacy endpoints and evaluations are summarised in Table 8. 


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Table 8 
Secondary Efficacy Endpoints and Evaluations 
Measure 
Timepoint 
Variable  
Endpoint 
Tumor response 
according to RECIST 
criteria v 1.1 
At (visits 1, 6, 9, 
12, 16) 
Tumor response 
(CR, PR, SD or 
PD) 
• 
Objective response rate (ORR) 
according to RECIST data 
presentation model 
• 
Disease Control Rate (DCR) at 12 
months 
• 
Influence of typical/atypical 
carcinoids on DCR at 9 months 
• 
Time to Response (TTR) 
• 
Duration of Response 
• 
Time to progression (TTP) 
• 
Progression free survival (PFS) 
• 
Agreement between the central 
assessment of tumor radiological 
response and the local one 
• 
Best overall response 
• 
 
NSE and CgA plasma 
level 
each visit (visits 2, 
4, 6, 9, 12, 16) 
CgA and NSE 
 
• 
Biochemical Response 
• 
Prognostic and predictive value of 
CgA and NSE on PFS, ORR and 
DCR 
Biomarkers expression 
visits  1 
(availability of 
tissue sample) 
SSTR2, Ki67, 
MGMT 
 
• 
Prognostic value of biomarkers 
expression for PFS, ORR and DCR at 
9 and 12 months 
 
7.3 
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.  
7.3.1 
Responder Subjects 
Responders are subjects showing disease control at 9 months (Visit 12) according to RECIST 
criteria v 1.1 (see Appendix 1) defined as objective response or stability of the disease. They 
include: CR (complete response), PR (partial response) or SD (stable disease). 
Measurable disease lesions must be accurately measured in at least one dimension with 
longest diameter ≥ 10 mm with CT scan (with minimum lesion size no less than double the 
slice thickness).  
Tumor Evaluation with CT scan 
Tumor evaluation (chest, abdomen and pelvis) will be assessed at screening visit (V1) by 
means of triphasic CT scan. Measurable lesions, i.e., target lesions and the non-target lesions, 
by which subsequent response assessments will be judged, must be identified during tumor 
assessment at baseline (based on CT scan performed at screening visit). 
A CT scan or MRI, for imaging progression disease evaluation, done within 12 months prior 
to screening visit must be available and will be considered for subjects selection. 
Confirmation of a measurable tumour lesion presence will be done through a  CT scan at 
screening visit, (V1). 
A triphasic CT scan (chest, abdomen and pelvis) has to be repeated every 3 months and at 
End of Study (EOS) or at Early Withdrawal. The CT scan report must be available at the time 
of scheduled visits; the exam could be performed within maximum 10 days before the visit. 


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All CT scans must be performed at the investigational site; each site must have a designated 
radiologist or other physician responsible for the interpretation of CT scans, to evaluate CT 
scan report according to RECIST v 1.1 criteria. The same radiologist/physician should 
perform the evaluation for the entire duration of the study.  
Clinical decisions and evaluation assessments according to the endpoints will be done locally 
by the investigator with the local radiologist consultation.  
A second set of all original images are required for independent review to be performed by a 
centralized independent radiologist. The independent review will be performed at the end of 
the study and in addition to the local radiologist assessment. Treatment decisions during the 
study will be based on Investigator assessment. The primary analysis will be performed on the 
local RECIST v 1.1 assessment; a sensitivity analysis will be performed on the independent 
review. Agreement between the local and the independent review will be assessed.   
Baseline requirement 
All subjects should have at least one measurable target lesion. Measurable target lesions must 
be accurately measured in at least one dimension with longest diameter ≥ 10 mm with CT 
scan (with minimum lesion size no less than double the slice thickness), according to RECIST 
criteria v 1.1. 
Target lesions 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at screening visit (V1). Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated measurements. A 
sum of the longest diameters for all target lesions will be calculated and reported as the 
baseline sum of the longest diameters. The baseline sum of the longest diameters will be used 
as reference by which to characterize the objective tumour response. 
Response assessment 
Disease control rate is defined as SD, PR or CR according to RECIST criteria v 1.1. 
Partial response (PR) requires at least a 30% decrease in the sum of the longest diameters of 
all target lesions, taking as reference the baseline sum of the longest diameters. Complete 
response (CR) requires disappearance of all target and non-target lesions.  
Progression is either a 20% or more increase in the sum of the  longest diameters of all target 
lesions taking as reference the smallest sum on study, or the appearance of a new lesion, or 
the unequivocal progression of non-target lesions. 
Best Overall Response 
The best overall response to study treatment is the highest objective response achieved by the 
subject until the End of study/Early Withdrawal visit (V16), and will be rated according to 
RECIST v 1.1 criteria for reporting of results and include the following categories: 
• 
complete response (CR), 
• 
partial response (PR), 
• 
stable disease (SD), 
• 
progressive disease (PD) 
For Subjects with Measurable Disease the definition is as follows (Table 9): 


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Table 9 
Best Overall Response 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
 
Note: 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
7.3.2 
WHO performance score 
The WHO or Zubrod score (after C. Gordon Zubrod) will be collected at V1, V6, V9, V12 
and EOS, also known as Eastern Cooperative Oncology Group (ECOG) score, runs from 0 to 
5, with 0 denoting perfect health and 5 death (See Appendix 2).  
 
7.3.3 
Biomarkers 
NSE and CgA biomarkers (centralized evaluation) 
To detect biochemical response (CgA) and to evaluate the prognostic and predictive value of 
NSE and CgA, 
 
 
 
 
 
SSTR2, Ki-67 and MGMT (centralized evaluation) 
In order to evaluate the prognostic value of SSTR2, Ki67 and MGMT biomarkers expression, 
centralised immunohistochemistry assays, using appropriate specific antibodies, will be 
performed on tissue obtained from paraffin embedded primary tumour surgery specimens or 
biopsies: every effort should be done by the site staff to make them available. Biomarkers 
predictive value will be evaluated in terms of PFS, ORR and DCR at V12 and V16. 
Tumour tissue samples must be prepared and shipped by each centre to the central laboratory, 
according to procedures and time frame specified in the Study Manual. 
 
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7.3.4 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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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 (see Section 3.5 for a definition of the study duration) and 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. 
The safety of combination therapy will be monitored monthly through haematology renal, and 
biochemistry evaluations and TMZ dosage adjusted accordingly. 
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 IMP has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until the end of the study (as defined in Section 3.5). 
Natural progression or deterioration of the disease under study will be recorded as part of the 
efficacy evaluation and should not be recorded as an AE/SAE. 
Death due to disease progression will be recorded as part of the efficacy evaluation and will 
not be subject to expedited reporting to regulatory authorities. 
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 disease. 
These signs and symptoms should only be reported as AEs/SAEs (depending on the 
investigator’s judgement) if they are: 
• 
Judged by the investigator to be unusually severe or accelerated disease or 
• 
If the investigator considers the deterioration of disease signs and symptoms to be 
caused directly by the IMP. 
If there is any uncertainty about an AE being due solely to the disease under study, it should 
be reported as an AE/SAE as appropriate. 
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 version 4.03-14 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:  


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• 
Mild: symptoms do not alter the subject’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject 
• 
Severe: symptoms definitely hazardous to wellbeing, significant impairment of 
function or incapacitation. 
• 
Life threatening: any event that places the subject at immediate risk of death from the 
event as it occurred, i.e. it does not include a reaction that, had it occurred in a more 
severe form, might have caused death (also see Section 8.1.4). 
8.1.2.2 
Causality Classification 
The relationship of an AE to IMP administration will be classified according to the following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive de-challenge and/or re-
challenge) to assume a causal relationship with IMP 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 IMP administration. 
8.1.2.3 
Assessment of Expectedness 
The expectedness of an AE shall be determined by the sponsor according to the summary of 
product characteristics (SmPC) or package insert (PI) for an authorised medicinal product that 
is being used according to the terms and conditions of the marketing authorisation. If the IMP 
has marketing authorisations in several countries with different SmPCs or PIs, one will be 
selected as the reference document for assessing expectedness. 
The reference document for assessing expectedness of AEs/event in this study will be the 
current SmPCs. 
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 IMP schedule of administration (change in dosage, delay in 
administration, IMP 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) that result in a change in IMP dosage or administration 
schedule, or in discontinuation of the IMP, 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, the subject should be asked a non-leading question such as: “How have you felt 
since starting the new treatment/last dose/the last assessment?” 


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All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to IMP, will be recorded on the AE page(s) of the CRF/eCRF, including all AEs 
occurred within 4 weeks after the last dose of IMP, either one has been administered (i.e. 
lanreotide ATG or TMZ). Events involving drug reactions, accidents, illnesses with onset 
during the treatment phase of the study, or exacerbation’s of pre-existing illnesses should be 
recorded according to the National Cancer Institute (NCI) terminology. 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. IMP or other illness). The investigator is required to assess causality and record that 
assessment on the CRF/eCRF. Follow up of the AE, after the date of IMP 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 IMP 
must be reported immediately (within 24 hours of the investigator’s knowledge of the event) 
to the pharmacovigilance contact specified at the beginning of this protocol. If the immediate 
report is submitted by telephone, this must be followed by detailed written reports using the 
SAE report form. 
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 hospitalisation or prolongation of existing hospitalisation, 
excluding admission for social or administrative reasons (see further), 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a 
substantial disruption of a person's ability to conduct normal life functions, 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who received 
the IMP, 
(6) 
Is an important medical event that may not result in death, be life threatening, or 
require hospitalisation when, based upon appropriate medical judgement, may 
jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in in-subject hospitalisation, 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 
SAEs database system. 


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• 
Hospitalisation 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 hospitalisation is defined as any extension of an in-subject 
hospitalisation beyond the stay anticipated/required in relation to the original reason for 
the initial admission, as determined by the investigator or treating physician. For 
protocol-specified hospitalisation in clinical studies, prolongation is defined as any 
extension beyond the length of stay described in the protocol. Prolongation in the 
absence of a precipitating, treatment emergent, clinical AE (i.e. not associated with the 
development of a new AE or worsening of a pre-existing condition) may meet criteria 
for "seriousness" but is not an adverse experience and thus is not subject to immediate 
reporting to the sponsor.  
• 
Pre-planned or elective treatments/surgical procedures should be noted in the subject’s 
screening 
documentation. 
Hospitalisation 
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 IMP 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 (pharmacovigilance.italy@ipsen.com) within 24 hours for each 
SAE: 
• 
Study number 
• 
Centre number 
• 
Subject number 
• 
AE/SAE 
• 
Investigator's name and contact details 
The additional information included in the SAE form must be provided to the sponsor or 
representative as soon as it is available. The investigator should always provide an assessment 
of causality for each event reported to the sponsor. Upon receipt of the initial report, the 
sponsor will ask for the investigator's causality assessment if it was not provided with the 
initial report. 
The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to separate a primary AE considered as the 
foremost untoward medical occurrence from secondary AEs which occurred as complications. 
8.1.5 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP has 
interfered with a contraceptive method. If pregnancy occurs during the study, the outcome of 
the pregnancy will then need to be collected post-study and it may be necessary to discontinue 
administration of the IMP.  
Information regarding pregnancies must be collected on the AE page of the CRF/eCRF and 
reported to the sponsor as an SAE. The sponsor will request further information from the 


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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 IMP must also 
be reported to the investigator for onward reporting to the sponsor. 
 If the investigator becomes aware of a pregnancy occurring in the partner of a subject 
participating in the study, this should be reported to the sponsor. After the partner has given 
written consent, she should be counselled and followed as described above. Monitoring of the 
partner should continue until conclusion of the pregnancy. 
8.1.6 
Deaths 
All AEs resulting in death either during the study period or within 4 weeks after the last dose 
of IMP either one has been administered (i.e. lanreotide ATG or TMZ), must be reported as 
an SAE 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 
9.1.1). 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 NOS, 
• 
Disease progression NOS, 
• 
Multi-organ failure, 
• 
Sudden death. 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the IMP (see Section 4.3). 
If the IMP 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). 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring during the study to the 
Competent Authorities (CA), IECs and other investigators concerned by the IMP. Reporting 
will be done in accordance with the applicable regulatory requirements. 
8.2 
Clinical Laboratory Tests 
Blood samples will be collected at each visit (see Table 6 and Section 5.2) for the evaluation 
of haematology and biochemistry; urine samples will be collected at Visits 1, 2, 4, 5, 6, 9, 12, 
16 for urinalysis.  
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 


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section of the CRF/eCRF (see Section 8.1.2.4 for abnormal laboratory tests that should be 
recorded as AEs). 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to Baseline (V2) values 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 
Haematology 
Blood samples (about 5 mL, according to Local Laboratory Procedures) will be collected in a 
potassium ethylene-diamine-tetra-acetic acid (EDTA) tube to assess the following parameters: 
RBC count, haemoglobin, haematocrit, MCV, MCH, MCHC, WBC count, ANC, Platelets, 
Glycated Haemoglobin (HbA1c). 
Blood samples (about 3 mL according to Local Laboratory Procedures) will be collected in a 
citrated tube to assess the following coagulation parameters: activated partial thromboplastin 
time (aPTT), prothrombin time (PT) and and international normalised ratio (INR). 
8.2.2 
Blood Biochemistry 
Blood samples (about 5 mL, according to Local Laboratory Procedures) will be collected in 
an activator gel tube to assess the following parameters: urea, serum creatinine (Cr), total 
serum bilirubin (direct bilirubin only if total serum bilirubin is out of range) , electrolytes 
(chloride, sodium, potassium, calcium, phosphate), lactate dehydrogenase (LDH), ALT, AST, 
gamma glutamyl transferase (γGT), albumin, total protein, total cholesterol, triglycerides, 
fasting glucose, insulin, C-peptide, vitamin B12, TSH, FT3, FT4. 
 
Blood samples (about 10 mL) will be collected at screening visit (V1) to perform Serology 
assessments (hepatitis B surface antigen, hepatitis C antibody), according to Local Laboratory 
Procedures. 
 
CrCl will be calculated using Cockcroft-Gault Equation (Figure 4). 


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Figure 4 Cockcroft-Gault Equation 
 
8.2.3 
Urinalysis 
Fresh urine samples (at least 10 mL) will be collected to assess the following parameters: pH, 
protein, ketones, total bilirubin, blood, WBC, urobilinogen, glucose, nitrite and specific 
gravity and microscopy if necessary. Analysis by dipstick is allowed. 
Microscopy will be performed, if indicated, but results will not be collected in the eCRF. If in 
the opinion of the investigator there are any clinically significant abnormalities in microscopy, 
they will be recorded as an AE in the eCRF. 
8.2.4 
Pregnancy Test 
A human chorionic gonadotrophin (βHCG) serum test will be performed for all female 
subjects of childbearing potential at Screening (V1) and if clinically indicated thereafter. Any 
subject becoming pregnant during the study will be withdrawn. All pregnancies that occur 
during the study are to be reported as described in Section 8.1.5. 
8.2.5 
Other Clinical Laboratory Tests 
If necessary, additional clinical laboratory tests will be performed to ensure the safety of the 
subjects, but will not be an assessment of the safety of the study drug. 
8.3 
Physical Examination 
Physical examinations will be conducted at each visit. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 
the end of the study will be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
8.4 
Vital Signs 
Blood pressure (Systolic and Diastolic) 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 in supine, sitting or standing position according to clinical practice. Absolute 
values and change from Baseline (V2) will be analysed. 
8.5 
Electrocardiography 
An ECG analysis will be included as a safety evaluation/endpoint in this study. 
The ECGs will be recorded at screening (V1), V9 and EOS. 


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Twelve lead ECGs will be recorded so that the different ECG intervals (RR, PR, QRS, QT) 
can be measured QTc will be measured automatically according the Bazett formula 
[Corrected QT (QTC) = Bazett's Formula = QT Interval / √ (RR interval)  RR Interval = 
60/HR]. The ECG will be recorded with the subject in supine position after five minutes of 
rest until four regular consecutive complexes are available. Automated ECG intervals 
estimates taken from the ECG recorder will be used in this study. 
Any clinically significant abnormalities will be recorded as AEs. 
8.6 
Echocardiography 
M- and B-mode echocardiography will be performed at screening (V1), V9 and EOS. The 
following assessments, as recommended by ENETS Consensus Guidelines [44] will be 
performed:  
• 
Valves function and morphology 
• 
Left and Right Ventricular size and function 
• 
Patency of the foramen ovale 
• 
Wall thickness 
8.7 
Gallbladder echography  
Within 4 weeks prior to first study treatment intake, ultrasound examination of the gallbladder 
will be performed on each subject by Gallbladder echography. The measurement will be 
repeated at V9 and EOS. It is highly recommended to use the technique used at the screening 
visit for the following assessments of gallbladder function for each subject.  


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9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
Pharmacokinetics and pharmacodynamics are not assessed in this study. 


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10 
STATISTICS 
10.1 
Analyses Populations 
The following population will be used during statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent). 
• 
Intention to treat (ITT)/Safety population: All subjects who received at least one 
dose of study medication (either LAN ATG 120 mg or TMZ).  
• 
Per protocol (PP) population: All subjects in the ITT population for whom no major 
protocol violations/deviations occurred. 
10.1.1 
Populations Analysed 
The primary analysis based on the primary efficacy endpoint(s) will be performed on the 
ITT/Safety population. In addition, PP analysis may be performed as a supportive analysis. 
The analyses of safety data will be performed based on the ITT/safety 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 and its impact on inclusion in each analysis population (ITT/safety and PP 
populations) for any subject will be specified. The final list of protocol deviations impacting 
the PP population will be reviewed during the data review meeting held prior to database 
lock. The list of major protocol deviations impacting inclusion in the populations will be 
reviewed during the data review meeting held prior to database lock. The list will be updated 
to include any additional major protocol deviations impacting inclusion in all populations. 
10.2 
Sample Size Determination 
Sample size and statistical assumption were made according to a Fleming’s Single Stage 
Design. 
To demonstrate the efficacy of TMZ associated to Lanreotide, we consider the proportion of 
responders as subjects with DCR after 9 months of therapy.  
The following assumptions are made: 
• 
The proportion of responders should be equal or greater than 30% to be clinically 
relevant (π1), 
• 
a proportion of responders equal or lower than 10% is considered as not acceptable 
(π0), 
• 
the 1-sided error probability is set to α = 0.025 and  
• 
the power is set to 90% (β = 0.10). 
The 1-sided hypotheses to be tested are: 
π < π0 and π > π1; 
35 evaluable subjects are needed. 
Estimating a 10% of drop-out rate the total number of subjects to be treated is set to N=40. 
Calculations were made using “Statistical Tables for the Design of Clinical Trials” [43]. 
10.3 
Significance Testing and Estimations 
The statistical test on the primary objective will be performed one sided with a type I error 
rate set at 2.5%. 
All other statistical tests will be performed two sided with a type I error set at 5 %.  


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10.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external Contract Research Organisation (CRO), 
managed by the sponsor’s Specialty Franchise Clinical Operations Department. 
A Statistical Analysis plan (SAP) describing the planned statistical analysis in detail with 
tables, figures and listings (TFLs) templates will be developed as a separate document. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® (version 8 
or higher). 
 
