Clinical trial NCT02678780
Conditions: Neuroendocrine Tumors
Sponsor: Grupo Espanol de Tumores Neuroendocrinos
Start date: 2015-10-01; Completion date: 2020-08-01
Enrollment: 123 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, international, multi-center, open label, stratified, exploratory phase II study evaluating the efficacy and safety of lenvatinib in patients with advanced/metastatic, neuroendocrine tumors of the pancreas after progression to a previous targeted agent (cohort A) or gastrointestinal tract after progression to somatostatin analogues (cohort B).

Detailed description:
Trial to assess the efficacy of Lenvatinib in metastatic neuroendocrine tumor. The primary endpoint of the study is overall response rate (ORR) by RECIST v 1.1 upon central radiologic assessment.

Number of patients: 110 patients Estimated duration of subject participation: 24 months

Arms: arm 1: Patients with advanced/metastatic, histologically confirmed, grade 1/2 (G1/G2) of 2010 WHO (World Health Organization) classification neuroendocrine tumors of the pancreas after progression to a previous targeted agent.

Treatment: Dosing schedule of 24 mg once a day of Lenvatinib (two 10-mg capsules + one 4-mg capsule) arm 2: Patients with advanced/metastatic, histologically confirmed, grade 1/2 (G1/G2) of 2010 WHO (World Health Organization) classification neuroendocrine tumors of gastrointestinal tract after progression to somatostatin analogues Treatment: Dosing schedule of 24 mg once a day of Lenvatinib (two 10-mg capsules + one 4-mg capsule)
Interventions: intervention 1: Lenvatinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
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TRIAL TO ASSESS THE EFFICACY OF LENVATINIB IN METASTATIC 
NEUROENDOCRINE TUMORS (TALENT STUDY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
GETNE (Grupo Español de Tumores Neuroendrocrinos) 
Coordinator: 
Dr. Jaume Capdevila 
Type of Document: 
Clinical Trial Protocol 
EudraCT number: 
2015-001467-39 
Phase: 
II 
Version: 
4.0 
Release date: 
April 04th, 2016 
 
Notice: Part or all the information included in this document may be unpublished material and it should be 
treated as confidential and property of the sponsor. It may not be disclosed to any unauthorized person, 
including publications and presentations, without the written consent of the Sponsor. 
 
 


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1. Synopsis 
Sponsor 
GETNE (Grupo Español de Tumores Neuroendrocrinos) 
París 162, Pral. 1ª. 08036, Barcelona 
Phone:93 451 17 24; Fax: 93 451 43 66 
Contact: getne@getne.org  
Clinical trial title 
“TRIAL TO ASSESS THE EFFICACY OF LENVATINIB IN 
METASTATIC NEUROENDOCRINE TUMORS (TALENT STUDY).” 
Protocol number 
GETNE1509 (TALENT) 
Study Coordinator and 
Principal Investigator 
Dr. Jaume Capdevila 
Medical Oncology Department. Gastrointestinal and Endocrine 
Tumor Unit 
Vall d'Hebron University Hospital 
Pg Vall d'Hebron, 119-129; 08035 Barcelona 
Tel. +34934894350; Fax. +34932746781 
jacapdevila@vhebron.net; jcapdevila@onco.cat 
Planned sites 
Approximately 25 sites in several countries in Europe (planned sites 
in Spain, Italy, United Kingdom, and Austria) 
Name and qualifications 
of the persons in 
charge of Monitoring 
Experior, S.L. 
C/ Vicente Galmés, 1A; 46139 La Pobla de Farnals (Valencia) 
Tel: 902.105.255; Fax: 96.145.21.91 
Experimental Drug  
Lenvatinib 
Lenvatinib 
will 
be 
provided 
as 
#4-size 
hydroxypropyl 
methylcellulose (HPMC) capsules in 2 strengths differentiated by 
color: 4-mg capsule (yellowish-red cap and body) and 10-mg 
capsule (yellowish-red cap with yellow body). 
Dosing schedule of 24 mg once a day (two 10-mg capsules + one 
4-mg capsule) has been selected for continued lenvatinib 
development 
Trial Phase 
II 
Design 
Prospective, international, multi-center, open label, stratified, 
exploratory phase II study evaluating the efficacy and safety of 
lenvatinib 