 
10.4.1 
Demographic and Other Baseline Characteristics 
Descriptive summary statistics (n, mean, standard deviation (SD), median, minimum, 
maximum) or frequency counts of demographic and baseline data (medical history, 
concomitant disease (predosing AEs and ongoing medical history, prior medications and 
therapies, baseline symptoms, etc) will be presented for the ITT/safety population. 
10.4.2 
Homogeneity of Treatment Groups 
Not applicable. 
10.4.3 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects screened and included in each of the populations 
will be tabulated. The reasons for subject exclusions from each of the populations will also be 
tabulated. In addition, the numbers of subjects who were treated, discontinued and completed 
will be tabulated. Primary reasons for discontinuation of study treatment will be tabulated. 
10.4.4 
Pharmacokinetic Data 
Not applicable. 
10.4.5 
Efficacy Evaluation 
As indicated in Section 7.1, the primary efficacy variable is response of subjects to the study 
combination therapy, 9 months (V 12) after first treatment administration.  Responders are 
subjects showing disease control according to RECIST criteria v 1.1, defined as objective 
response or stability of the disease. They include: CR (complete response), PR (partial 
response) or SD (stable disease). The response rate will be analysed by an exact binomial 
proportion test for one-way tables in the ITT/safety population. A supportive analysis will be 
performed on the PP population. In addition a sensitivity analysis will be performed on both 
populations based on the independent assessment performed at the end of the study by the 
central reading committee.  
As indicated in Section 7.2, the secondary efficacy endpoints are: 
• 
Best Overall Response defined as the best response recorded from the time of the first 
treatment until disease progression/recurrence or the end of study, according to 
RECIST criteria v 1.1 (CR, PR, SD, PD  
• 
 analysed using frequency tables; 
• 
Chromogranin A (CgA) levels will be detected at baseline and during treatment period 
every 3 months as a surrogate efficacy endpoint (biochemical response). Subjects will 
be considered to have an objective biochemical response if there is a ≥50% reduction in 
plasma CgA from baseline level, while stable disease is defined as decrease ≥25% and 
less than 50%, as the best response to study treatment. 
CCI


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• 
Chromogranin A (CgA) and NSE levels assessed at Visit 2, Visit 4, Visit 6, visit 9, visit 
12 and EOS will be presented by mean values, standard deviations, minimum, 
maximum and 95%-confidence intervals of the mean at each timepoint (for raw values 
and changes from baseline). In addition, both of these parameters will be analysed by 
ANCOVA for repeated measures, using baseline values as covariates.  
• 
Progression Free Survival (PFS) is defined as the time from 1st treatment administration 
until progression according to RECIST criteria vs 1.1. 
PFS of subjects who are lost to follow-up and those who have not progressed at EOS will be 
censored at the date of the last disease assessment subject to rules summarised in Table 10. 
Table 10 Censoring Rules for PFS 
Situation 
Date of Censoring 
No baseline evaluable assessment  
Date of 1st treatment administration 
Two or more not evaluable (NE) 
assessments before PD or death 
Date of last evaluable disease assessment before the second NE 
assessment 
No PD 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented 
progression  
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or 
other reason  
Date of last evaluable disease assessment 
Initiation of medications or therapies not 
permitted during the study (including new 
anti-cancer therapies) 
Date of last evaluable disease 
assessment prior to the initiation of not permitted 
medication or therapies. 
 
The distribution of PFS times will be estimated using the Kaplan-Meier method. The median 
PFS and its associated 95 % CI will be estimated.  
• 
Time to response (TTR) is defined as the time from 1st treatment administration to the 
first objective tumor response (PR or CR) according to RECIST criteria vs 1.1.  
TTR of subjects who are lost to follow-up or die prior to any objective tumor response 
will be censored at the date of the last disease assessment subject to rules summarised 
in Table 11.  
Table 11 Censoring Rules for TTR 
Situation 
Date of Censoring 
No baseline evaluable assessment  
Date of 1st treatment administration 
PD or death 
Date of last evaluable disease assessment before PD or death. 
No PR nor CR 
Date of last evaluable disease assessment 
Treatment discontinuation  
Date of last evaluable disease assessment 
 
• 
The distribution of TTR will be estimated using the Kaplan-Meier method. The median 
TTR and its associated 95 % CI will be estimated.  
Duration of response is defined as the time from onset of the first objective tumor 
response (PR or CR) to objective tumor progressions (PD) according to RECIST 
criteria vs 1.1. 
Subjects without any PR or CR will not be taken into account in this analysis. Duration 
of response of subjects who are lost to follow or do not progress following the first 
objective tumor response will be censored at the date of the last disease assessment. 


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The distribution of duration of response will be estimated using the Kaplan-Meier 
method. The median duration of response and its associated 95 % CI will be estimated.  
• 
Time to progression (TTP) is defined as the time from first treatment administration to 
the first objective tumor progression (PD) according to RECIST criteria vs 1.1. 
TTP of subjects who are lost to follow-up, and those who have not progressed at EOS 
will be censored at the date of the last disease assessment subject to rules summarised 
in Table 12. 
Table 12 Censoring Rules for TTP 
Situation 
Date of Censoring 
No baseline evaluable assessment  
Date of 1st treatment administration 
Two or more not evaluable (NE) assessments 
before PD or death 
Date of last evaluable disease assessment before the second NE 
assessment 
No PD 
Date of last evaluable disease assessment 
Treatment discontinuation for undocumented 
progression  
Date of last evaluable disease assessment 
Treatment discontinuation for toxicity or 
other reason  
Date of last evaluable disease assessment 
Initiation of medications or therapies not 
permitted during the study (including new 
anti-cancer therapies) 
Date of last evaluable disease 
assessment prior to the initiation of not permitted 
medication or therapies. 
 
The distribution of TTP times will be estimated using the Kaplan-Meier method. The median 
TTP and its associated 95 % CI will be estimated.  
• 
Best overall response according to RECIST criteria v 1.1 (CR, PR, SD, PD) 
• 
Objective Response Rate (ORR): Complete Response (CR), Partial Response (PR) at 
12 months 
• 
Disease Control Rate (DCR): Complete Response (CR), Partial Response (PR) and 
Stable Disease (SD) at 9 and 12 months 
• 
The influence of typical carcinoids and atypical carcinoid on the Disease control rate 
(DCR) at 9 months (V 12) will be analysed using frequency tables. 
• 
The prognostic and predictive value of NSE and CgA biomarkers levels on PFS will be 
analysed using a Cox-proportional hazard model and the influence on DCR at 9 and 12 
months (V 12 and V 16) will be analysed using a logistic model. 
• 
The prognostic value of biomarkers expression (immunohistochemistry assay SSTR2, 
Ki67 and MGMT status in tissue obtained from paraffin embedded primary tumour 
surgery specimens  or biopsies) for PFS will be analysed using a Cox-proportional 
hazard model  and the influence on ORR and DCR at 9 and 12 months (V 12 and V 16) 
will be analysed using a logistic model. 
• 
The agreement of the central assessments of radiological response and the local one 
will be analysed using Cohen’s kappa. 
10.4.6 
Adjustment for Country/Centre Effect 
No adjustment per centre will be performed.   
10.4.7 
Safety Evaluation 
All safety data will be included in the subject data listings. Analyses and summary tables will 
be based upon the safety population.  


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Adverse events reported by investigators using the NCI-CTC classification (version 4.03) will 
be coded using MedDRA dictionary (version 20.0 or higher).  
Summary incidence tables will be provided, classified by body system, preferred term and 
associated NCI/CTC worst grade. In the event of multiple occurrences of the same AEs being 
reported by the same subject, the maximum intensity (Grade 5 > Grade 4 > Grade 3 > Grade 2 
> Grade 1 > missing > not applicable) will be chosen. Dose delays, dose interruptions will be 
listed by cycle. 
Haematological and biochemistry toxicities will be recorded and graded according to the 
NCI-CTC criteria. All haematology and biochemistry parameters by subject will be listed. In 
addition, summary tables will be presented by maximum intensity, drug relationship and 
AEs/TEAEs associated with premature withdrawal of study medication. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving the first dose of IMP, or  
• 
it was present prior to receiving the first dose of IMP but the intensity increased during 
the active phase of the study, or  
• 
it was present prior to receiving the first dose of IMP, the intensity is the same but the 
drug relationship became related during the active phase of the study.  
All TEAEs will be flagged in the AEs listings. 
Concomitant medication will be coded by using WHO Drug Dictionary (version 2009) and 
will be summarised with the number and percentage of subjects receiving concomitant 
medication by drug class and preferred drug name. 
Summary statistics (mean, median, SD and range as appropriate) by overall will be presented 
for vital signs, blood pressure, heart rate, ECG parameters, clinical laboratory tests 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 normal or abnormal exams. 
10.5 
Subgroup Analyses 
Subgroup analyses will be performed according to the typical/atypical classification.  
10.6 
Interim Analyses 
No interim analysis will be performed. 


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11 
ACCESS TO SOURCE DATA AND DOCUMENTS 
Authorised personnel from external CAs and sponsor authorised Quality Assurance personnel 
may carry out inspections and audits. The purpose of an audit is to ensure that ethical, 
regulatory and quality requirements are fulfilled in all studies performed by the sponsor. 
Auditors and inspectors must have direct access to study documents and site facilities as 
specified in Section 12.4, and to any other locations used for the purpose of the study in 
question (e.g. laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
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 IEC/IRB, except when 
necessary to eliminate immediate safety concerns to the subjects or when the change involves 
only logistics or administration. The principal investigator and the sponsor will sign the 
protocol amendment. 
12.1.2 
Protocol Deviations, Violations, and Exceptions 
A protocol deviation is nonadherence to protocol specific study procedures or schedules that 
does not involve inclusion/exclusion criteria, primary objective evaluation criteria, and/or 
GCP guidelines. Deviations are considered minor and do not impact the study. 
A protocol violation is any significant divergence from the protocol, i.e. nonadherence on the 
part of the subject, the investigator, or the sponsor to protocol specific inclusion/exclusion 
criteria, primary objective evaluation criteria, and/or GCP guidelines. Protocol violations will 
be identified and recorded, by study centre personnel, on the CRF. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific entry criteria 
to allow subjects to enter a study. If under extraordinary circumstances such action is 
considered ethically, medically, and scientifically justified for a particular subject, prior 
approval from the sponsor and the responsible IRB/IEC, in accordance with the Standard 
Operating Procedure (SOP), is required before the subject will be allowed to enter the study. 
If investigative centre personnel learn that a subject who did not meet protocol eligibility 
criteria was entered in a study (a protocol violation), they must immediately inform the 
sponsor. Such subjects will be discontinued from the study, except in an exceptional instance 
following review and written approval by the sponsor and the responsible IRB/IEC, according 
to the applicable SOP. 
12.2 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of subject management, both before starting any study 
procedures and during the course of the study (e.g. when new staff become involved). The 
investigator must assure that all study staff members are qualified by education, experience, 
and training to perform their specific responsibilities. These study staff members must be 
listed on the study centre authorisation form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
12.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring this data to verify that the rights and wellbeing of 
subjects are protected, that study data are accurate (complete and verifiable to source data) 
and that the study is conducted in compliance with the protocol, GCP and regulatory 
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Sponsor assigned monitors will conduct regular site visits. The investigator will allow direct 
access to all relevant files (for all subjects) and clinical study supplies (dispensing and storage 
areas) for the purpose of verifying entries made in the eCRF, and assist with the monitor’s 
activities, if requested. Adequate time and space for monitoring visits should be made 
available by the investigator. 
The site must complete the eCRFs according to the 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 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. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the investigator by the monitor for 
clarification/correction. The investigator must ensure that queries are dealt with promptly. All 
data changes and clarifications can be viewed in the audit trail function of the eCRF. 
 
12.6 
Steering Committee 
Since September 2016 a Study Steering Committee has been designated. The role of the Study 
Steering Committee (SSC) is to provide overall supervision for the ATLANT Study in 
collaboration with the Trial Sponsor (Ipsen).  
The ATLANT Steering Committee member’s responsibilities are the following:  
 To leverage external and internal expertise in the planning and execution of the study 
 To identify and resolve study obstacles and issues 
 To provide advice and support to the Sponsor on medical and safety aspects of the 
trial.  
 To analyze and comment the study results  
 To facilitate the communication with the participating sites 
 To collaborate with the Trial Sponsor in the Scientific Communications & 
Publications of study results 
 To agree to proposals for substantial protocol amendments 


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The ATLANT Study Steering Committee will consist of 3 external members experts in 
treatment of lung NETs. The SSC will consist of the following KOLs: 
 
 Alfredo Berruti – U.O.Oncologia A.O. Spedali Civili (Brescia) 
 Nicola Fazio – Unità Oncologia Medica Gastrointestinale e Tumori Neuroendocrini 
IEO (Milano) 
 Piero Ferolla – SC Oncologia Medica A.O. U. di Perugia Ospedale “Santa Maria della  
           Misericordia (Perugia) 
The formal designation of SSC members, their activities as well as the confidentiality of all 
information/study document/data are described and regulated by the specific contract properly 
signed by parties. 


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13 
ETHICS 
13.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, 
the Declaration of Helsinki and ICH GCP Guidelines (Section 1 or 1.6). 
In addition, this study will adhere to all local regulatory requirements and Food and Drug 
Administration (FDA), 21 CFR Part 11, Electronic Records, Electronic Signatures, and FDA, 
Guidance for Industry: Computerized Systems Used in Clinical Trials. 
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject recruitment procedures (e.g. 
advertisements), any written information to be provided to subjects and a statement from the 
IEC/IRB that they comply with GCP requirements. The IEC/IRB approval must identify the 
protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has 
started, amendments should be made only in exceptional circumstances. Changes that do not 
affect subject safety or data integrity are classified as administrative changes and generally do 
not require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
13.2 
Informed Consent 
Prior to study entry, the investigator, or a person designated by the investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject, subject’s 
legally acceptable representative or impartial witness. Written informed consent must be 
obtained prior to the subject entering the study (before initiation of any study-related 
procedure and administration of the IMP). Sufficient time will be allowed to discuss any 
questions raised by the subject. 
The sponsor will provide a sample informed consent form. The final version controlled form 
must be agreed to by the sponsor, and the IEC/IRB 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. 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject or as a result of protocol 
amendments. In this instance approval should always be given by the IEC/IRB. It is the 
investigator’s responsibility to ensure that all subjects subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
previously described. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 
The investigator should, with the consent of the subject, inform the subject’s primary 
physician about their participation in the clinical study. 


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13.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s Regulatory Affairs group will ensure all legal 
regulatory aspects are covered, and obtain approval of the appropriate regulatory bodies, prior 
to study initiation in regions where an approval is required. 
13.4 
Confidentiality Regarding Study Subjects 
The investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In CRFs 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. initials and identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the CRF. 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, IMP 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.  
The investigator must, as a minimum, provide an electronic signature (e-signature) to each 
case report book to attest to the accuracy and completeness of all the data. If any changes are 
made to the eCRF, after a form has been locked and electronically signed, the investigator 
will be required to perform an additional e-signature authorising agreement with any new 
information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on 
each item entered. 
14.2 
Data Management 
Electronic Data Capture (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 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 Monitoring Procedures). Any data documentation removed from the investigator 
site(s) will be tracked by the CRO and the monitor. 
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately, 
and suitable queries are raised to resolve any missing or inconsistent data. The investigator will 
receive their data, from the clinical study, in an electronic format (PDF files) which will be an 
exact copy of the eCRF, and will include the full audit trail, for archiving purposes and future 
reference. 
Any queries generated during the data management process will also be tracked by the 
contracted data management CRO/will be raised within the EDC system. It is the central study 
monitor’s responsibility to ensure that all queries are resolved by the relevant parties. 
The sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history and concomitant medication terms will be performed by 
the sponsor’s Coding Group. Concomitant medications will be coded using WHODRUG and 
AEs/Surgical procedures/Non drug Therapies/Medical history terms will be coded using 
MedDRA. 


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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.  
Trial documents must be retained according to current and applicable regulatory requirements 
and national laws. 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 Local legislation 
(AIFA, D.M. 51, 21-Dec 2007). 
15.2 
Insurance, Indemnity and Compensation 
The sponsor will provide Product Liability insurance for all subjects included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 


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


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17 
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19. 
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Walter T et al. New treatment strategies in advanced neuroendocrine tumours. Dig 
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Chan JA and Kulke MH. New treatment options for subjects with advanced 
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Welin S et al. Clinical effect of Temozolomide-based chemotherapy in poorly 
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Eriksson B. New drugs in neuroendocrine tumors: rising of new therapeutic 
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Kulke MH et al. O6-methylguanine DNA methyltransferase deficiency and response to 
Temozolomide-based therapy in subjects with neuroendocrine tumors. Clin Cancer 
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Perry JR1 et Al. Phase II trial of continuous dose-intense Temozolomide in recurrent 
malignant glioma: RESCUE study. J Clin Oncol. 2010 Apr 20;28(12): Erratum in J 
Clin Oncol. 2010 Jul 20;28(21):3543 


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37. 
Kyung-Ko et Al. Metronomic treatment of Temozolomide increases anti-angiogenicity 
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Caplin M., Baudin E., Ferolla P. et al. in submission to Annals of Oncology 2014 
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Neuroendocrine Tumors: Ehocardiography. Neuroendocrinology. 2009;90:190-193 


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18 
LIST OF APPENDICES 
Appendix 1 RECIST Criteria version 1.1 ................................................................. 88 
Appendix 2 WHO Performance status ..................................................................... 92 
Appendix 3 Common Terminology Criteria for Adverse Events (CTCAE) ............ 94 
Appendix 4 Protocol Amendment #1 ....................................................................... 96 
Appendix 5 Protocol Amendments  # 2 and 3 ........................................................ 103 
 


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Appendix 1 RECIST Criteria version 1.1 
 


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RECIST Criteria version 1.1  
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions are used 
in the RECIST and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g. skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g. skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
• 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung.  However, CT is preferable.  
• 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
• 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved in 
MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease.  Furthermore, as with CT, 
the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters 
for all scanners, body parts, and diseases.  Ideally, the same type of scanner should be 
used and the image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should be performed with breath-hold scanning techniques, if 
possible. 
• 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST measurements 
and can be used interchangeably with conventional CT in accurately measuring cancer 
lesions over time.  Note, however, that the PET portion of the CT introduces additional 
data which may bias an investigator if it is not routinely or serially performed.   


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• 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
Evaluation of Target Lesions 
• 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
• 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
• 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered progressions). 
• 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study 
Evaluation of Non-Target Lesions 
• 
Complete Response (CR): 
Disappearance 
of 
all 
non-target 
lesions 
and 
normalization of tumor marker level.  All lymph nodes must be non-pathological in 
size (<10 mm short axis). 
• 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a subject to be considered in complete clinical response. 
• 
Non-CR/Non-PD: 
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
• 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 


IPSEN GROUP 
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For Subjects with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Subjects with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised 
 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
 


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Appendix 2 WHO Performance status 
 


IPSEN GROUP 
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WHO Performance status 
Grade 
Explanation of activity 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 


IPSEN GROUP 
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Appendix 3 Common Terminology Criteria for Adverse Events (CTCAE) 
 


IPSEN GROUP 
A-93-52030-325 
 
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PROTOCOL: FINAL 3.0 (INCLUDING AMENDMENT #2 AND #3) 16 NOVEMBER 2017  PAGE 95/110 
 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
 

SAP_001.pdf: 
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0DQDJHULDO
*07
PPD
PPD
PPD
PPD


 
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STATISTICAL AND ANALYSIS PLAN 
 
EFFICACY AND SAFETY OF LANREOTIDE ATG 120 MG IN COMBINATION 
WITH TEMOZOLOMIDE IN SUBJECTS WITH PROGRESSIVE WELL 
DIFFERENTIATED THORACIC NEUROENDOCRINE TUMORS 
A PHASE II, MULTICENTRE, SINGLE ARM, OPEN-LABEL TRIAL 
 
 
PROTOCOL VERSION AND DATE: 
FINAL 3.0: 16 NOVEMBER 2017 
 
 
 
SAP Version 
Date 
Final, Version 2.0 
04 May 2020 


 
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STUDY NUMBER: 
A-93-52030-325 
EUDRACT NUMBER 
2014-005579-10 
PROTOCOL TITLE: 
EFFICACY AND SAFETY OF LANREOTIDE ATG 
120 
MG 
IN 
COMBINATION 
WITH 
TEMOZOLOMIDE 
IN 
SUBJECTS 
WITH 
PROGRESSIVE 
WELL 
DIFFERENTIATED 
THORACIC NEUROENDOCRINE TUMORS  
SAP VERSION: 
Final version 2.0 
SAP DATE: 
04 May 2020 
 
Further to your review and agreement to the Statistical and Analysis Plan version 
indicated above, please sign to indicate approval for your area of responsibility: 
 
Responsibility 
Name, title & Office 
Signature 
Date 
Biostatistics & Data 
Management Director 
 
Boulogne Billancourt, 
France 
 
 
Medical Development 
Director 
 
Ipsen SpA - 
Assago, Italy 
 
 
 
Responsibility 
Name, title & Office 
Signature 
Date 
Study statistician 
 
Biotrial Biometrics, Rennes, France 
 
 
Manager statistician 
 
Biotrial Biometrics, Rennes, France 
 
 
 
IMPORTANT: This completed record (with additional sheets, where required), confirms the 
above-mentioned Statistical and Analysis Plan version became the Final Statistical and 
Analysis Plan 
PPD
PPD
PPD
PPD


 
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History of Changes 
Old Version 
Number 
Date Old 
Version 
Date New 
Version 
Reason for Change 
Page 
Section 
Was 
Is 
11 
1.2 
16SEP2019 
04MAY2020 
Delete sentence stating that the primary 
endpoint will be based on subjects who 
completed all scheduled visit until V12, 
since disease control rate will also be 
assessed according to subjects withdrawn 
before 9 months. 
21 
21 
25 
26 
41 
41 
44 
45 
3.1.1 
3.1.2 
3.2.1.1.1 
3.2.1..1.2 
3.2.1.2.7 
3.2.1.2.8 
3.2.1.2.13 
3.2.1.2.14 
16SEP2019 
04MAY2020 
Deletion of reference to visits 12 and 16 
after the mentions of the 9 and 12 months 
assessments since subjects withdrawn 
earlier will also be considered. 
22 
3.2.1 
16SEP2019 
04MAY2020 
Update of the summary of efficacy 
analyses to describe the amended analyses. 
25 
3.2.1.1.1 
16SEP2019 
04MAY2020 
Update of the primary endpoint definition 
to include subjects withdrawn before 
9 months in the assessment of DCR at 
9 months. 
Addition of the threshold 10 % for the 
statistical test of the proportion of 
responders. 
26 
3.2.1..1.2 
16SEP2019 
04MAY2020 
Update of the sensitivity analyses to 
include 
subjects 
withdrawn 
before 
9 months in the assessment of DCR at 
9 months. 
41 
3.2.1.2.7 
16SEP2019 
04MAY2020 
Update of the objective rate definition to 
include subjects withdrawn before 9 and 
12 months in the assessments at 9 and 
12 months. 
41 
3.2.1.2.8 
16SEP2019 
04MAY2020 
Update of the DCR at 12 months definition 
to include subjects withdrawn before 
12 months in the assessment. 
45 
57 
61 
3.2.1.2.14 
6 
7.2 
16SEP2019 
04MAY2020 
Update of publications references. 


 
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56 
5 
16SEP2019 
04MAY2020 
Modification of the primary endpoint 
reported as a change from the protocol. 
66 
7.3 
16SEP2019 
04MAY2020 
Update of the list of TFLs according to 
modifications done in the body of the 
document 
 
 
 
 
 


 
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TABLE OF CONTENTS 
1 
INFORMATION TAKEN FROM THE PROTOCOL ............................................. 11 
1.1 
Study objectives ............................................................................................................. 11 
1.1.1 
Primary objective ......................................................................................... 11 
1.1.2 
Secondary objectives ................................................................................... 11 
1.2 
Study design ................................................................................................................... 12 
1.2.1 
Study population ......................................................................................... 12 
1.2.2 
Study exposure ............................................................................................ 13 
1.3 
Methods and procedures .............................................................................................. 13 
1.3.1 
Subject identification and allocation to study treatment ........................... 13 
1.3.2 
Subjects assessments ................................................................................... 13 
1.3.2.1 
Efficacy assessments .................................................................................... 13 
1.3.2.2 
Safety assessments ....................................................................................... 13 
1.3.2.3 
Other assessments ........................................................................................ 15 
1.3.2.4 
Withdrawal/discontinuation ......................................................................... 15 
1.3.3 
Schedule of assessments ............................................................................. 17 
1.3.4 
Planned sample size .................................................................................... 20 
2 
SUBJECT POPULATIONS (ANALYSIS SETS) ...................................................... 21 
2.1 
Efficacy .......................................................................................................................... 21 
2.1.1 
Intention-to-treat (ITT)/safety population ................................................. 21 
2.1.2 
Per-protocol population (PP) ...................................................................... 21 
2.2 
Safety .............................................................................................................................. 21 
3 
STATISTICAL METHODS ........................................................................................ 22 
3.1 
Statistical analysis strategy .......................................................................................... 22 
3.1.1 
Primary efficacy endpoint ........................................................................... 22 
3.1.2 
Secondary efficacy endpoints ..................................................................... 22 
3.1.3 
Safety endpoints .......................................................................................... 23 
3.1.4 
Multiplicity .................................................................................................. 23 
3.1.5 
Significance testing and estimation ............................................................ 23 
3.2 
Analysis methods ........................................................................................................... 23 
3.2.1 
Efficacy ........................................................................................................ 23 
3.2.1.1 
Primary efficacy analysis ............................................................................. 28 
3.2.1.2 
Secondary efficacy analyses ........................................................................ 29 
3.2.2 
Safety ........................................................................................................... 49 
3.2.2.1 
Adverse events .............................................................................................. 49 
3.2.2.2 
Laboratory data ........................................................................................... 50 
3.2.2.3 
Vital signs ..................................................................................................... 51 
3.2.2.4 
ECG .............................................................................................................. 51 
3.2.2.5 
Echocardiography ........................................................................................ 52 
3.2.2.6 
Gallbladder echography .............................................................................. 52 


 
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3.2.3 
Missing data and outliers ............................................................................ 52 
3.2.3.1 
Missing data ................................................................................................. 52 
3.2.3.2 
Missing or incomplete dates ........................................................................ 53 
3.2.3.3 
Outliers ........................................................................................................ 53 
3.2.4 
Subject disposition ....................................................................................... 53 
3.2.5 
Withdrawals ................................................................................................. 54 
3.2.6 
Demographic and baseline characteristics ................................................ 54 
3.2.7 
Medical and surgical history ...................................................................... 54 
3.2.8 
Subject compliance ..................................................................................... 55 
3.2.9 
Prior and concomitant medications, therapies and surgical procedures.. 55 
3.2.10 
Derived data ................................................................................................. 56 
3.2.11 
Visit windows ............................................................................................... 56 
3.2.12 
Rules and data formats ............................................................................... 57 
3.2.13 
Pooling of centres ........................................................................................ 58 
3.2.14 
Interim analysis ........................................................................................... 58 
3.2.15 
Role of independent data monitoring committee (DMC)/interim data 
review committee [if applicable] ................................................................. 58 
3.2.16 
Covariates and analysis of subgroups ........................................................ 58 
4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS . 59 
4.1 
Hardware ....................................................................................................................... 59 
4.2 
Software ......................................................................................................................... 59 
4.3 
Validation programs ..................................................................................................... 59 
4.4 
Restitution of the programs ......................................................................................... 59 
5 
CHANGES FROM PROTOCOL ................................................................................ 60 
6 
REFERENCES .............................................................................................................. 61 
7 
APPENDICES ............................................................................................................... 62 
 
LIST OF TABLES 
Table 1 
Study procedures and assessments .................................................................... 18 
Table 2 
Summary of all efficacy analyses ....................................................................... 23 
Table 3 
PFS analysis assessed locally .............................................................................. 30 
Table 4 
Event status for various scenarios with missing data ...................................... 31 
Table 5 
PFS analysis assessed centrally .......................................................................... 32 
Table 6 
TTR analysis assessed locally ............................................................................. 34 
Table 7 
TTR analysis assessed centrally ......................................................................... 35 
Table 8 
DOR analysis assessed locally ............................................................................ 37 
Table 9 
DOR analysis assessed centrally ........................................................................ 39 
Table 10 
TTP analysis assessed locally .............................................................................. 41 
Table 11 
TTP analysis assessed centrally .......................................................................... 43 
Table 12 
Visit windows ....................................................................................................... 57 
 


 
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LIST OF FIGURES 
Figure 1 
Study design ......................................................................................................... 12 
 
CCI


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADaM: 
Analysis Data Model 
AE: 
Adverse Event/Experience 
ANC: 
Absolute Neutrophils Count 
aPTT: 
activated Partial Thromboplastin Time 
ATG: 
Autogel 
ALT: 
Alanine aminotransferase 
AST: 
Aspartate aminotransferase 
ATC: 
Anatomic Therapeutic Class 
ANCOVA: 
Analysis of Covariance 
BMI: 
Body Mass Index 
BOR: 
Best Overall Response 
ßHCG:  
Human Chorionic Gonadotrophin  
CgA: 
Chromogranin A 
CI: 
Confidence Interval 
Cr: 
Serum creatinine 
CR: 
Complete Response 
CS: 
Clinically Significant 
CT: 
Computed Tomography 
CTC: 
Common Toxicity Criteria 
CTCAE: 
Common Terminology Criteria for Adverse Events 
DCR: 
Disease Control Rate 
DOR: 
Duration Of Response 
DMC: 
Data Monitoring Committee 
ECG: 
ElectroCardioGram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
Electronic Case Report Form 
EOS: 
End Of Study 
EW: 
Early Withdrawal 
FDA: 
Food and Drug Administration 
FT3: 
Free Triiodothyronine 
FT4: 
Free Thyroxine 
γ-GT: 
Gamma glutamyl transferase 
HbA1c: 
Glycated haemoglobin 


 
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HBV: 
Hepatitis B surface antigen 
HCV: 
Hepatitis C antibody 
IC: 
Informed consent 
ICH: 
International Conference on Harmonisation 
IMP: 
Investigational Medicinal Product 
INR: 
International Normalised Ratio 
ITT: 
Intention-To-Treat 
KM: 
Kaplan-Meier  
LDH: 
Lactate Dehydrogenase 
LLN: 
Lower Limit of Normal range 
LOCF: 
Last Observation Carried Forward 
MCH: 
Mean Cell Haemoglobin 
MCHC: 
Mean Cell Haemoglobin Concentration 
MCV: 
Mean Corpuscular Volume 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MGMT: 
O6-methylguanine-DNA methyltransferase 
MRI: 
Magnetic Resonance Imaging  
NCI: 
National Cancer Institute 
NCI–CTCAE: 
National Cancer Institute – Common Toxicity Criteria for Adverse 
Events 
NCR:  
Non-Complete Response  
NCS: 
Not Clinically Significant 
NE: 
Not Evaluable 
NET: 
NeuroEndocrine Tumor 
NPD: 
Non-Progressive Disease  
NSE: 
Neuron-Specific Enolase 
NYHA: 
New York Heart Association 
ORR: 
Objective Response Rate 
PD: 
Progressive Disease 
PFS: 
Progression-Free Survival 
PP: 
Per-Protocol 
PR: 
Partial Response 
PRRT: 
Peptide Receptor Radionuclide Therapy 
PT: 
Prothrombin Time 
QC:  
Quality control 


 
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QRS: 
QRS interval duration 
QT: 
Time interval for ventricular depolarisation and repolarisation 
QTc: 
Corrected QT interval 
RBC: 
Red Blood Cells 
RECIST: 
Response Evaluation Criteria In Solid Tumours 
SAP: 
Statistical and Analysis Plan 
SAE: 
Serious Adverse Event/Experience 
SAS®: 
Statistical Analysis System® 
SD: 
Stable Disease 
SI: 
Standard International 
SIRT: 
Selective Internal Radiotherapy  
SSTR2: 
Somatostatin Receptor type 2 
TACE: 
Transcatheter Arterial Chemoembolization  
TAE: 
Transcarterial Emoembolization  
TARF 
Thermo-Ablation with Radio-Frequency  
TEAE: 
Treatment Emergent Adverse Event/Experience 
TFLs: 
Tables, Figures and Listings 
TMZ: 
Temozolomide 
TNM: 
Tumor Node Metastasis 
T-NET: 
Thoracic NeuroEndocrine Tumor 
TPR:  
Time Point Response 
TSH: 
Thyroid-Stimulating Hormone 
TTP: 
Time To Progression 
TTR: 
Time To Response 
ULN: 
Upper Limit of Normal range 
v: 
Version 
V: 
Visit 
W: 
Week 
WBC: 
White Blood Cell 
WHO: 
World Health Organization 
WHO-DD: 
World Health Organization – Drug Dictionary 


 
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1 
INFORMATION TAKEN FROM THE PROTOCOL 
1.1 
Study objectives 
1.1.1 
Primary objective 
To evaluate the efficacy of Lanreotide Autogel (ATG) 120 mg in combination with 
Temozolomide (TMZ) in subjects with unresectable advanced neuroendocrine tumour of the 
lung or thymus (typical and atypical carcinoids according to the World Health 
Organization (WHO) 2004 criteria) as Disease Control Rate (DCR) at 9 months (i.e. 
Complete Response (CR), Partial Response (PR) or Stable Disease (SD)), according to 
Response Evaluation Criteria In Solid Tumours (RECIST) criteria version 1.1. 
 
1.1.2 
Secondary objectives 
• 
To assess, according to RECIST criteria v 1.1: 
- 
Progression-Free Survival (PFS), 
- 
Time to Response (TTR), 
- 
Duration of Response (DOR), 
- 
Time to Progression (TTP), 
- 
Best Overall Response (BOR) defined as the best response recorded from the 
time of first treatment until disease progression/recurrence or the end of study 
(CR, PR, SD, Progressive Disease (PD)), 
- 
Objective Response Rate (ORR) at 9 and 12 months: CR, PR, 
- 
DCR at 12 months: CR, PR and SD, 
- 
The influence of typical carcinoids and atypical carcinoids on the DCR at 
9 months. 
• 
To assess the biochemical response [Chromogranin A (CgA) plasma levels]. 
• 
To assess neuron-specific enolase (NSE) and CgA biomarkers levels prognostic and 
predictive value. 
• 
To assess the prognostic value of biomarkers expression (immunohistochemistry assay 
Somatostatin 
receptor 
type 
2 (SSTR2), 
Ki67 
and 
O6-methylguanine-DNA 
methyltransferase (MGMT) status in tissue obtained from paraffin embedded primary 
tumour surgery specimens or biopsies) for PFS, ORR, and DCR. 
• 
To assess the agreement of the central assessment of tumor radiological response and 
the local one on the DCR at 9 months. 
• 
To evaluate the safety of study treatments as assessed by the following: 
- 
occurrence of adverse events (AEs) throughout the study, 
- 
clinical laboratory test results (haematology, biochemistry at each study visit, 
and urinalysis at visits 1 (V1 - screening), V6, V9, V12 and V16 (End of 
Study (EOS)) or early withdrawal (EW)), 
- 
vital signs (blood pressure, heart rate and body weight) measurements at each 
study visit, 
- 
electrocardiogram (ECG), electrocardiography at V1, V9 and V16 (EOS) or EW, 
- 
physical examination at each study visit, 
- 
concomitant medications usage throughout the study, 
- 
gallbladder echography at V1, V9 and V16 (EOS) or EW. 


 
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1.2 
Study design 
This is a phase II, open-label, single arm, prospective, multicenter, non-comparative, pilot 
study to evaluate the efficacy and safety of Lanreotide ATG 120 mg/28 days in combination 
with TMZ 250 mg/day for 5 consecutive days/28 days on DCR, in adult subjects with a 
histologically documented unresectable advanced (locally or metastatic) well or moderately 
differentiated neuroendocrine tumor (NET) of the lung or thymus (typical and atypical 
carcinoids), according to the WHO 2004 criteria. The study consists of a screening period 
(maximum 4 weeks), followed by a 52-week open-label phase. 
At screening visit (V1), after informed consent (IC) for the study has been obtained, an 
eligibility Computed Tomography (CT) scan (total body) must be performed, unless a CT 
scan was already performed in the last 28 days, then it would be considered suitable for the 
screening tumour evaluation. 
At baseline visit (V2), performed after a maximum of 4 weeks after V1, subjects fulfilling the 
inclusion and exclusion criteria will be treated with Lanreotide ATG 120 mg every 28 days 
and TMZ 250 mg daily for 5 consecutive days every 28th days (in case of bone marrow 
toxicity the dose may subsequently be reduced to 180 mg daily for 5 consecutive days of each 
month) for a maximum treatment period of 52 weeks (about 12 months) or until disease 
progression, death or unacceptable toxicity, subject/physician decision, whichever comes first. 
Subjects who complete all scheduled visits or who progress or die before the end of the study 
will be considered to have completed the study. 
Subjects who complete the study will have final procedures and assessments performed at the 
final visit (V16, i.e. EOS). Subjects who withdraw from the study before the completion of 
the evaluation period will have an early withdrawal (EW) visit and should perform all 
assessments provided at final visit (V16 EOS).  
At their last study visit (EOS V16 W52), subjects still benefiting from treatment (according to 
the investigator judgement) will have the option to continue to receive the combination of 
Lanreotide ATG 120 mg and TMZ 250 mg. In such a situation, Lanreotide ATG 120 mg and 
TMZ 250 mg will be provided free of charge by the Sponsor to the investigational sites under 
its commercial packaging, for a maximum of 12 months. During this post-trial treatment, the 
investigator will report immediately to Ipsen Pharmacovigilance Contact any safety concerns 
arising from the use of the product. 
Figure 1 Study design 
 
 
1.2.1 
Study population 
40 subjects with progressive well or moderately differentiated thoracic neuroendocrine 
tumor (T-NET) (lung and thymic carcinoids) are planned to be enrolled in this study. 
 


 
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1.2.2 
Study exposure 
Subjects’ enrolment will last approximately 20 months and the overall duration of the study 
will be approximately 3 years. 
Subjects are expected to participate in this study for a minimum of 53 weeks and up to 
56 weeks, considering that the study will consist of a 4-week (maximum) screening period, 
and a 52-week open-label phase. 
The subject’s participation in the study will be considered to have ended at the time of the last 
visit (V16 - EOS), 4 weeks after the last IMP intake. 
The study will be considered to have started when the first subject has provided his/her signed 
informed consent. 
The study will be considered to have ended after the last subject last visit has been performed. 
 