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Primary Endpoint 
The primary endpoint of the study is overall response rate (ORR) by 
RECIST v 1.1 upon central radiologic assessment 
Study population and 
total number of 
subjects 
Patients with advanced/metastatic, histologically confirmed, grade 
1/2 (G1/G2) of 2010 WHO classification neuroendocrine tumors of 
the pancreas after progression to a previous targeted agent (cohort 
A) or gastrointestinal tract after progression to somatostatin 
analogues (cohort B). 
Number of patients: 110 patients in total (55 per each cohort) 
Objectives 
Primary objective 
To assess the efficacy of lenvatinib on tumor objective response 
rate in two independent cohorts of patients with advanced 
neuroendocrine tumors: patients with advanced/metastatic G1/G2 
pancreatic neuroendocrine tumors after progression to a previous 
targeted agent (cohort A), and patients with advanced/metastatic 
G1/G2 neuroendocrine tumors of gastrointestinal tract after failure 
to somatostatin analogues therapy (cohort B). 
Secondary objectives 
To determine the safety and tolerability of lenvatinib. 
To estimate the early tumor shrinkage rate and the deepness of 
response of lenvatinib in each cohort of patients. 
To estimate progression-free survival in both cohorts of patients. 
Exploratory objectives 
To evaluate biochemical response (changes in CgA and NSE 
levels) and its association with response rate and progression-free 
survival. 
To assess whether baseline tumor and blood biomarkers may be 
predictive of response to lenvatinib. 
To explore additional hypotheses related to biomarkers and 
relationship to lenvatinib, neuroendocrine tumors, other endocrine 
disorders and/or cancer which may arise from internal or external 
research activities. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this 
study: 
1. Subjects must have histologically confirmed diagnosis of one 
of the following advanced/metastatic neuroendocrine tumor 


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types:  
a) WHO Classification G1/G2 (Ki67<20% and mitotic count 
≤20 mitoses x 10 HPF) pancreatic neuroendocrine tumor 
b) WHO Classification G1/G2 (Ki67<20% and mitotic count 
≤20 mitoses x 10 HPF) gastrointestinal neuroendocrine 
tumor (including stomach, small intestine and colorectal 
origins). 
2. Subjects must have evidence of measurable disease meeting 
the following criteria: 
a)  At least 1 lesion of ≥ 1.0 cm in the longest diameter for a 
non-lymph node, or ≥ 1.5 cm in the short-axis diameter for a 
lymph node, which is serially measurable according to 
RECIST 
1.1 
(Appendix 
I) 
using 
computerized 
tomography/magnetic resonance imaging (CT/MRI). If there 
is only one target lesion and it is a non-lymph node, it 
should have a longest diameter of ≥ 1.5 cm. 
b) Lesions that have had external beam radiotherapy (EBRT) 
or loco-regional therapies such as radiofrequency (RF) 
ablation or liver embolization must show evidence of 
progressive disease based on RECIST 1.1 to be deemed a 
target lesion. 
3. Subjects must show evidence of disease progression by 
radiologic image techniques within 12 months (an additional 
month will be allowed to accommodate actual dates of 
performance of scans, i.e., within ≤ 13 months) prior to signing 
informed consent, according to RECIST 1.1 (Appendix I). 
4. Subjects must meet the following inclusion criterion regarding 
primary tumor site: 
a) Pancreatic origin: progression after a previous targeted 
agent (including mTOR inhibitors, such as everolimus or 
antiangiogenic therapies, such as sunitinib, sorafenib, 
axitinib, bevacizumab within others). Combination therapies 
in the same treatment line (such as sorafenib plus 