1.3 
Methods and procedures 
1.3.1 
Subject identification and allocation to study treatment 
After IC is obtained, subjects who are screened will be allocated a subject number. All 
screened subjects must be identifiable throughout the study. The investigator will maintain a 
list of subject numbers and names to enable records to be found at a later date if required. 
Following confirmation of eligibility for the study, subjects will be treated as follows: 
• 
Lanreotide ATG 120 mg every 28 days, deep subcutaneous injection for a maximum of 
48 weeks, for a total number of 13 injections. 
• 
TMZ 250 mg hard capsules, for 5 consecutive days every 28 days, oral route, for a 
maximum of 48 weeks. 
 
1.3.2 
Subjects assessments 
1.3.2.1 
Efficacy assessments 
• 
Tumor assessment according to RECIST criteria v 1.1 will be assessed at V1 
(screening), V6, V9, V12 and V16 (EOS) or EW locally (by the investigator with the 
local radiologist consultation). Central review will be performed at the end of the study 
by a centralized independent radiologist (according to Biotrial Core Lab Image Review 
Charter). 
• 
NSE and CgA plasma levels will be collected at V2, V4, V6, V9, V12 and V16 (EOS) 
or EW. 
• 
WHO performance status (ECOG) at V1 (screening), V6, V9, V12 and V16 (EOS) or 
EW. 
 
1.3.2.2 
Safety assessments 
• 
AEs: 
AEs will be monitored from the time that the subject gives IC and throughout the study and 
will be elicited by direct, non-leading questioning or by spontaneous reports. 
• 
Clinical laboratory test: 
Blood samples will be collected at each visit for the evaluation of haematology and 
biochemistry, excepted for haematology and biochemistry at V2 if V1 haematology and 
biochemistry blood sample has been performed less than 7 days before, and at V3 bis only 
some haematological parameters were required. Urine samples will be collected at V1 


 
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(screening), V4, V5, V6, V9, V12 and V16 (EOS) or EW for urinalysis. All clinically relevant 
abnormal laboratory tests occurring during the study will be repeated at appropriate intervals 
until they return to baseline (V2) values 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. 
- 
For haematology, the following parameters will be collected: red blood 
cells (RBC) count, haemoglobin, haematocrit, mean corpuscular volume (MCV), 
mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC), 
white blood cell (WBC) count, absolute neutrophils count (ANC), platelets and 
glycated haemoglobin (HbA1c), as well as coagulation indexes: activated partial 
thromboplastin time (aPTT), prothrombin time (PT) and international normalised 
ratio (INR). 
- 
For blood biochemistry, the following parameters will be collected: urea, serum 
creatinine (Cr), total serum bilirubin, direct bilirubin (only when total serum 
bilirubin is out of ranges), chloride, sodium, potassium, calcium, phosphate, 
lactate 
dehydrogenase (LDH), 
alanine 
aminotransferase (ALT), 
aspartate 
aminotransferase (AST), gamma glutamyl transferase (γ-GT), albumin, total 
protein, total cholesterol, triglycerides, fasting glucose, insulin, C-peptide, 
Vitamin B12, 
Thyroid-Stimulating 
Hormone (TSH), 
Free 
Triiodothyronine (FT3) and Free Thyroxine (FT4). 
- 
For serology, the following parameters will be collected at V1 (screening) only: 
hepatitis B surface antigen (HBV) and hepatitis C antibody (HCV). 
- 
For urinalysis, the following parameters will be collected: pH, protein, ketones, 
total bilirubin, blood, WBC, urobilinogen, glucose, nitrite and specific gravity by 
dipstick and microscopy if necessary. Microscopy will be performed, if 
indicated, but results will not be collected in the electronic case report 
form (eCRF). If in the opinion of the investigator there are any clinically 
significant abnormalities in microscopy, they will be recorded as an AE. 
• 
Physical examinations will be conducted at each visit. Any clinically significant 
physical examination findings (abnormalities) observed during the study will be 
reported as AEs. 
• 
Vital signs will be collected at each visit: blood pressure (systolic and diastolic) and 
heart rate (excepted at V1, V9 and V16 when it will be measured during the ECG) will 
be assessed with an automated device. Blood pressure and heart rate will be recorded in 
supine, sitting or standing position according to clinical practice. 
• 
Electrocardiogram (ECGs) will be recorded at V1 (screening), V9 and V16 (EOS) or 
EW. Twelve-lead ECGs will be recorded so that the different ECG intervals (RR 
duration, PR duration), QRS interval duration (QRS), time interval for ventricular 
depolarisation and repolarisation (QT)) can be measured, as well as heart rate. 
Corrected QT interval (QTc) will be measured automatically according to the Bazett's 
formula. Any clinically significant abnormalities will be recorded as AEs. 
• 
Echocardiography: M- and B-mode echocardiography will be performed at V1 
(screening), V9 and V16 (EOS) or EW. The following assessments will be performed: 
- 
valves function (with cardiac valvular regurgitation severity and cardiac valve 
stenosis severity) and morphology for mitral, aortic and tricuspid valves, 
- 
left and right ventricular morphology and function, 
- 
left atrium, aorta, pericardium and pericardial effusion morphology, 
- 
patency of the foramen ovale, 


 
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- 
interpretation of clinical significance. 
• 
Gallbladder echography: at V1 (screening), ultrasound examination of the gallbladder 
will be performed on each subject by gallbladder echography. The measurement will be 
repeated at V9 and V16 (EOS) or EW. 
 
1.3.2.3 
Other assessments 
The following assessments will be collected at the screening visit (V1): 
• 
Demography (sex, age, race), 
• 
New York Heart Association (NYHA) functional classification evaluation of cardiac 
disease, 
• 
A human chorionic gonadotrophin (ßHCG) serum test (i.e. pregnancy test) performed 
for all female subjects of childbearing potential at screening (V1) and if clinically 
indicated thereafter, 
• 
Medical/surgical history (including documented histology of typical/atypical carcinoid 
of lung or thymus according to WHO 2004 criteria), 
• 
Disease history (date of diagnosis, tumor localization, mitotic count, foci of necrosis, 
metastasis, Tumor Node Metastasis (TNM) staging according to UICC/AJCC 7th 
Edition TNM System), 
• 
Prior medications and non-drug therapies (others than for T-NETs), 
• 
Prior medications for T-NETs, 
• 
Prior chemotherapy, radiotherapy, locoregional therapies (TAE, TACE, TARF, SIRT), 
prior therapy with Peptide Receptor Radionuclide Therapy (PRRT) for T-NETs, prior 
targeted therapy and prior surgical procedure in the past year, 
• 
Octreoscan or GA-DOTA/TATE/TOC-PET within 12 months (overall and by method of 
imaging),, 
• 
Eligibility checks (inclusion/exclusion criteria). 
• 
Biomarkers expression (immunohistochemistry assay SSTR2, Ki67 and MGMT status 
in tissue obtained from paraffin embedded primary tumour surgery specimens or 
biopsies) if tissue samples are available at screening. 
 
Concomitant medications for T-NETs, concomitant medications/non-drug therapies/surgical 
procedures other than for T-NETs as well as treatment administrations will also be collected 
throughout the study. 
 
1.3.2.4 
Withdrawal/discontinuation 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, 
pregnancy, or other reasons concerning the health or wellbeing of the subject, or in the case of 
lack of cooperation. In addition, a subject may be withdrawn from the study as described in 
protocol sections 3.6, 4.3, 5.2.5.1 and 8.1.7. 
If one or more of the following occurs, the subject will be discontinued from study 
medication: 
CCI


 
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• 
In case of disease progression as defined in the RECIST criteria v 1.1 (refer to protocol 
appendix 1); 
• 
In case of AEs, serious AEs (SAEs), serious and unexpected worsening of clinical 
conditions, or any other reasons that, in the investigator's judgement, may jeopardize 
the subject safety. 
If one or more of the following occurs the subject will be withdrawn from the study: 
(1) 
IC withdrawal / Subject's request; 
(2) 
Occurrence of disease(s) which can interfere with subject's final evaluation; 
(3) 
Administration of prohibited drugs; 
(4) 
If TMZ is not tolerated and unacceptable toxicity persists even after TMZ dose 
reduction (see section 1.3.3 with the schedule of assessments for dose adaptation of 
TMZ); 
(5) 
According to clinical judgement of the investigator or to their own request; 
(6) 
Substantial non-compliance with the requirements of the study; 
(7) 
Development of a situation which would, in the Judgment of the investigator, affect 
clinical study endpoint measurements with a significant degree; 
(8) 
Subjects lost to follow- up; 
(9) 
Subject death. 
Discontinued subjects will not be replaced. 
Should a subject decide to withdraw from the study after administration of IMP, 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 and an explanation given of 
why the subject is withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the eCRF. The 
investigator will provide or arrange for appropriate follow-up (if required) for subjects 
withdrawing from the study, and will document the course of the subject’s condition. 
If a subject withdraws consent, every attempt will be made to determine the reason. If the 
reason for withdrawal is an AE or a clinically significant laboratory test abnormality, 
monitoring will continue until the event has resolved or stabilised, until the subject is referred 
to the care of a local health care professional, or until a determination of a cause unrelated to 
the IMP or study procedure is made. The specific AE or test result(s) must be recorded on the 
eCRF. All evaluations should be performed, according to the protocol, on the last day the 
subject receives IMP, or as soon as possible thereafter. 
In case of subject discontinuation due to SAE or AE, the evolution of the SAE or AE will be 
followed up and recorded by the investigator till the outcome definition. If possible, subjects 
removed from the study should perform concomitantly with the study drug interruption, a 
final physical examination, an ECG recording, a check of the concomitant medications, a 
blood sampling for chemistry and haematology, a recording of the clinic (office) blood 
pressure and heart rate. 
 
 
 If a subject wishes to withdraw his/her consent, the 
investigator must inform the study monitor in writing of the subject’s decision. Within the 
sponsor, the request for sample withdrawal will be forwarded to the repository leader. If the 
samples are in the sponsor’s repository (or at the central laboratory prior to shipping to the 
repository), the repository leader will ensure destruction of the samples and all corresponding 
CCI


 
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aliquots and issue confirmation of the withdrawal, which will be forwarded to the 
investigator. If the samples are still at the investigator site at the time the subject withdraws 
his/her consent, the investigator must inform the study monitor and destroy the samples. The 
study monitor will forward confirmation of the destruction to the repository leader. 
 
1.3.3 
Schedule of assessments 
The schedule of procedures and assessments during the study is summarised in Table 1. 
 


 
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Table 1 
Study procedures and assessments 
 


 
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CCI
CCI


 
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1.3.4 
Planned sample size 
Sample size and statistical assumption were made according to a Fleming’s Single Stage 
Design.  
To demonstrate the efficacy of TMZ associated to Lanreotide, the proportion of responders as 
subjects with DCR after 9 months of therapy was considered. 
The following assumptions were made: 
• 
The proportion of responders should be equal or greater than 30 % to be clinically 
relevant (π
1), 
• 
a proportion of responders equal or lower than 10 % was considered as not acceptable 
(π
0), 
• 
the 1-sided error probability was set to α = 0.025 and 
• 
the power should be 90 % (β = 0.10). 
The 1-sided hypotheses to be tested are: 
π ≤ π
0 and π ≥ π
1; 
35 evaluable subjects are needed. 
Estimating a 10 % of drop-out rate the total number of subjects to be treated is set to N = 40. 
Calculations were made using “Statistical Tables for the Design of Clinical Trials”. 
 


 
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2 
SUBJECT POPULATIONS (ANALYSIS SETS) 
The following populations will be used during the statistical analyses: the Screened 
population i.e. all subjects screened (i.e. who signed the informed consent), the intention-to-
treat (ITT)/safety population and the per-protocol (PP) population, as described below. 
2.1 
Efficacy 
2.1.1 
Intention-to-treat (ITT)/safety population 
The ITT/Safety population is all subjects who received at least one dose of study medication 
(either Lanreotide ATG 120 mg or TMZ). 
 
2.1.2 
Per-protocol population (PP) 
The PP population is all subjects in the ITT/Safety population for whom no major protocol 
violations/deviations occurred. 
Criteria for exclusion from the PP population will be provided in the deviations specifications 
document. Listings of subjects regarding inclusion in each population and satisfying the 
population definition and associated data will be reviewed by the study team. 
Reasons for exclusion from PP population will be presented in a summary table. 
 
2.2 
Safety 
The analyses of safety data will be performed on the ITT/Safety population. 
 


 
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3 
STATISTICAL METHODS 
3.1 
Statistical analysis strategy 
The statistical analyses will be performed in accordance with International Conference on 
Harmonisation (ICH) E9 guideline and will be based on the pooled data from the individual 
study sites, unless otherwise stated. 
Statistical analyses described in this document will be performed by Biotrial Biometrics, 
Rennes, France, using the Statistical Analysis System (SAS) software 9.4 release or higher 
(SAS Institute Inc. Cary NC USA). 
 
3.1.1 
Primary efficacy endpoint 
The primary endpoint is the percentage of responders (DCR according to RECIST criteria 
v 1.1 assessed locally by the investigator, after tumor evaluation (by CT scan or MRI) 
identifying measurable lesions (i.e. target, non-target and new lesions) by which subsequent 
response assessment is judged) at 9 months after first treatment administration, defined as 
objective response (including CR and PR) or stability of the disease (i.e. SD). 
 
3.1.2 
Secondary efficacy endpoints 
Secondary endpoints are: 
• 
DCR at 9 months assessed centrally by the independent radiologist, after review of 
collected tumor evaluation (i.e. CT scan or MRI images) identifying measurable lesions 
(i.e. target, non-target and new lesions) by which subsequent response reassessment is 
done, 
• 
PFS from first treatment administration until progression, according to RECIST criteria 
v 1.1 locally and centrally, 
• 
TTR defined as the time from first treatment administration to the first objective tumor 
response (PR or CR according to RECIST criteria v 1.1 locally and centrally), 
• 
DOR defined as the time from onset of the first objective tumor response (PR or CR) to 
objective tumor progression (PD, according to RECIST criteria v 1.1 locally and 
centrally) or death from any cause, 
• 
TTP defined as the time from first treatment administration to the first objective tumor 
progression (PD) observed according to RECIST criteria v 1.1 locally and centrally, 
• 
BOR according to RECIST criteria v 1.1 locally and centrally defined as the best 
response recorded from the time of first treatment until disease progression/recurrence 
or the end of study (CR > PR > Non-CR/Non-PD (NCR/NPD) > SD >  PD > ND > 
NE), 
• 
ORR locally and centrally at 9 and 12 months: CR or PR, 
• 
DCR locally and centrally at 12 months: CR, PR and SD, 
• 
The influence of type of carcinoid (typical, atypical, carcinoid neuroendocrine tumor) 
on the DCR at 9 months locally and centrally, 
• 
Biochemical response according to decrease in CgA plasma level in subjects with 
baseline CgA level greater than upper limit of normal range (ULN) throughout the 
study (at V2, V4, V6, V9, V12 and V16). Biochemical objective response is defined as 
a decrease of CgA ≥ 50 %, while stable disease as a decrease ≥ 25 % and less than 
50 %, as their best response to study treatment, 


 
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• 
Value of NSE and CgA levels at baseline and at 1, 3, 6, 9 and 12 months (EOS) or EW 
(i.e. at V4, V6, V9, V12 and V16), to assess their predictive and prognostic value, 
• 
Biomarkers expression (immunohistochemistry assay centrally assessed SSTR2, Ki67 
and MGMT status in tissue obtained from paraffin embedded primary tumour surgery 
specimens or biopsies) correlated to tumor response for PFS, ORR, DCR locally and 
centrally at 9 and 12 months, to assess their prognostic value. 
• 
Agreement between central and local assessment of tumor radiological response. 
• 
Blood MGMT methylation centralized assessment done at V2, V12 and EOS described 
in a separate SAP. 
 
3.1.3 
Safety endpoints 
The safety and tolerability of Lanreotide in combination with TMZ will be assessed 
throughout the study by evaluating AEs/SAEs, changes from baseline in physical 
examination, vital signs (blood pressure, heart rate and body weight), laboratory tests 
(haematology, blood chemistry, urinalysis), diagnostic tests (ECG, echocardiography, 
gallbladder echography) and concomitant medication usage. 
Assessments of AEs will be evaluated for timing, seriousness and relatedness and graded for 
type; incidence and severity according to the National Cancer Institute (NCI) using the 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.03-14 June 2010 
(refer to protocol appendix 3). 
 
3.1.4 
Multiplicity 
No multiple testing will be performed in this study. 
 
3.1.5 
Significance testing and estimation 
The statistical test on the primary objective will be performed one sided with a type I error 
rate set at 2.5 %.  
All other statistical tests will be performed two sided with a type I error set at 5 %. 
 
3.2 
Analysis methods 
3.2.1 
Efficacy 
The efficacy analyses will be described below, but here is a summary: 
Table 2 
Summary of all efficacy analyses 
Time 
Assessment 
Population 
Additional information 
TFL 
Number 
Disease control rate 
At 9 months 
Local 
ITT/Safety 
Considering: 
- all subjects attending 9 months, 
- subjects with PD prior or at 9 months 
and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
9 months as failures. 
14.2.1.1.1 


 
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Time 
Assessment 
Population 
Additional information 
TFL 
Number 
Disease control rate 
At 9 months 
Local 
ITT/Safety 
Considering all treated subjects except 
subjects withdrawn before 9 months for 
reason other than PD or missing 
assessment. 
14.2.1.1.3 
 
 
 
Considering: 
- subjects with assessments between 7.5 
and 
10.5 
months 
as 
9-month 
assessment 
- subjects with PD prior or at 9 months 
and,  
- subjects withdrawn for reason other 
than PD or missing reason before 
9 months as failures. 
14.2.1.1.4 
 
 
 
Influence of typical and atypical 
carcinoids 
14.2.1.6.1 
 
 
 
Influence of NSE and CgA - Logistic 
regression 
14.2.8.6.1 
 
 
 
Influence of biomarkers expression - 
Logistic regression 
14.2.9.4.1 
 
 
PP 
Considering: 
- all subjects attending 9 months, 
- subjects with PD prior or at 9 months 
and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
9 months as failures. 
14.2.1.1.2 
 
Central 
ITT/Safety 
Considering: 
- all subjects attending 9 months, 
- subjects with PD prior or at 9 months 
and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
9 months as failures. 
14.2.1.2.1 
 
 
 
Influence of typical and atypical 
carcinoids 
14.2.1.6.2 
 
 
 
Influence of NSE and CgA - Logistic 
regression 
14.2.8.6.2 
 
 
 
Influence of biomarkers expression – 
Logistic regression 
14.2.9.4.2 
 
 
PP 
Considering: 
- all subjects attending 9 months, 
- subjects with PD prior or at 9 months 
and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
9 months as failures. 
14.2.1.2.2 


 
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Time 
Assessment 
Population 
Additional information 
TFL 
Number 
Disease control rate 
At 9 months 
NA 
ITT/Safety 
Agreement of the central assessment of 
tumor radiological response and the 
local one 
14.2.10.1 
At 12 months Local 
ITT/Safety 
Considering: 
- all subjects attending 12 months, 
- subjects with PD prior or at 
12 months and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
12 months as failures. 
14.2.1.3.1 
 
 
 
Influence of NSE and CgA - Logistic 
regression 
14.2.8.6.3 
 
 
 
Influence of biomarkers expression - 
Logistic regression 
14.2.9.4.3 
 
Central 
ITT/Safety 
Considering: 
- all subjects attending 12 months, 
- subjects with PD prior or at 
12 months and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
12 months as failures. 
14.2.1.3.2 
 
 
 
Influence of NSE and CgA - Logistic 
regression 
14.2.8.6.4 
 
 
 
Influence of biomarkers expression - 
Logistic regression 
14.2.9.4.4 
Time point response 
Per 
time 
point 
Local 
ITT/Safety 
NA 
14.2.1.4.1.1 
 
 
PP 
NA 
14.2.1.4.1.2 
 
Central 
ITT/Safety 
NA 
14.2.1.4.2.1 
 
 
PP 
NA 
14.2.1.4.2.2 
Diameters of target tumor lesions 
Per 
time 
point 
Local 
ITT/Safety 
NA 
14.2.1.5.1 
 
Central 
ITT/Safety 
NA 
14.2.1.5.2 
Progression-free survival 
NA 
Local 
ITT/Safety 
NA 
14.2.2.1.1 
 
 
 
Figure 
14.2.2.2.1 
 
 
 
Influence of NSE and CgA - Cox 
proportional hazard model 
14.2.8.4.1 
 
 
 
Influence of biomarkers expression - 
Cox proportional hazard model 
14.2.9.2.1 
NA 
Central 
ITT/Safety 
NA 
14.2.2.1.2 
 
 
 
Figure 
14.2.2.2.2 
 
 
 
Influence of NSE and CgA - Cox 
proportional hazard model 
14.2.8.4.2 


 
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Time 
Assessment 
Population 
Additional information 
TFL 
Number 
Progression-free survival 
NA 
Central 
ITT/Safety 
Influence of biomarkers expression - 
Cox proportional hazard model 
14.2.9.2.2 
Time to response 
NA 
Local 
ITT/Safety 
NA 
14.2.3.1.1 
 
 
 
Figure 
14.2.3.2.1 
 
Central 
ITT/Safety 
NA 
14.2.3.1.2 
 
 
 
Figure 
14.2.3.2.2 
Duration of response 
NA 
Local 
ITT/Safety 
NA 
14.2.4.1.1 
 
 
 
Figure 
14.2.4.2.1 
NA 
Central 
ITT/Safety 
NA 
14.2.4.1.2 
 
 
 
Figure 
14.2.4.2.2 
Time to progression 
NA 
Local 
ITT/Safety 
NA 
14.2.5.1.1 
 
 
 
Figure 
14.2.5.2.1 
NA 
Central 
ITT/Safety 
NA 
14.2.5.1.2 
 
 
 
Figure 
14.2.5.2.2 
Best overall response 
NA 
Local 
ITT/Safety 
NA 
14.2.6.1 
NA 
Central 
ITT/Safety 
NA 
14.2.6.2 
Objective response rate 
At 9 months 
Local 
ITT/Safety 
Considering: 
- all subjects attending 9 months, 
- subjects with PD prior or at 9 months 
and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
9 months as failures. 
14.2.7.1.1 
 
 
 
Influence of NSE and CgA - Logistic 
regression 
14.2.8.5.1 
 
 
 
Influence of biomarkers expression - 
Logistic regression 
14.2.9.3.1 
 
Central 
ITT/Safety 
Considering: 
- all subjects attending 9 months, 
- subjects with PD prior or at 9 months 
and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
9 months as failures. 
14.2.7.1.2 
 
 
 
Influence of NSE and CgA - Logistic 
regression 
14.2.8.5.2 
 
 
 
Influence of biomarkers expression - 
Logistic regression 
14.2.9.3.2 


 
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Time 
Assessment 
Population 
Additional information 
TFL 
Number 
Objective response rate 
At 12 months Local 
ITT/Safety 
Considering: 
- all subjects attending 12 months, 
- subjects with PD prior or at 
12 months and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
12 months as failures. 
14.2.7.2.1 
 
 
 
Influence of NSE and CgA - Logistic 
regression 
14.2.8.5.3 
 
 
 
Influence of biomarkers expression - 
Logistic regression 
14.2.9.3.3 
 
Central 
ITT/Safety 
Considering: 
- all subjects attending 12 months, 
- subjects with PD prior or at 
12 months and, 
- other subjects withdrawn for reason 
other than PD or missing reason before 
12 months as failures. 
14.2.7.2.2 
 
 
 
Influence of NSE and CgA - Logistic 
regression 
14.2.8.5.4 
 
 
 
Influence of biomarkers expression - 
Logistic regression 
14.2.9.3.4 
CgA 
Per 
time 
point 
Central 
ITT/Safety 
CgA (µg/L and in x ULN) - Summary 
statistics on raw data and changes from 
baseline 
14.2.8.1.1 
 
 
 
CgA (in x ULN) - Summary statistics 
by class 
14.2.8.1.2 
 
 
 
CgA (in x ULN) - Shift tables  
14.2.8.1.3 
 
 
 
 
 
Global 
Central 
ITT/Safety 
ANCOVA on the change from baseline 
of CgA in x ULN - Full model 
14.2.8.1.4 
 
 
 
ANCOVA on the change from baseline 
of CgA in x ULN - Additive model 
14.2.8.1.5 
NSE 
Per 
time 
point 
Central 
ITT/Safety 
NSE (µg/L and in x ULN) - Summary 
statistics on raw data and changes from 
baseline 
14.2.8.2.1 
 
 
 
NSE (in x ULN) - Summary statistics 
by class 
14.2.8.2.2 
 
 
 
NSE (in x ULN) - Shift tables 
14.2.8.2.3 
Global 
Central 
ITT/Safety 
ANCOVA on the change from baseline 
of NSE in x ULN - Full model 
14.2.8.2.4 
 
 
 
ANCOVA on the change from baseline 
of NSE in x ULN- Additive model 
14.2.8.2.5 


 
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Time 
Assessment 
Population 
Additional information 
TFL 
Number 
Biochemical response 
Per 
time 
point 
NA 
ITT/Safety 
NA 
14.2.8.3 
WHO performance status scale (ECOG) 
Per 
time 
point 
NA 
ITT/Safety 
Frequency table 
14.2.11.1 
 
 
 
Shift table 
14.2.11.2 
Biomarkers expression 
Per 
time 
point 
NA 
ITT/Safety 
Summary statistics 
14.2.9.1 
Should an analysis be performed on the PP population (if there is a difference of at least 10 % 
between ITT/Safety and PP populations), the tables on efficacy parameters (from 14.2.13.1 to 
14.2.11.2) will be repeated and numbered adding one level in the numbering (i.e. 1 for ITT/Safety 
population and 2 for Per Protocol Population). 
 
3.2.1.1 
Primary efficacy analysis 
3.2.1.1.1 Disease control rate (DCR) at 9 months as per investigator 
The primary efficacy variable is the response of subjects to the study combination therapy, 
9 months after first treatment administration. Responders are subjects showing DCR 
according to RECIST criteria v 1.1 assessed locally, defined as objective response (i.e. CR 
and PR) or stability of the disease (SD).  
Primary efficacy analyses will be performed on the ITT/Safety population. 
The number of assessed subjects at 9 months according to their response status (CR / PR / SD 
/ NE / NCR NPD / Missing), with the number of subjects in PD prior or at 9 months, and the 
number of withdrawn subjects before 9 months with reason other than PD will be displayed. 
The DCR will be based on all subjects in the ITT/Safety population with subjects with PD 
prior or at 9 months as well as subjects with missing assessment and withdrawn subjects from 
any reason considered as failures. 
The DCR will be analysed by an exact binomial proportion test for one-way tables in the 
ITT/Safety population and will then be compared to the thresholds of 30 % and of 10 % using 
the following SAS Freq procedure: 
 
 
 
 
 
 
 
 
; 
The proportion of responders will be displayed along with the 95 % Clopper-Pearson 
Confidence Intervals (CI), a one sided test with an α of 0.025 should be used. The one-sided 
p-values from the exact binomial test comparing the proportion of responders to 0.3 (i.e. 
30 %) and to 0.1 (i.e. 10 %) will be displayed. 
 
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3.2.1.1.2 Disease control rate (DCR) rate at 9 months - sensitivity analyses 
A supportive analysis of the primary analysis of local DCR at 9 months, using the same 
methodology, will be performed on the PP population. 
A sensitivity analysis of local DCR at 9 months will be performed on the ITT/Safety 
population excluding the subjects withdrawn before 9 months with reason other than PD or 
missing assessment and considering subjects with PD prior or at 9 months as failures. 
In addition, a sensitivity analysis will be performed in order to consider assessments done 
between 7.5 and 10.5 months as 9 months assessments when 9-month assessment is missing 
using the same methodology as the primary analysis, i.e. considering PD prior or at 9 months 
and subjects withdrawn with other or missing reasons as failures. 
The analyses of DCR at 9 months will also be repeated based on the central tumour response 
assessment on the ITT/Safety and PP populations considering subjects with PD prior or at 
9 months and subjects withdrawn for other or missing reason as failures. 
 
3.2.1.2 
Secondary efficacy analyses 
All secondary efficacy analyses will be performed on the ITT/Safety population and all 
RECIST based secondary analyses will be performed both on the local and the central 
assessments. 
Time point response (TPR) at each visit will be analysed on the ITT/Safety population as well 
as on the PP population. All other secondary efficacy analyses will also be performed on the 
PP population if there is a difference of at least 10 % between ITT/Safety and PP populations. 
 
3.2.1.2.1 Time point response and sum of the largest diameters of target tumor lesions 
The TPR to study treatment which is the observed response for each subject at each visit from 
the time of first treatment until disease progression/recurrence or the end of study, and 
classified as 
CR, PR, SD, PD, 
Non-Complete Response (NCR)/Non-Progressive 
Disease (NPD) and not evaluable (NE) per RECIST criteria v 1.1 will be presented using 2 
separate descriptive summaries, one using local review and the second one using central 
review. 
The sum of the largest diameters of target tumor lesions will be summarized at each visit as 
well as the change and the percentage change from screening and the change and percentage 
change from nadir. Two separate descriptive summaries of the largest diameters will be 
presented, one using local review and the second using central review. 
 
3.2.1.2.2 Progression-free survival 
3.2.1.2.2.1 Local assessment 
The secondary efficacy endpoint 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 where 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 a progression endpoint 
in this analysis. 
In case of locally assessed PD followed by death, the first event will be considered in the 
analysis. 
Definition of progression date: 


 
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The PD date is assigned to the first time at which PD can be declared. 
• 
For PD based on a new lesion, the PD date is the date of the first radiological 
assessment when the new lesion was detected. 
• 
For PD based on an increase in the sum of the target lesion measurements, the PD date 
is the date of the last radiological assessment of target lesions that shows the predefined 
increase in the sum of the target lesion measurements. 
Definition of censoring date: 
• 
Censoring dates are defined in subjects with no PD or death before end of study or 
withdrawal. In these subjects, the censoring date is defined as the last date on which 
progression status was ‘adequately’ assessed. This is taken to be the date of the last 
radiological assessment at which the target lesions were evaluated by local investigator 
review. 
• 
In the case of prohibited medication/therapy, this is taken to be the last date of 
radiological assessment prior to the initiation of such medications/therapies. 
• 
PDs occurring after more than one missed visit will be censored in the analysis at the 
last adequate assessment before the missing assessments, where adequate assessment is 
considered to be the last radiological assessment that was considered evaluable by the 
investigator. 
Definition of PFS time: 
The PFS time will be calculated as the time from first treatment administration to either 
locally assessed PD or death. 
PFS time = [(Date of event – date of first treatment administration) + 1] / 7 (weeks) 
Table 3 specifies the event and censoring dates to be used in the analysis of PFS via local 
review; these are based on the FDA Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, May 2007. 
Table 3 
PFS analysis assessed locally 
Situation 
Date of event or censoring 
Outcome 
No screening evaluable assessment 
Date of first treatment administration 
Censored 
PD documented locally (either based on new lesion or 
increase in the sum of the target lesion measurements 
during the study) 
Date 
of 
radiological 
assessment 
showing PD 
Event 
Two or more NE assessments before PD or death 
Date of last radiological assessment 
before the second NE assessment 
Censored 
No PD 
Date of last radiological assessment 
Censored 
Treatment discontinuation for undocumented progression Date of last radiological assessment 
Censored 
Treatment discontinuation for toxicity or other reason 
Date of last radiological assessment 
Censored 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) 
Date of last radiological assessment 
before 
initiation 
of 
non-permitted 
medication or therapy 
Censored 
Death (due to any cause) before first PD assessment 
Date of death 
Event 
Death (due to any cause) between adequate assessment 
visits 
Date of death 
Event 
Death or progression after more than one missed visit 
Date of last radiological assessment 
Censored 
Table 4 displays the event status for various scenarios with missing data. 


 
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Table 4 
Event status for various scenarios with missing data 
Scan Time Week 12 Week 24 Week 36 Week 52 
Event Status 
Scenario 1 
Missing 
PD 
 
 
Event at week 24 
Scenario 2 
Missing Missing 
PD 
 
Censoring at screening 
Scenario 3 
Missing 
SD 
PD 
 
Event at week 36 
Scenario 4 
Missing Missing 
SD 
PD 
Event at week 52 
Scenario 5 
SD 
SD 
Missing 
PD 
Event at week 52 
Scenario 6 
SD 
Missing 
SD 
PD 
Event at week 52 
The distribution of PFS times will be estimated using the Kaplan-Meier (KM) product limit 
method. The 25th percentile, median and 75th percentile PFS times and their corresponding 
two-sided 95 % CI will be estimated. Confidence intervals for median time to progression or 
death due to any cause as well as the 25th and 75th percentile CIs will be calculated using the 
method of Brookmeyer and Crowley (1982), which is the default method within SAS® 
version 9 and higher. 
The results of the analysis will be presented in summary tables and KM plots will be 
constructed. Summary tables will present the numbers and percentages of subjects with local 
progression or death due to any cause, the numbers and percentages of observed and censored 
subjects. The summaries will also include the median time to local progression or death due to 
any cause as well as the 25th and 75th percentiles, the percentage of subjects who had 
progressed or had died at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and V16), and the 
associated 95 % CIs for each of these outcomes. Kaplan-Meier curves will be constructed and 
will display the number of subjects at risk at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and 
V16). 
 
 
 
 
 
 
 
 
 
  
 
3.2.1.2.2.2 Central assessment 
The secondary efficacy endpoint of PFS according to central review will include centrally 
assessed PD and deaths. Other data will be censored including investigator assessed PD 
occurring before centrally assessed PD and deaths. 
Clinical progression (i.e. centrally assessed documented progression even though the 
progression is not assessed by the investigator) is considered as a progression endpoint in this 
analysis. 
In case of centrally assessed PD followed by death, the first event will be considered in the 
analysis unless an investigator assessed PD occurred before then the data would be censored. 
Definition of progression date: 
The PD date is assigned to the first time at which PD can be declared. 
• 
For PD based on a new lesion, the PD date is the date of the first radiological 
assessment when the new lesion was detected. 
• 
For PD based on an increase in the sum of the target lesion measurements, the PD date 
is the date of the last radiological assessment of target lesions that shows the predefined 
increase in the sum of the target lesion measurements. 
Definition of censoring date: 
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• 
Censoring dates are defined in subjects with no PD or death before end of study or 
withdrawal. In these subjects, the censoring date is defined as the last date on which 
progression status was ‘adequately’ assessed. This is taken to be the date of the last 
radiological assessment at which the target lesions were evaluated by central review. 
• 
In the case of locally declared PD, not confirmed by the central independent 
radiologist, the subject will be censored at the date of local PD. 
• 
In the case of prohibited medication/therapy, this is taken to be the last date of 
radiological assessment prior to the initiation of such medications/therapies. 
• 
PDs occurring after more than one missed visit will be censored in the analysis at the 
last adequate assessment before the missing assessments, where adequate assessment is 
considered to be the last radiological assessment that was considered evaluable by the 
central review. 
Definition of PFS time: 
The PFS time will be calculated as the time from first treatment administration to either 
centrally assessed PD or death. 
PFS time = [(Date of event – date of first treatment administration) + 1] / 7 (weeks) 
Table 5 specifies the event and censoring dates to be used in the analysis of PFS via central 
review; these are based on the FDA Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, May 2007. 
Table 5 
PFS analysis assessed centrally 
Situation 
Date of event or censoring 
Outcome 
No screening evaluable assessment 
Date of first treatment administration 
Censored 
PD documented centrally (either based on new lesion or 
increase in the sum of the target lesion measurements 
during the study) 
Date 
of 
radiological 
assessment 
showing PD 
Event 
PD documented locally only (either based on new lesion 
or increase in the sum of the target lesion measurements 
during the study) 
Date 
of 
radiological 
assessment 
showing PD 
Censored 
Two or more NE assessments before PD or death 
Date of last radiological assessment 
before the second NE assessment 
Censored 
No PD 
Date of last radiological assessment 
Censored 
Treatment discontinuation for undocumented progression Date of last radiological assessment 
Censored 
Treatment discontinuation for toxicity or other reason 
Date of last radiological assessment 
Censored 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) 
Date of last radiological assessment 
before 
initiation 
of 
non-permitted 
medication or therapy 
Censored 
Death (due to any cause) before first PD assessment 
Date of death 
Event 
Death (due to any cause) between adequate assessment 
visits 
Date of death 
Event 
Death or progression after more than one missed visit 
Date of last radiological assessment 
Censored 
The distribution of PFS times will be estimated using the KM product limit method. The 25th 
percentile, median and 75th percentile PFS times and their corresponding two-sided 95 % CI 
will be estimated. Confidence intervals for median time to progression or death due to any 
cause as well as the 25th and 75th percentile CIs will be calculated using the method of 


 
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Brookmeyer and Crowley (1982), which is the default method within SAS® version 9 and 
higher. 
The results of the analysis will be presented in summary tables and KM plots will be 
constructed. Summary tables will present the numbers and percentages of subjects with 
central progression or death due to any cause, the numbers and percentages of observed and 
censored subjects. The summaries will also include the median time to central progression or 
death due to any cause as well as the 25th and 75th percentiles, the percentage of subjects who 
had progressed or had died at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and V16), and the 
associated 95 % CIs for each of these outcomes. Kaplan-Meier curves will be constructed and 
will display the number of subjects at risk at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and 
V16). 
 
 
 
 
 
 
 
 
 
  
 
3.2.1.2.3 Time to response 
Time to response (TTR) is defined as the time from first
 treatment administration to the first 
objective tumor response (PR or CR) according to RECIST criteria v 1.1. TTR will be 
analysed separately using the local and central assessments. 
 