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bevacizumab, chemotherapy plus antiangiogenic drugs) are 
considered one treatment line and are allowed to be 
included in the study. Patients must be treated with only 
one previous line of targeted agent(s)-based therapy. 
Previous therapy with somatostatin analogues and/or 
interferon is allowed and is not considered as a previous 
targeted agent therapy.  
b) Gastrointestinal origin: progression after therapy with 
antitumoral doses of somatostatin analogs (octreotide LAR 
30 mg every 28 days or Lanreotide 120 mg every 28 days) 
and/or interferon treatment. 
5.  Only for patients with pancreatic origin neuroendocrine 
tumors, one previous line with chemotherapy is allowed. 
6. Concomitant somatostatin analogues are allowed in both 
cohorts during the study. 
7. Patients with known brain metastases who have completed 
whole 
brain 
radiotherapy, 
stereotactic 
radiosurgery 
or 
complete surgical resection, will be eligible if they have 
remained clinically stable, asymptomatic and off of steroids for 
at least one month. 
8. All prior chemotherapy or radiation-related toxicities must have 
resolved to < Grade 2 (following CTCAE V 4.03 grade levels), 
except alopecia and infertility. 
9. Subjects must have an Eastern Cooperative Oncology Group 
(ECOG) Performance Status of 0 − 1 (Appendix II). 
10. Previous liver locoregional therapies, such as (chemo) 
embolization, 
radiofrequency 
or 
liver-directed 
radioembolization, 
or 
systemic 
peptide-receptor 
radionucleotide therapy are allowed if the procedure was 
performed at least 6 months previous the informed consent 
form signature. 
11. Adequately 
controlled 
blood pressure 
with 
or without 
antihypertensive medications, defined as BP < 150/90 mmHg 


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at screening and no change in antihypertensive medications 
within 1 week prior to the Screening Visit. 
12. Adequate renal function defined as calculated creatinine 
clearance ≥ 30 mL/min per the Cockcroft and Gault formula 
(Appendix III). 
13. Adequate bone marrow function, defined as:  
a) Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 × 
103/µL). 
b) Platelets ≥ 100,000/mm3 (≥ 100 × 109/L). 
c) Hemoglobin ≥ 9.0 g/dL. 
14. Adequate blood coagulation function as evidenced by an 
International Normalized Ratio (INR) ≤ 1.5. Prophylactic low 
molecular weight heparin therapy is allowed. 
15. Adequate liver function:  
a) Bilirubin ≤ 1.5 × the upper limit of normal (ULN) except for 
unconjugated hyperbilirubinemia or Gilbert’s syndrome. 
b) Alkalin phosphatase, alanine aminotransferase (ALT), and 
aspartate aminotransferase (AST) ≤ 3 × the ULN (≤ 5 × 
ULN if subject has liver metastases). 
16. Males or females age ≥ 18 years at the time of informed 
consent. 
17.  All females must have a negative serum or urine pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of beta 
human chorionic gonadotropin (β-hCG) at the baseline visit 
(and/or within 72h prior to the first dose of study drug). 
Females of childbearing potential must agree to use a highly 
effective 
method 
of 
contraception 
(e.g., 
total 
sexual 
abstinence*, an intrauterine device, a double-barrier method 
such as condom + spermicide or condom + diaphragm with 
spermicide or have a vasectomized partner with confirmed 
azoospermia*) throughout the entire study period and for 30 
days after study drug administration. The only subjects who 


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will be exempt from this requirement are postmenopausal 
women (defined as women who have been amenorrheic for at 
least 12 consecutive months, in the appropriate age group, 
without other known or suspected primary cause) or subjects 
who have been sterilized surgically or who are otherwise 
proven sterile (i.e., bilateral tubal ligation with surgery at least 
1 
month 
prior 
to 
dosing, 
hysterectomy, 
or 
bilateral 
oophorectomy with surgery at least 1 month prior to dosing). 
The women using oral hormonal contraceptives should add an 
additional barrier method as there is unknown whether 
lenvatinib may reduce the effectiveness of the hormonal 
contraceptives. All women who are of reproductive potential 
and who are using hormonal contraceptives must have been 
on a stable dose of the same hormonal contraceptive product 
for at least 4 weeks prior to dosing and must continue to use 
the same contraceptive during the study and for 30 days after 
study drug discontinuation. 
** Sexual abstinence will be acceptable only when this is in 
line with the preferred and usual lifestyle of the subject. 
18. Male subjects who are partners of women of childbearing 
potential must use or their partners must use a highly effective 
method of contraception (e.g., condom + spermicide, condom 
+ diaphragm with spermicide, IUD) beginning at least 1 
menstrual cycle prior to starting study drug(s), throughout the 
entire study period, and for 30 days after the last dose of study 
drug, unless they are sexually abstinent or have undergone a 
successful vasectomy. Those with partners using hormonal 
contraceptives must also be using an additional approved 
method of contraception, as described previously. 
19. Voluntary provision of written informed consent and the 
willingness and ability to comply with all aspects of the 
protocol. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from 
this study:  
1. WHO Classification G3 neuroendocrine tumors of the 