3.2.1.2.3.1 Local assessment 
Objective tumor response (PR or CR) will be assessed locally by the investigator. 
Definition of response date:  
The response date is assigned to the date of the first radiological assessment when PR or CR 
can be declared locally. 
Definition of censoring date:  
• 
Censoring dates are defined in subjects with no PR or CR assessed locally before end 
of study, withdrawal, lost to follow-up or death as the last date on which response was 
‘adequately’ assessed i.e. the date of the last radiological assessment. 
• 
In the case of prohibited medication/therapy, this is taken to be the last date of 
radiological assessment prior to the initiation of such medications/therapies. 
• 
Response occurring after more than one missed visit will be censored in the analysis at 
the last adequate assessment before the missing assessments, where adequate 
assessment is considered to be the last radiological assessment that was considered 
evaluable by the investigator. 
Definition of TTR time: 
The TTR time will be calculated as the time from first treatment administration to the first PR 
or CR declared locally. 
TTR time = [(Date of event – date of first treatment administration) + 1] / 7 (weeks) 
Table 6 specifies the event and censoring dates to be used in the analysis of TTR via local 
review; these are based on the FDA Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, May 2007. 
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Table 6 
TTR analysis assessed locally 
Situation 
Date of event or censoring 
Outcome 
No screening evaluable assessment 
Date of first treatment administration 
Censored 
CR or PR documented locally 
Date 
of 
radiological 
assessment 
showing response 
Event 
Two or more NE assessments before CR or PR 
documented locally 
Date of last radiological assessment 
before the second NE assessment 
Censored 
No CR or PR documented locally 
Date of last radiological assessment 
Censored 
Treatment discontinuation for undocumented progression Date of last radiological assessment 
Censored 
Treatment discontinuation for toxicity or other reason 
Date of last radiological assessment 
Censored 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) 
Date of last radiological assessment 
before 
initiation 
of 
non-permitted 
medication or therapy 
Censored 
The distribution of TTR times will be estimated using the KM product limit method. The 25th 
percentile, median and 75th percentile TTR times and their corresponding two-sided 95 % CI 
will be estimated. Confidence intervals for median TTR as well as the 25th and 75th 
percentile CIs will be calculated using the method of Brookmeyer and Crowley (1982), which 
is the default method within SAS® version 9 and higher. 
The results of the analysis will be presented in summary tables and KM plots will be 
constructed. Summary tables will present the numbers and percentages of subjects with 
response, the numbers and percentages of observed and censored subjects. The summaries 
will also include the median TTR as well as the 25th and 75th percentiles, the percentage of 
subjects who had a response at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and V16), and the 
associated 95 % CIs for each of these outcomes. Kaplan-Meier curves will be constructed and 
will display the number of subjects at risk at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and 
V16). 
The SAS Lifetest procedure will be used as follows: 
 
 
 
 
 
 
 
 
3.2.1.2.3.2 Central assessment 
Objective tumor response (PR or CR) will be assessed centrally by the independent 
radiologist. 
Definition of response date:  
The response date is assigned to the date of the first central radiological assessment when PR 
or CR can be declared by the independent radiologist. 
Definition of censoring date:  
• 
Censoring dates are defined in subjects with no PR or CR assessed centrally before end 
of study, withdrawal, lost to follow-up or death as the last date on which response was 
‘adequately’ assessed i.e. the date of the last radiological assessment. 
• 
In the case of prohibited medication/therapy, this is taken to be the last date of 
radiological assessment prior to the initiation of such medications/therapies. 
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• 
Response occurring after more than one missed visit will be censored in the analysis at 
the last adequate central assessment before the missing central assessments, where 
adequate assessment is considered to be the last radiological assessment that was 
considered evaluable by the independent radiologist. 
Definition of TTR time: 
The TTR time will be calculated as the time from first treatment administration to the first PR 
or CR declared centrally. 
TTR time = [(Date of event – date of first treatment administration) + 1] / 7 (weeks) 
Table 7 specifies the event and censoring dates to be used in the analysis of TTR via central 
review; these are based on the FDA Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, May 2007. 
Table 7 
TTR analysis assessed centrally 
Situation 
Date of event or censoring 
Outcome 
No screening evaluable assessment 
Date of first treatment administration 
Censored 
CR or PR documented centrally 
Date 
of 
radiological 
assessment 
showing response 
Event 
Two or more NE assessments before CR or PR 
documented centrally 
Date of last radiological assessment 
before the second NE assessment 
Censored 
No CR or PR documented centrally 
Date of last radiological assessment 
Censored 
Treatment discontinuation for undocumented progression Date of last radiological assessment 
Censored 
Treatment discontinuation for toxicity or other reason 
Date of last radiological assessment 
Censored 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) 
Date of last radiological assessment 
before 
initiation 
of 
non-permitted 
medication or therapy 
Censored 
The distribution of TTR times will be estimated using the KM product limit method. The 25th 
percentile, median and 75th percentile TTR times and their corresponding two-sided 95 % CI 
will be estimated. Confidence intervals for median TTR as well as the 25th and 75th 
percentile CIs will be calculated using the method of Brookmeyer and Crowley (1982), which 
is the default method within SAS® version 9 and higher. 
The results of the analysis will be presented in summary tables and KM plots will be 
constructed. Summary tables will present the numbers and percentages of subjects with 
response, the numbers and percentages of observed and censored subjects. The summaries 
will also include the median TTR as well as the 25th and 75th percentiles, the percentage of 
subjects who had a response at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and V16), and the 
associated 95 % CIs for each of these outcomes. Kaplan-Meier curves will be constructed and 
will display the number of subjects at risk at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and 
V16). 
The SAS Lifetest procedure will be used as follows: 
 
 
 
 
 
 
 
 
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3.2.1.2.4 Duration of response 
Duration of response (DOR) is defined as the time from onset of the first objective tumor 
response (PR or CR) to objective tumor progression (PD) according to RECIST criteria v 1.1 
assessed locally and also centrally afterwards in separate analyses. 
Subjects without any PR or CR will not be taken into account in the analyses. Additionally, 
subjects with response occurring after more than one missed visit and subjects taking 
prohibited medication/therapy prior to PR or CR declaration will not be taken into account in 
the analyses. 
 
3.2.1.2.4.1 Local assessment 
DOR is defined as time from the date of the first radiological assessment when PR or CR can 
be declared locally to the date of the first radiological assessment when PD can be assessed 
locally after a PR or CR local declaration. 
Definition of censoring date:  
Censoring dates are defined only for subjects with PR or CR assessed locally before the end 
of study, withdrawal, lost to follow-up or death. 
• 
Subjects without PD assessed locally before end of study, withdrawal, lost to follow-up 
or death will be censored at the last date on which response was ‘adequately’ assessed 
i.e. the date of the last radiological assessment. 
• 
In the case of prohibited medication/therapy, this is taken to be the last date of 
radiological assessment prior to the initiation of such medications/therapies. 
• 
PD assessed locally occurring after more than one missed visit will be censored in the 
analysis at the last adequate assessment before the missing assessments, where 
adequate assessment is considered to be the last radiological assessment that was 
considered evaluable by the investigator. 
Definition of DOR time: 
The DOR time will be calculated as the time from the date of the first radiological assessment 
when PR or CR can be declared locally to the date of the first radiological assessment when 
PD can be assessed locally after a PR or CR declaration. 
• 
DOR time = [(Date of local progression or censoring – date of first local PR or CR 
radiological assessment) + 1] / 7 (weeks) 
Table 8 specifies the event and censoring dates to be used in the analysis of DOR via local 
review; these are based on the FDA Guidance for Industry: Clinical Trial Endpoints for the 
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Table 8 
DOR analysis assessed locally 
Situation 
Date of event or censoring 
Outcome 
No screening evaluable assessment 
Not applicable 
Not included in 
the analysis 
No PR or CR declared locally 
Not applicable 
Not included in 
the analysis 
Two or more NE assessments before PR or CR local 
declaration 
Not applicable 
Not included in 
the analysis 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) before a 
local assessment of CR or PR for the given subject 
Not applicable 
Not included in 
the analysis 
PD documented locally 
Date 
of 
radiological 
assessment 
showing PD 
Event 
Two or more NE assessments before PD local declaration Date of last radiological assessment 
before the second NE assessment 
Censored 
No PD documented locally 
Date of last radiological assessment 
Censored 
Treatment discontinuation for undocumented progression Date of last radiological assessment 
Censored 
Treatment discontinuation for toxicity or other reason 
Date of last radiological assessment 
Censored 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) after local 
response declaration 
Date of last radiological assessment 
before 
initiation 
of 
non-permitted 
medication or therapy 
Censored 
PD documented locally after more than one missed visit 
Date of last radiological assessment
prior to PD 
Censored 
The distribution of DOR times will be estimated using the KM product limit method. The 
25th percentile, median and 75th percentile DOR times and their corresponding two-sided 
95 % CI will be estimated. Confidence intervals for median DOR as well as the 25th and 75th 
percentile CIs will be calculated using the method of Brookmeyer and Crowley (1982), which 
is the default method within SAS® version 9 and higher. 
The results of the analysis will be presented in summary tables and KM plots will be 
constructed. Summary tables will present the numbers and percentages of subjects with 
response tabulated by the number and percentage of responders with progression and of 
censored subjects. The summaries will also include the median DOR as well as the 25th and 
75th percentiles. Kaplan-Meier curves will be constructed and will display the number of 
subjects at risk at 24, 36 and 52 weeks (i.e. V9, V12 and V16). 
The SAS Lifetest procedure will be used: 
 
 
 
 
 
 
 
 
 
3.2.1.2.4.2 Central assessment 
DOR is defined as time from the date of the first radiological assessment when PR or CR can 
be declared centrally to the date of the first radiological assessment when PD can be assessed 
centrally after a PR or CR central declaration and without prior local PD declaration. 
Definition of censoring date: 
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Censoring dates are defined only for subjects with PR or CR assessed centrally before the end 
of study, withdrawal, lost to follow-up or death. 
• 
Subjects without PD assessed centrally before end of study, withdrawal, lost to follow-
up or death will be censored at the last date on which response was ‘adequately’ 
assessed i.e. the date of the last radiological assessment. 
• 
Subjects with PD assessed locally before a PD is assessed centrally will be censored at 
the date of the local PD assessment. 
• 
In the case of prohibited medication/therapy, this is taken to be the last date of 
radiological assessment prior to the initiation of such medications/therapies. 
• 
PD assessed locally occurring after more than one missed visit will be censored in the 
analysis at the last adequate assessment before the missing assessments, where 
adequate assessment is considered to be the last radiological assessment that was 
considered evaluable by the investigator. 
Definition of DOR time: 
The DOR time will be calculated as the time from the date of the first radiological assessment 
when PR or CR can be declared locally to the date of the first radiological assessment when 
PD can be assessed locally after a PR or CR declaration. 
• 
DOR time = [(Date of local progression or censoring – date of first local PR or CR 
radiological assessment) + 1] / 7 (weeks) 
Table 9 specifies the event and censoring dates to be used in the analysis of DOR via local 
review; these are based on the FDA Guidance for Industry: Clinical Trial Endpoints for the 
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Table 9 
DOR analysis assessed centrally 
Situation 
Date of event or censoring 
Outcome 
No screening evaluable assessment 
Not applicable 
Not included in 
the analysis 
No PR or CR declared centrally 
Not applicable 
Not included in 
the analysis 
Two or more NE assessments before PR or CR central 
declaration 
Not applicable 
Not included in 
the analysis 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) before a 
central assessment of CR or PR for the given subject 
Not applicable 
Not included in 
the analysis 
PD documented centrally 
Date 
of 
radiological 
assessment 
showing PD 
Event 
Two or more NE assessments before PD central
declaration 
Date of last radiological assessment 
before the second NE assessment 
Censored 
No PD documented centrally 
Date of last radiological assessment 
Censored 
Treatment discontinuation for undocumented progression Date of last radiological assessment 
Censored 
Treatment discontinuation for toxicity or other reason 
Date of last radiological assessment 
Censored 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) after 
central response declaration 
Date of last radiological assessment 
before 
initiation 
of 
non-permitted 
medication or therapy 
Censored 
PD documented centrally after more than one missed visit Date of last radiological assessment
prior to PD 
Censored 
The distribution of DOR times will be estimated using the KM product limit method. The 
25th percentile, median and 75th percentile DOR times and their corresponding two-sided 
95 % CI will be estimated. Confidence intervals for median DOR as well as the 25th and 75th 
percentile CIs will be calculated using the method of Brookmeyer and Crowley (1982), which 
is the default method within SAS® version 9 and higher. 
The results of the analysis will be presented in summary tables and KM plots will be 
constructed. Summary tables will present the numbers and percentages of subjects with 
response tabulated by the number and percentage of responders with progression and of 
censored subjects. The summaries will also include the median DOR as well as the 25th and 
75th percentiles. Kaplan-Meier curves will be constructed and will display the number of 
subjects at risk at 24, 36 and 52 weeks (i.e. V9, V12 and V16). 
The SAS Lifetest procedure will be used: 
 
 
 
 
 
 
 
 
 
3.2.1.2.5 Time to progression 
Time to progression (TTP) is defined as the time from first treatment administration to the 
first objective tumor progression (PD) according to RECIST criteria v 1.1. TTP will be 
assessed locally and also centrally. 
 
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3.2.1.2.5.1 Local assessment 
Time to progression according to local review will include investigator assessed PD and the 
other data will be censored. 
Clinical progression (i.e. locally assessed documented progression where the subject is 
withdrawn from the study due to clinical judgement of progression, however the progression 
is not confirmed by the independent centralized review) is considered as a progression 
endpoint in this analysis. 
Definition of progression date: 
The PD date is assigned to the first time at which PD can be declared. 
• 
For PD based on a new lesion, the PD date is the date of the first radiological 
assessment when the new lesion was detected. 
• 
For PD based on an increase in the sum of the target lesion measurements, the PD date 
is the date of the last radiological assessment of target lesions that shows the predefined 
increase in the sum of the target lesion measurements. 
Definition of censoring date: 
• 
Censoring dates are defined in subjects with no PD before end of study or withdrawal. 
In these subjects, the censoring date is defined as the last date on which progression 
status was ‘adequately’ assessed. This is taken to be the date of the last radiological 
assessment at which the target lesions were evaluated by local investigator review. 
• 
In the case of prohibited medication/therapy, this is taken to be the last date of 
radiological assessment prior to the initiation of such medications/therapies. 
• 
PDs occurring after more than one missed visit will be censored in the analysis at the 
last adequate assessment before the missing assessments, where adequate assessment is 
considered to be the last radiological assessment that was considered evaluable by the 
investigator. 
Definition of TTP time: 
The TTP time will be calculated as the time from first treatment administration to locally 
assessed PD. 
TTP time = [(Date of event – date of first treatment administration) + 1] / 7 (weeks) 
Table 10 specifies the event and censoring dates to be used in the analysis of TTP via local 
review; these are based on the FDA Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, May 2007. 


 
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Table 10 TTP analysis assessed locally 
Situation 
Date of event or censoring 
Outcome 
No screening evaluable assessment 
Date of first treatment administration 
Censored 
PD documented locally (either based on new lesion or 
increase in the sum of the target lesion measurements 
during the study) 
Date 
of 
radiological 
assessment 
showing PD 
Event 
Two or more NE assessments before PD 
Date of last radiological assessment 
before the second NE assessment 
Censored 
No PD 
Date of last radiological assessment 
Censored 
Treatment discontinuation for undocumented progression Date of last radiological assessment 
Censored 
Treatment discontinuation for toxicity or other reason 
Date of last radiological assessment 
Censored 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) 
Date of last radiological assessment 
before 
initiation 
of 
non-permitted 
medication or therapy 
Censored 
Death (due to any cause) before first PD assessment 
Date of last radiological assessment 
Censored 
Death (due to any cause) between adequate assessment 
visits 
Date of last radiological assessment 
Censored 
Death or progression after more than one missed visit 
Date of last radiological assessment 
Censored 
The distribution of TTP times will be estimated using the Kaplan-Meier (KM) product limit 
method. The 25th percentile, median and 75th percentile TTP times and their corresponding 
two-sided 95 % CI will be estimated. Confidence intervals for median TTP as well as the 25th 
and 75th percentile CIs will be calculated using the method of Brookmeyer and Crowley 
(1982), which is the default method within SAS® version 9 and higher. 
The results of the analysis will be presented in summary tables and KM plots will be 
constructed. Summary tables will present the numbers and percentages of subjects with local 
progression, the numbers and percentages of observed and censored subjects. The summaries 
will also include the median TTP as well as the 25th and 75th percentiles, the percentage of 
subjects who had progressed at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and V16), and the 
associated 95 % CIs. Kaplan-Meier curves will be constructed and will display the number of 
subjects at risk at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and V16). 
The SAS Lifetest procedure will be used as follows: 
 
 
 
 
 
 
 
 
  
 
3.2.1.2.5.2 Central assessment 
Time to progression according to central review will include centrally assessed PD and the 
other data will be censored including investigator assessed PD occurring before centrally 
assessed PD. 
Clinical progression (i.e. centrally assessed documented progression even though the 
progression is not assessed by the investigator) is considered as a progression endpoint in this 
analysis. 
In case of centrally assessed PD followed by death, the first event will be considered in the 
analysis unless an investigator assessed PD occurred before then the data would be censored. 
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Definition of progression date: 
The PD date is assigned to the first time at which PD can be declared. 
• 
For PD based on a new lesion, the PD date is the date of the first radiological 
assessment when the new lesion was detected. 
• 
For PD based on an increase in the sum of the target lesion measurements, the PD date 
is the date of the last radiological assessment of target lesions that shows the predefined 
increase in the sum of the target lesion measurements. 
Definition of censoring date: 
• 
Censoring dates are defined in subjects with no PD before end of study or withdrawal. 
In these subjects, the censoring date is defined as the last date on which progression 
status was ‘adequately’ assessed. This is taken to be the date of the last radiological 
assessment at which the target lesions were evaluated by independent review. 
• 
In the case of locally declared PD not confirmed by the independent radiologist, the 
subject will be censored at the date of local PD. 
• 
In the case of prohibited medication/therapy, this is taken to be the last date of 
radiological assessment prior to the initiation of such medications/therapies. 
• 
PDs occurring after more than one missed visit will be censored in the analysis at the 
last adequate assessment before the missing assessments, where adequate assessment is 
considered to be the last radiological assessment that was considered evaluable by the 
central review. 
Definition of TTP time: 
The TTP time will be calculated as the time from first treatment administration to centrally 
assessed PD without prior locally assessed PD. 
TTP time = [(Date of event – date of first treatment administration) + 1] / 7 (weeks) 
Table 11 specifies the event and censoring dates to be used in the analysis of TTP via central 
review; these are based on the FDA Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, May 2007. 


 
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Table 11 TTP analysis assessed centrally 
Situation 
Date of event or censoring 
Outcome 
No screening evaluable assessment 
Date of first treatment administration 
Censored 
PD documented centrally (either based on new lesion or 
increase in the sum of the target lesion measurements 
during the study) 
Date 
of 
radiological 
assessment 
showing PD 
Event 
PD documented locally only (either based on new lesion 
or increase in the sum of the target lesion measurements 
during the study) 
Date 
of 
radiological 
assessment 
showing PD 
Censored 
Two or more NE assessments before PD 
Date of last radiological assessment 
before the second NE assessment 
Censored 
No PD 
Date of last radiological assessment 
Censored 
Treatment discontinuation for undocumented progression Date of last radiological assessment 
Censored 
Treatment discontinuation for toxicity or other reason 
Date of last radiological assessment 
Censored 
Initiation of medications or therapies not permitted during 
the study (including new anti-cancer therapies) 
Date of last radiological assessment 
before 
initiation 
of 
non-permitted 
medication or therapy 
Censored 
Death (due to any cause) before first PD assessment 
Date of last radiological assessment 
Censored 
Death (due to any cause) between adequate assessment 
visits 
Date of last radiological assessment 
Censored 
Death or progression after more than one missed visit 
Date of last radiological assessment 
Censored 
The distribution of TTP times will be estimated using the KM product limit method. The 25th 
percentile, median and 75th percentile TTP times and their corresponding two-sided 95 % CI 
will be estimated. Confidence intervals for median TTP as well as the 25th and 75th 
percentile CIs will be calculated using the method of Brookmeyer and Crowley (1982), which 
is the default method within SAS® version 9 and higher. 
The results of the analysis will be presented in summary tables and KM plots will be 
constructed. Summary tables will present the numbers and percentages of subjects with 
central progression, the numbers and percentages of observed and censored subjects. The 
summaries will also include the median TTP as well as the 25th and 75th percentiles, the 
percentage of subjects who had progressed at 12, 24, 36 and 52 weeks (i.e. V6, V9, V12 and 
V16), and the associated 95 % CIs for each of these outcomes. Kaplan-Meier curves will be 
constructed and will display the number of subjects at risk at 12, 24, 36 and 52 weeks (i.e. V6, 
V9, V12 and V16). 
The SAS Lifetest procedure will be used as follows: 
 
 
 
 
 
 
 
 
  
 
3.2.1.2.6 Best overall response 
Best overall response (BOR) to study treatment according to RECIST criteria v 1.1 will be 
derived as the highest objective response achieved by the subject from the time of first 
treatment until disease progression/recurrence or the end of study and will be classified as: 
CR > PR > Non-CR/Non-PD (NCR/NPD) > SD> PD > ND > NE. Confirmation with a 
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similar response is not required and response could be assessed only once to be considered as 
the BOR, however the delay between an observation of stability of the disease (SD) and 
screening should be ≥ 4 weeks and the duration of objective response (CR or PR) or stability 
(SD) should be ≥ 4 weeks before a progression (PD) to be considered as confirmed. The 
following results will be displayed: "N" the number of subjects in the ITT/Safety population, 
"n" the number and percentages of evaluable subjects by overall response categories and 
"Missing" the number of missing observations, with n CR + n PR + n SD + n NCR/NPD + 
n PD + n NE+ Missing = N. 
Two separate descriptive summaries of BOR will be presented, first showing BOR assessed 
locally and second showing BOR assessed centrally. 
 
3.2.1.2.7 Objective response rate 
The objective response rate (ORR), i.e. the proportion of subjects with CR or PR will be 
described along with the 95 % CI at 9 and 12 months. Two separate descriptive summaries of 
the ORR will be presented, one using local review and the second using central review 
displaying the number and percentages of subjects by response, considering subjects with PD 
prior to 9 and 12 months with respectively PD at 9 and 12 months, and subjects withdrawn 
before the assessment for reason other than PD or missing as failures. 
 
3.2.1.2.8 Disease control rate at 12 months 
DCR at 12 months will be assessed locally and centrally. 
As specified in section 3.2.1.1.1, the number of assessed subjects at 12 months according to 
their response status with the number of subjects in PD prior or at 12 months, and the number 
of withdrawn subjects before 12 months with reason other than PD or missing will be 
displayed. The DCR will be based on all subjects in the ITT/Safety population with subjects 
with PD prior or at 12 months as well as withdrawn subjects from any reason considered as 
failures. 
The DCR will be analysed by an exact binomial proportion test for one-way tables in the 
ITT/Safety population and will then be compared to the thresholds of 30 % and 10 %. 
The proportion of responders will be displayed along with the two-sided 95 % Clopper-
Pearson CI using the following SAS Freq procedure for the local assessment compared to 
30 % and 10 %: 
 
 
 
 
 
 
 
 
 
 
3.2.1.2.9 Influence of type of carcinoid 
The influence of type of carcinoid (derived as typical, atypical or carcinoid neuroendocrine 
tumor according to foci of necrosis and mitotic count at screening as defined in Appendix 2) 
on the local and central DCR at 9 months will be analysed using a frequency table in the 
ITT/Safety population. For definition of DCR at 9 months, see section 3.2.1.1.  
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The proportion (with its 95 % CI) of subjects with DCR will be tabulated by derived carcinoid 
type and compared with a Fisher exact test using the following SAS Freq procedure (e.g. for 
the local assessment): 
 
 
 
 
 
 
3.2.1.2.10 
CgA and NSE levels 
Raw values and corresponding changes from baseline, as well as parameter expressed in ULN 
and corresponding changes from baseline will be described for CgA and NSE at baseline and 
at 1, 3, 6, 9 and 12 months (EOS) or EW using summary statistics and 95 % CI of the mean at 
each timepoint. Classes of ULN (< 1 ULN, 1-2 ULN, > 2 ULN) will also be derived and 
presented using summary statistics. Shift tables between baseline and each post-baseline visit 
will also be presented using classes of ULN (< 1 ULN, 1-2 ULN, > 2 ULN). 
In addition, CgA and NSE will be analysed on change from baseline of the parameter 
expressed in ULN by an analysis of covariance (ANCOVA) for repeated measures, using 
baseline values and the derived carcinoid type as covariates. Two models will be tested: a full 
model with the interaction between derived carcinoid type and visit, and an additive model 
without the interaction.  
The following SAS Mixed procedure will be used for the additive model: 
 
 
 
 
 
 
 
 
Where R2A1HI is the change from baseline of the value expressed in ULN as defined in 
ADaM implementation guide and R2BL is the baseline of the value expressed in ULN. 
The following SAS Mixed procedure will be used for the full model: 
 
 
 
 
 
 
 
 
If the interaction is found significant (p-value of interaction < 0.1), the model will be run by 
visit. 
The type of covariance matrix will be chosen using the AIC criterion. The covariance matrix 
minimizing the AIC criterion will be chosen for the final analysis. The following covariance 
matrices 
will 
be 
tested: 
variance 
components (VC), 
compound 
symmetry (CS), 
unstructured (UN). Models will be rerun using the different matrices and the corresponding 
outputs will be provided in the statistical appendices, the model with the smallest AIC will be 
displayed in the summary table. 
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If the ANCOVA normality hypothesis (i.e. non-normality of the residuals) does not hold, a 
Friedman ANOVA will be used. 
 
3.2.1.2.11 
Biochemical response 
CgA plasma levels will be measured at baseline (V2) and during the treatment period at 1 and 
3 months and every 3 months as a surrogate efficacy endpoint (i.e. at V4, V6, V9, V12 and 
V16). Subjects with baseline CgA level greater than ULN will be assessed for biochemical 
response and classified as responders if they have a decrease in CgA ≥ 50 % compared to 
baseline CgA, as having a stable disease if they have a decrease < 50 % or an increase ≤ 25 % 
compared to baseline CgA and as non-responders if they have an increase > 25 % compared 
to baseline. 
The number and proportion of subjects in each of the biochemical response categories (i.e. 
biochemical responder, biochemical stable disease and biochemical non-responder) will be 
summarised at each evaluated visit along with the 95 % CI. 
 
3.2.1.2.12 
Prognostic and predictive value of NSE and CgA levels on PFS 
The classes (< 1 ULN, 1-2 ULN, > 2 ULN) of baseline NSE and CgA levels will be 
investigated as prognostic and predictive value of PFS assessed locally and centrally. 
The following steps will be followed to assess the prognostic factors of CgA and NSE on PFS 
locally assessed. 
Step 1: 
NSE, CgA and derived carcinoid type will be tested in separate Cox proportional hazards 
models. Any factors found to be significant at p ≤ 0.20 (via the Wald chi-square test statistic) 
will be considered to be potentially important. The association between each covariate and 
treatment will be further explored by presenting separate KM plots for each level of the 
covariate. 
An example of SAS® code implementation follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Step 2: 
In a second step, each pre-selected parameter will be tested with the other retained parameters 
at the 0.001 level to confirm that there is no strong link between them (using a chi-square 
test). If independence is not met for 2 parameters (p < 0.001), the choice will be made 
according to clinical and statistical relevance. 
An example of SAS® code implementation follows: 
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Step 3: 
All selected parameters will be entered into a multivariate Cox model. The stepwise variable 
selection method in the SAS® procedure PHREG will be performed with p <= 0.20 to enter 
variables in the model, and p >= 0.05 to remove variables from the model, to select the best 
model. The final model will be adjusted on derived carcinoid type regardless of the 
parameters significance. 
The maximum likelihood estimates of model coefficients (with associated standard error, 
degrees of freedom, Wald Chi-square statistic and p-value) will be presented for the final 
model along with the HRs and 95 % CIs. 
An example of SAS® code implementation follows: 
 
 
 
 
 
 
 
 
 
 
 
  
The assumptions of proportional hazards (PH) will be examined graphically by plotting ln(-
ln(S(t))) versus t or ln(t) and looking for parallelism. The corresponding assessments will be 
displayed in the statistical appendices and a footnote stating that the assumptions hold will be 
added in the table presenting the final model. 
 
Similar steps will be followed to assess the prognostic factors of CgA and NSE on central 
PFS replacing PARQUAL='Local Assessment' by PARQUAL='Central Assessment'. 
 
3.2.1.2.13 
Prognostic and predictive value of NSE and CgA levels on ORR and DCR 
The classes (< 1 ULN, 1-2 ULN, > 2 ULN) of baseline NSE and CgA levels will be 
investigated as prognostic and predictive value on ORR and DCR assessed locally and 
centrally at 9 and 12 months. 
The following steps will be followed to assess the prognostic factors of CgA and NSE on 
ORR locally assessed at 9 months. 
Step 1: 
NSE, CgA and derived carcinoid type will be tested in separate logistic regression models. 
Any factors found to be significant at p ≤ 0.20 (via the Wald chi-square test statistic) will be 
considered to be potentially important.  
An example of SAS® code implementation follows: 
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Step 2: 
In a second step, each pre-selected parameter will be tested with the other retained parameters 
at the 0.001 level to confirm that there is no strong link between them (using a chi-square 
test). If independence is not met for 2 parameters (p < 0.001), the choice will be made 
according to clinical and statistical relevance. 
An example of SAS® code implementation follows: 
 
 
 
 
 
 
  
Step 3: 
All selected parameters will be entered into a multivariate logistic regression model. The 
stepwise variable selection method in the SAS® procedure Logistic will be performed with 
p ≤ 0.20 to enter variables in the model, and p ≥ 0.05 to remove variables from the model, to 
select the best model. 
The maximum likelihood estimates of model coefficients (with associated standard error, 
degrees of freedom, Wald Chi-square statistic and p-value) will be presented for the final 
model along with the adjusted proportions and 95 % CIs. 
An example of SAS® code implementation follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The Hosmer and Lemeshow goodness-of-fit test for the final selected model will be assessed. 
Similar steps will be followed to assess the prognostic factors of CgA and NSE on central 
ORR replacing PARQUAL='Local Assessment' by PARQUAL='Central Assessment' and on 
DCR replacing PARAMCD='ORR' by PARAMCD='DC'. 
 
3.2.1.2.14 
Prognostic value of biomarkers expression on PFS, ORR and DCR 
Biomarkers expression, i.e. immunohistochemistry assay SSTR2 (including categories of 
HER-2 score (0, 1+, 2+, 3+ and positive versus negative), H-score (from 0 to 300 as 
quantitative variable and positive versus negative according to the Specht publication) and 
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IRS score (categories of scores according to the Specht publication), Ki67 (as class: < 4, [4-
25[, ≥ 25 according to Rindi publication) and MGMT status (including percentage of positive 
nuclei stained (quantitative variable and positive versus negative according to Schmitt 
publication), H-score (from 0 to 300 as quantitative variable) and percentage of methylated 
sites (quantitative variable and positive versus negative according to Schmitt publication) for 
protein levels in tissue obtained from paraffin embedded primary tumour surgery specimens 
or biopsies, will be described at baseline using summary statistics. If any of those biomarkers 
are not collected at screening in all subjects, its evaluation as a prognostic factor might be 
compromised, so the relevance of its inclusion in the analyses will be reviewed prior to 
database lock. 
As described above, the prognostic value of the biomarkers expression at screening on PFS 
will be assessed locally and centrally using Cox proportional hazard models. 
As described above, the prognostic value of the biomarkers expression at screening on ORR 
and DCR at 9 and 12 months assessed locally and centrally will be analysed using logistic 
regression models. 
3.2.1.2.15 
Agreement of the central assessment of tumor radiological response and the 
local one on the DCR 
Differences between central radiology review and local investigator review will be assessed 
according to the DCR status at 9 months as defined in section 3.2.1.1. Summary tables will 
present the number of agreements and disagreements between the evaluators (central versus 
local) along with the p-values from the kappa test. 
A kappa statistic will be employed to evaluate the concordance between the central and the 
local review. If either result from the central review or the local review is not applicable, the 
outcome will be denoted as “disagreement”. An example of SAS® code implementation 
follows: 
 
 
 
 
 
3.2.1.2.16 
WHO performance status (ECOG) 
WHO performance status (ECOG) will be described at each visit and a shift table between 
screening and each visit will be produced. 
 
3.2.2 
Safety 
All safety data will be included in the data listings and the summary tables will be based on 
the ITT/Safety population. 
3.2.2.1 
Adverse events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 20.0. 
Listings will be presented and sorted by subject, start date of AEs, primary system organ 
class, preferred term and verbatim text for all AEs recorded during the study. 
Listings of death, of serious adverse events (SAE), of drug-related AEs, of AEs with NCI-
CTCAE grade > 2, of AEs leading to drug withdrawal, of AEs leading to drug reduction and 
of AEs leading to drug interruption will also be presented. 
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Treatment Emergent Adverse Events (TEAE) will be flagged (*) in the AEs listing and will 
be summarised. 
A TEAE is defined as any AE that occurs during the active phase of the study (i.e. between 
the start of the first treatment and 4 weeks after the end of the last study treatment) if: 
(1) 
it was not present prior to receiving the first dose of IMP, or 
(2) 
it was present prior to receiving the first dose of IMP but the intensity/grade increased 
or the AE became serious during the active phase of the study, or 
(3) 
it was present prior to receiving the first dose of IMP, the intensity/grade is the same 
but the causality changed to “related” during the active phase of the study. 
An overall summary table of all TEAEs will be presented. For this table, in the event of 
multiple episodes of the same event being reported by the same subject, the NCI-CTCAE 
worst grade and related causality (if any) will be described and in the cross classification of 
causality and NCI-CTCAE worst grade, any subject experiencing multiple AEs with different 
intensities for each causality category will be counted for each grade.  
 
TEAEs will be summarised with the number and percentage of subjects with TEAEs 
classified by primary system organ class and preferred term (ordered alphabetically) and by 
associated NCI-CTCAE worst grade. The number of occurrences of a TEAE will also be 
presented. 
In addition, summary tables will also be presented for serious TEAEs, serious TEAEs by 
associated NCI-CTCAE worst grade, non-serious TEAEs by associated NCI-CTCAE worst 
grade, TEAEs per decreasing frequency, related TEAEs by associated NCI-CTCAE worst 
grade, non-related by associated NCI-CTCAE worst grade TEAEs, TEAEs by associated 
NCI-CTCAE worst grade and worst causality, TEAEs by associated NCI-CTCAE worst 
grade and worst causality including subject identification, TEAEs leading to drug withdrawal 
by associated NCI-CTCAE worst grade, TEAEs leading to dose reduction of Temozolomide 
by associated NCI-CTCAE worst grade and TEAEs leading to dose interruption by 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 NCI-CTCAE worst grade (grade 5 > grade 4 > grade 3 > grade 2 > grade 1 
> missing > not applicable) and the worst causality (related > missing > not related) will be 
chosen.  
Deaths will also be summarised with the number and percentage of dead subjects and the 
cause of death (disease progression, adverse event or other) overall and by period (i.e. during 
the treatment period, defined from the first drug intake to the last drug intake plus 4 weeks, or 
the follow-up period for deaths occurring after the last intake plus 4 weeks). 
 
3.2.2.2 
Laboratory data 
A listing of NCI-CTCAE grades with corresponding laboratory ranges will be provided. 
Laboratory data (haematology, biochemistry and urinalysis) will be listed in SI units and 
abnormal values will be flagged (High [H] for values above the upper limit of normal 
range (ULN), Low [L] for values below the lower limit of normal range (LLN), clinically 
significant [CS], not clinically significant [NCS]) where applicable with also the NCI–
CTCAE grade (for haematology, biochemistry). Any unscheduled laboratory assessments will 
be flagged [U] in the listings. 
A listing will present all values for a subject with at least one clinically significant abnormal 
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In some local laboratories, the parameters have been collected as percentages instead of the 
standard units expected, so these data will only be listed and considered as missing in the 
tables. 
 
3.2.2.2.1 Haematology and biochemistry 
For haematology and biochemistry parameters, the baseline will be defined as the last 
measurement collected prior to the first dose of study drug. 
For haematology and biochemistry parameters, summary statistics will be presented at each 
scheduled assessment for actual values and changes from baseline. Shift tables for all 
parameters will be presented of the number and percentage of subjects with low, normal or 
high values. 
Haematological and biochemistry toxicities will be recorded and graded according to the 
NCI–CTCAE criteria, version 4.03, dated: 14 June 2010. A listing of NCI–CTCAE grade 3 
and 4 toxicities will be produced. And the number and percentage of subjects with NCI–
CTCAE grades 3 and 4 toxicities will be summarised by parameter and worst NCI-CTCAE 
grade during the treatment period (defined from the first intake to the last intake plus 4 weeks 
i.e. from V2 to V16). 
Additionally, a listing of out of range values with all parameters including those not graded 
with NCI- CTCAE will be provided with the H and L flags. 
 
3.2.2.2.2 Urinalysis 
For categorical urinalysis data (absent/trace/positive and normal/abnormal/not evaluable), 
frequency tables will be presented at each scheduled assessment. In addition, shift tables 
between screening and each scheduled assessment will also be presented. 
For continuous urinalysis data, summary statistics will be presented at each scheduled 
assessment for actual values and changes from screening. 
Additionally, a listing of abnormal clinical significant values will be provided. 
 
3.2.2.3 
Vital signs 
Vital signs (supine, sitting and standing systolic and diastolic blood pressures, heart rate and 
weight) will be listed at each assessment by subject. Any unscheduled vital signs will be 
flagged [U] in the listing. 
Baseline values will be defined as the last vital signs measurement collected prior to the first 
dose of study drug.  
Summary statistics will be presented at each scheduled assessment for actual values and 
changes from baseline. 
 
3.2.2.4 
ECG 
ECG results will be listed at each timepoint by subject. Any unscheduled assessment will be 
flagged [U] in the listings. 
Continuous ECG parameters will be presented using summary statistics at each scheduled 
assessment for actual values and changes from screening. 
ECG interpretation of clinical significance (within normal limits / abnormal, not clinically 
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frequency table at each post-dose assessment and a shift table between baseline and post-
baseline assessments of the number and percentage of subjects. 
Additionally, the worst ECG interpretation between post-dose assessments (abnormal, 
clinically significant > abnormal, not clinically significant > not evaluable > within normal 
limits) will be described. 
 
3.2.2.5 
Echocardiography 
Echocardiography results will be listed at each timepoint by subject. Any unscheduled 
assessment will be flagged [U] in the listings. 
Continuous parameters will be presented using summary statistics at each scheduled 
assessment for actual values and changes from screening. 
Qualitative parameters will be presented using a frequency table at each scheduled 
assessment. 
For echocardiography interpretation of clinical significance (normal / abnormal, not clinically 
significant / abnormal, clinically significant / not evaluable), a frequency table will be 
presented at each post-dose assessment and for the worst value between post-dose 
assessments (abnormal, clinically significant > abnormal, not clinically significant > not 
evaluable > normal). 
 
3.2.2.6 
Gallbladder echography 
Gallbladder echography examinations will be listed at each assessment by subject. Any 
unscheduled assessment will be flagged [U] in the listings. 
Presence and absence of lithiasis and sludge and whether the lithiasis/sludge is symptomatic 
will be summarised at each assessment in frequency tables. Shift tables will also be presented 
between screening and each scheduled assessment. 
 
3.2.3 
Missing data and outliers 
3.2.3.1 
Missing data 
No missing value will be replaced. 
In the description of qualitative parameters, subjects with a value counted as “missing” at a 
visit will be presented. 
If there is a significant number of missing values for a subject (or if there is confirmed data 
appearing spurious), a decision will be made following consultation with the sponsor 
regarding the handling of these data in summaries, prior to the database lock. 
Any repeat or additional assessments performed will be included in the individual subject data 
listings. 
• 
Efficacy endpoints 
When tumour assessment visits are completely missing, rules from FDA Guidance for 
Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, May 2007 
will be implemented as described in section 3.2.1 Efficacy. 
• 
Safety endpoints 
If a value requires a retest (for laboratory values, vital signs, ECG, cardiac echography 
examination, and gallbladder echography), the last reliable non-missing value will be taken 
into account if measured before the administration; and the first non-missing reliable value for 
post-treatment assessments. An assessment is considered reliable if it is performed without 


 
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any technical problem and if the result is within the range of plausible values. For adverse 
events with missing information for the intensity and causality, the value will not be replaced 
and will be summarized as a separate category. 
For all other variables, no imputation will be made for missing data. 
 
3.2.3.2 
Missing or incomplete dates 
In all listings, missing or incomplete dates should be left as they have been recorded. 
However, for calculation / sorting / assignation based on dates, the following methods will be 
used: 
The most conservative approach will be systematically considered (i.e. if the onset date of an 
AE/concomitant medication is missing / incomplete, it is assumed to have occurred during the 
study treatment phase (i.e. a TEAE for AEs) except if the partial onset date or other data [stop 
date, …] indicates differently). 
A missing/incomplete date of medical history or disease diagnosis will be assumed to have 
occurred before any study treatment. 
If a partial date and the associated information do not allow to state about the assignation to a 
group / category, all the possible groups / categories will be considered (i.e. an AE could be 
assigned to several possible doses at event onset according to its partial onset date and stop 
date. Particularly an AE with missing start date will be assigned to each dose received before 
its end date. Similarly a medication with partial start and stop dates could be considered as 
prior and concomitant treatment). 
Where this is possible, the derivations based on a partial date will be presented as superior 
inequalities (i.e.: for an AE started in FEB2004 after the  administration performed on 
31JAN2004, the days since last dose will be “≥ 2”, similarly the duration of ongoing AEs or 
medication will be “≥ xx” according to the start and last visit dates). 
 
3.2.3.3 
Outliers 
A search of outliers should be performed before the database lock and actions with the 
sponsor should be defined. 
 
3.2.4 
Subject disposition 
The number and percentage of subjects enrolled and included in each population will be 
presented by centre for the screened population. 
A listing of the inclusion and exclusion criteria will be provided by subject, and subject 
eligibility will also be listed. 
A summary table and a flow chart will be provided for the ITT/Safety population presenting 
the number of subjects at each visit (scheduled and attended according to time windows) and 
in the flow chart identifying the number of subjects who continued, withdrew or completed 
over time. 
The reasons for subject exclusions from each population will also be tabulated on the 
screened population. 
All the major protocol deviations identified prior to unblinding will also be listed by subject. 
Additionally major protocol deviations with impact on the populations will be summarised on 
the ITT/Safety population. 


 
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A summary table will present the extent of subject exposure in the study. The length of 
exposure is calculated from the date of consent to the last study visit. 
Listings of dates of assessments (relative day) and of study duration will be presented by 
subject. The number and percentage of subjects at each planned visit during the study will be 
presented on the ITT/Safety population. 
 
3.2.5 
Withdrawals 
The number of subjects who were treated, and who discontinued and completed the study 
(local progression or completed all visits see Appendix 2) will be tabulated and listed. 
Primary reasons for discontinuation of study will be tabulated. Primary reasons for study 
discontinuation will also be presented by visit. 
 
3.2.6 
Demographic and baseline characteristics 
The baseline is the last available assessment prior to the first dose of study drug (Day 1). 
All demographic and baseline characteristics will be listed by subject. 
Summary statistics will be provided for demographic and baseline characteristics (i.e. sex, 
race, age, age class (< 65, ≥ 65), height, weight, Body Mass Index (BMI) and BMI class 
(< 18.5, [18.5; 25[, ≥ 25)), for the ITT/Safety population overall and by derived type of 
carcinoid.  
The following tumour characteristics (history and tissue analysis) will also be described: 
• 
Time since diagnosis (in months), 
• 
Location of the primary tumor (Thymus/Lung), 
• 
Foci of necrosis (local assessment at screening) and type if present, 
• 
Mitotic count (local assessment at screening), 
• 
Type of carcinoid (derived from absence/presence of foci of necrosis and mitotic count 
see Appendix 2), 
• 
TNM Staging according to UICC/AJCC 7th Edition TNM System assessed by the 
investigator, 
• 
TNM Staging according to UICC/AJCC 8th Edition TNM System, assessed centrally, 
• 
Octreoscan or GA-DOTA/TATE/TOC-PET result within 12 months, 
• 
SSTR2 status (central assessment including categories of HER-2 score (0, 1+, 2+ 3+ 
and positive versus negative), H-score (from 0 to 300 as quantitative variable and 
positive versus negative according to the Specht publication) and IRS score (qualitative 
variable according to the Specht publication), 
• 
Ki67 status (central assessment as score and in class: < 4, [4-25[, ≥ 25), 
• 
MGMT status (central assessment including percentage of positive nuclei stained 
(quantitative variable and positive versus negative according to Schmitt publication), 
H-score (from 0 to 300 as quantitative variable) and percentage of methylated sites 
(quantitative variable and positive versus negative according to Schmitt publication)). 
NYHA functional classification, serum pregnancy test examinations and serology results will 
also be listed and summarised. 
 
3.2.7 
Medical and surgical history 
Significant medical and surgical history will be coded using MedDRA Version 18.1 or later. 


 
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The listings will present the preferred term and verbatim text and be sorted by subject, 
primary system organ class, preferred term and verbatim text. 
A frequency table of the number and percentage of subjects will be provided for all medical 
and surgical history by primary system organ class and preferred term. 
 
3.2.8 
Subject compliance 
Duration of study drug exposure and compliance will be summarized separately for TMZ and 
Lanreotide ATG including number of cycles (i.e. for TMZ with one cycle means at least one 
capsule taken) and number of injections planned and performed (according to the treatment 
period duration) respectively and cumulative dose received, and study drug exposure will also 
be described overall. In addition, the percentage of subjects by level of compliance for each 
drug defined as follows will be provided: < 70 %, [70 %; 100 %[, 100%, ]100 %; 130 %[ and 
≥ 130 %. Additionally, the number of subjects with TMZ titration (down from 250 mg to 
180 mg, since up titration is not permitted) will be described by visit and overall. 
Listings will present the drug administrations (dose, quantity, date) by subject and visit for 
TMZ and Lanreotide ATG. In addition, the listings will present the difficulties recorded 
during drug administrations. Besides, a table will be produced to describe the reasons for 
discontinuation of study medications by visit. 
3.2.9 
Prior and concomitant medications, therapies and surgical procedures 
All prior and concomitant medications as well as prior therapies and surgical procedures for 
the study disease will be recorded on the eCRF.  
Any medications or therapies given to a subject for another indication within 28 days before 
study drug administration or during study drug administration will be indicated on the eCRF 
as well as concomitant surgical procedures. Dose and generic name or tradename will be 
indicated. All recorded data will be included in data listings. 
Prior and concomitant medications/therapies/procedures will be coded using World Health 
Organization – Drug dictionary (WHO-DD) Version of March 2016 or later. The therapeutic 
class will correspond to the second level of Anatomic Therapeutic Class (ATC) code, which 
corresponds to the first 3 digits. 
The date of first administration of study drug (study day 1) will be used as the cut-off date for 
the definition of prior and concomitant. A drug that started before study day 1 and is 
continuing at time of Day 1 will be considered as both, prior and concomitant. Prior, 
concomitant and both prior and concomitant will be flagged P, C and PC respectively, in all 
listings. 
The listings will be presented for the medications, therapies and surgical procedures for T-
NETs (separating prior chemotherapies, prior targeted therapies, prior other medications, prior 
radiotherapies, prior locoregional therapies and/or peptide receptor radionuclide therapies, 
prior surgical procedures and concomitant medications for T-NETs) and other than for T-
NETs independently (separating prior and concomitant non-drug therapies and other 
medications) and will be sorted by subject, chronological start date, therapeutic class, 
preferred name and verbatim name. 
Frequency 
tables 
of 
the 
number 
and 
percentage 
of 
subjects 
with 
prior 
medications/therapies/procedures will be provided by category (i.e. for T-NETs: prior surgical 
procedures, prior radiotherapies, prior locoregional therapies and/or peptide receptor 
radionuclide therapies, prior chemotherapies, prior targeted therapies, prior other medications; 
and other than for T-NETs: prior non-drug therapies and prior other medications). 


 
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Frequency tables of the number and percentage of subjects with concomitant 
medications/therapies/procedures will be provided by category (i.e. concomitant medications 
for T-NETs and concomitant medication other than for T-NETs as well as concomitant non-
drug therapies and concomitant surgical procedures) will be provided by therapeutic class and 
preferred name. 
Prohibited therapies will be identified, to do so the therapeutic class and preferred name will 
be specified in Appendix 1 to enable the database to be searched and to flag the concerned 
therapies in the listings. 
 
3.2.10 
Derived data 
The derived data are data which are calculated from the raw data in the eCRF and not 
included in the database. The list of derived data is displayed in Appendix 2. 
 
3.2.11 
Visit windows 
All data will be organised and analysed according to the derived attended visits. Since actual 
observation times may differ from the scheduled visit times and where this occurs the results 
should be allocated to the most appropriate visit using the assessment, evaluation and sample 
dates rather than the visit date which could be delayed. Therefore, time intervals (e.g. visit 
windows) have been constructed so that every observation collected can be allocated to a 
particular time point. If more than one record occurs within the same visit window where only 
one assessment is expected then the following rule should be applied: for pre-study 
assessments the last non-missing result prior to study drug administration should be used; for 
post-treatment assessments the closest non-missing result to the scheduled visit should be 
used. 


 
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Table 12 Visit windows 
Study phase 
Visit 
Time interval (days) 
 
 
 
Pre treatment 
Screening 
-28 to –1 
 
 
 
Treatment period 
Baseline 
1 (prior to first dose) 
Week 2 
2 to 17 
Week 3 
18 to 24 
Week 4 
25 to 42 
Week 8 
43 to 70 
Week 12 
71 to 98 
Week 16 
99 to 126 
Week 20 
127 to 154 
Week 24 
155 to 182 
Week 28 
183 to 210 
Week 32 
211 to 238 
Week 36 
239 to 266 
Week 40 
267 to 294 
Week 44 
295 to 322 
Week 48 
323 to 350 
 
 
 
End of study 
Week 52 
351 to 378 
A listing with visits as reported by the investigators and reallocated visits with time windows 
will be produced in order to identify visits according to the time they occurred including 
reallocated early withdrawal and appendix visits. 
3.2.12 
Rules and data formats 
Data will be presented using an appropriate number of decimal places (i.e. the number of 
decimal places used does not imply undue precision). Raw data will be presented to the 
number of decimal places collected, and derived data will be presented to an appropriate 
number of decimal places. The appropriate number of decimal places will be determined by 
general practice, mathematical rationale or scientific rationale (e.g. age should be presented in 
whole numbers). 
For summary statistics, the following will be presented: number of available observations (n), 
number of missing observations (missing), arithmetic mean and 95 % CI of the mean, 
standard deviation, median and the range (minimum, maximum). For categorical or discrete 
variables, the absolute and relative (percentage) numbers based on the available number of 
observations for each category will be presented, including 95 % CI (if required). 


 
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Mean, 95 % CI, median, standard deviation and standard error of the mean values will be 
reported to one decimal place greater than the raw/derived data that they summarise. 
Minimum and maximum values will be reported with the same precision as the raw data. 
Percentages will be based on the number of subjects in the specified analysis population with 
non-missing observations and will be reported to one decimal place and 0 % will not be 
presented (i.e. missing values will not be taken into account in the denominator). For 
description by visit, percentages will be based on the number of subjects in the specified 
analysis population attended the visit with non-missing observations. The denominator will be 
specified in a footnote to the tables for clarification if necessary. 
Lower and upper CI values should be presented to one decimal place more than the 
raw/derived data (i.e., to the same number of decimal places as the mean). 
P-values will be reported to four decimal places (e.g.: p=0.0037), after rounding. P-values 
which are less than 0.0001 will be presented as ‘< 0.0001’. 
All values below or above a limit of detection (e.g. < 0.1 or > 100) will be listed as such. For 
each parameter for which it is possible to have values below or above a limit of quantification, 
the rule to be used in the statistical tables is to replace values below or above a limit of 
quantification by the limit of quantification. 
All text fields must be left justified and numeric or numeric with some text specification (e.g.: 
not done, unknown, < 4.5, …) must be decimal justified. Dates and time will be presented in 
the format YYYY-MM-DDTHH:MM or YYYY-MM-DD if time is missing or not recorded. 
 
3.2.13 
Pooling of centres 
It is not planned to perform a subgroup analysis on individual or groups of centres. 
 
3.2.14 
Interim analysis 
No interim analysis will be performed. 
 
3.2.15 
Role of independent data monitoring committee (DMC)/interim data review 
committee [if applicable] 
No independent data monitoring committee/interim data review committee will be used in this 
study. 
 
3.2.16 
Covariates and analysis of subgroups 
If the frequency of subjects in each category allows it, subgroup analyses of typical versus 
atypical carcinoid type will be produced for the primary analysis. 
 


 
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4 
COMPUTER SYSTEMS, SOFTWARE AND VALIDATION OF PROGRAMS 
4.1 
Hardware 
The statistical analysis will be performed using a PC on a Windows 7 operating system. 
4.2 
Software 
All tables, listings and figures will be produced and statistical analysis performed using SAS 
v 9.4 or higher.  All outputs will be in Microsoft Word format. 
4.3 
Validation programs 
Biotrial Biometrics will provide a Quality Control (QC) and Validation Plan to Ipsen 
identifying the methods of validation like the double programming of the main safety and 
efficacy endpoint. 
The study statistician is responsible for reviewing each project program and output associated 
with the deliverable product. Program logs are reviewed for logical, syntax and fatal errors. 
The review in SAS includes, but is not limited to, all ERRORS, WARNINGS, BY-VALUE 
merge messages, NOTES, and UNINITIALIZED variables. Program logs are also reviewed 
for accurate and consistent variable and observation counts following each procedure and data 
step. 
The study statistician is responsible for checking and reviewing the work produced using 
whatever method he/she feels is appropriate (e.g., SAS code review, hand calculation, etc.) to 
reassure of the quality of the output. 
Outputs are reviewed for typographical errors, misspellings and nonsensical values or results 
and to check the consistency with the statistical and analysis plan. Outputs are cross-checked 
against each other for accuracy and consistency. For statistical tables, listings, appendix 
listings, and figures, this procedure includes comparison of subject group numbers, counts of 
subjects at each observation point, and consistency of results for variables between outputs. 
Findings of the QC reviews are communicated to the party responsible for making necessary 
changes. The programs will be retested after modifications. 
During the whole process of production and validation of the deliverables, the statistical 
programmer, the assistant and the study statistician complete the QC and statistical analysis 
results follow-up validation checklist. Once the validation of the deliverables is complete, i.e. 
when all analysis datasets and/or outputs are produced, integrated (where applicable) and 
reviewed, and no further change is required, the study statistician ticks the approved 
deliverables to indicate to the assistant that the outputs are ready to be compiled by section 
and then delivered to the sponsor. The summary QC forms produced will be printed and 
signed by the participants during the validation process at each outputs delivery and provided 
to the sponsor to support the validation at the end of the study. 
 
4.4 
Restitution of the programs 
All programs (including macros and analysis datasets) producing the tables, listings and 
statistical outputs along with associated logs should be given to the sponsor when the tables, 
listings, figures and statistical analyses will be finalised. 
Moreover, ADaM datasets will be provided to the sponsor with the first draft at 50 % of 
subjects, soft lock, first draft of the TFLs post lock and final TFLs. 


 
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5 
CHANGES FROM PROTOCOL 
In the protocol section 3 "STUDY DESIGN" paragraph 3.1 "GENERAL DESIGN AND 
STUDY SCHEMA", it is stated that “Subjects who complete all scheduled visits until Visit 
12 (36 weeks of treatment) will be considered to be evaluable for primary objective of the 
study.”. However, the steering committee advised as more appropriate for the primary 
objective to consider the subjects attending the 9 months assessment and to consider the 
subjects withdrawn before 9 months with PD as PD, while the other subjects withdrawn for 
reason other than PD or missing reason would also be considered as failure for disease 
control. 
The content of the echocardiography assessments was discussed during the eCRF design and 
were not described in the protocol. 
It was planned in the protocol to have a deviation when the compliance to Temozolomide is 
< 80 %, but to be consistent with other similar studies the threshold was updated to 70 %. 


 
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6 
REFERENCES 
(1) 
Response Evaluation Criteria In Solid Tumours (RECIST) criteria version 1.1, 
Eisenhauer et al., European Journal of Cancer 45 (2009) 228 – 247 
(2) 
International Conference on Harmonisation (ICH) E9 and Federal register Vol. 63, No. 
179 (September 1998). 
(3) 
SAS, Version 9.4. SAS Institute Inc., Cary, NC, USA, 2014. 
(4) 
FDA Guidance for Industry, “Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics”, May 2007 
(5) 
Brookmeyer, R. and Crowley, J. (1982), “A Confidence Interval for the Median 
Survival Time” Biometrics, 38, 29–41. 
(6) 
International Union Against Cancer (UICC) / American Joint Committee on Cancer 
(AJCC) Tumor-Node-Metastasis (TNM) Classification of Malignant Tumours, L.H. 
Sobin, M.K. Gospodarowicz and Ch. Wittekind, 7th Edition System, 2009 
(7) 
International Union Against Cancer (UICC) / American Joint Committee on Cancer 
(AJCC) Tumor-Node-Metastasis (TNM) Classification of Malignant Tumours, J.D. 
Brierley, M.K. Gospodarowicz and Ch. Wittekind,  8th Edition System, 2017 
(8) 
Specht, E., Kaemmerer, D., Sänger, J., Wirtz, R.M., Shultz, S. and Lupp, A. (2015), 
“Comparison of immunoreactive score, HER2/neu score and H score for the 
immunohistochemical evaluation of somatostatin receptors in bronchopulmonary 
neuroendocrine neoplasms” Hystopathology, 67, 368–377. 
(9) 
Rindi G, Klersy C, Inzani F, Fellegara G, Ampollini L, Ardizzoni A, Campanini N, 
Carbognani P, De Pas TD, Galetta D, Granone PL, Righi L, Rusca M, Spaggiari L, 
Tiseo M, Viale G, Volante M, Papotti M and Pelosi G, Grading the neuroendocrine 
tumours of the lung: an evidence-based proposal. (2014) Endocrine-Related Cancer, 21 
(1), 1-16. 
(10) Schmitt, A.M, Pavel, M., Rudolph, T., Dawson, H., Blank, A., Komminoth, P., 
Vassella, E. and Perren, A. (2014) "Prognostic and predictive roles of MGMT protein 
expression and promoter methylation in sporadic pancreatic neuroendocrine 
neoplasms" Neuroendocrinology 100, 35-44.