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pancreas and gastrointestinal tract. 
2. Two or more prior lines of targeted agents-based therapy in 
pancreatic origin and any previous line of targeted therapy for 
gastrointestinal origin or any ongoing antiproliferative 
treatment for advanced/metastatic neuroendocrine tumors, 
with the exception of somatostatin analogues therapy. 
3. More than one previous line of chemotherapy in pancreatic 
neuroendocrine tumors. 
4. Previous chemotherapy in gastrointestinal neuroendocrine 
tumors. 
5. Prior treatment with lenvatinib. 
6. Subjects who have received any anti-cancer treatment within 
21 days or any investigational agent within 30 days prior to 
the first dose of study drug and should have recovered from 
any toxicity related to previous anti-cancer treatment. This 
does not apply to the use of somatostatin analogues for 
symptomatic therapy. 
7. Major surgery within 3 weeks prior to the first dose of study 
drug. 
8. Subjects having > 1+ proteinuria on urine dipstick testing will 
undergo 24h urine collection for quantitative assessment of 
proteinuria. Subjects with urine protein ≥ 1 g/24h will be 
ineligible. 
9. Gastrointestinal malabsorption, or any other condition in the 
opinion of the investigator that might affect the absorption of 
lenvatinib. 
10. Significant cardiovascular impairment: history of congestive 
heart failure greater than New York Heart Association 
(NYHA) Class II, unstable angina; myocardial infarction or 
stroke within 6 months prior to the first dose of study drug, or 
cardiac arrhythmia requiring medical treatment. The left 
ventricular ejection fraction in the echocardiogram must be of 
at least 50%. 
11. Prolongation of QTcF interval to > 480 msec. 
12. Bleeding or thrombotic disorders or use of anticoagulants, 
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international normalized ration (INR) monitoring. Treatment 
with low molecular weight heparin (LMWH) is allowed. 
13. Active hemoptysis (bright red blood of at least 0.5 teaspoon) 
within 3 weeks prior to the first dose of study drug. 
14. Active infection (any infection requiring treatment). 
15. Active malignancy within the past 5 years (except for 
definitely treated melanoma in-situ, basal or squamous cell 
carcinoma of the skin, or carcinoma in-situ of the cervix). 
16. Known intolerance or hypersensitivity to the active substance 
(or any of the excipients). 
17. Any medical or other condition which, in the opinion of the 
investigator, would preclude participation in a clinical trial. 
18. Females who are pregnant or breastfeeding. 
19. Documented active alcohol or drug abuse. 
20. Patients with a prior history of non-compliance with medical 
regimens. 
Primary Analysis 
Data cut-off for the study primary analysis will take place after the 
last patient enrolled in the study has performed the second tumor 
assessment (week 12 after first dose of study drug, given that first 
evaluation will be performed 6 weeks after the first dose. Starting on 
week 12 subsequent tumor assessments will be performed every 12 
weeks until documentation of disease progression or start of another 
anticancer therapy 
Estimated duration of 
subject participation 
24 months 
Calendar and expected 
termination dates 
Recruitment Start: September 2015 
End of Recruitment Period: March 2017 
3rd Tumor assessment of LP (Primary Analysis): July 2017 
Database Lock for Interim Analysis: October 2017 
End of Follow up Period: March 2019 
FPFV: September 2015 
LPLV: September 2018 
Clinical Study Report: September 2019 


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2. Table of contents 
1. 
Synopsis 
2 
2. 
Table of contents 
10 
List of tables 
14 
3. 
Abbreviations 
15 
4. 
General information 
18 
4.1 
Trial identification 
18 
4.2 
Type of clinical trial 
18 
4.3 
Description of study drugs 
18 
4.4 
Sponsor 
18 
4.5 
Technician responsible for central radiology review 
18 
4.6 
CRO responsible for monitoring 
19 
4.7 
Participating Sites 
19 
4.8 
Trial planned duration 
19 
5. 
Rationale and objectives 
19 
5.1 
Overview of gastroenteropancreatic neuroendocrine tumors 
19 
5.2 
Introduction of investigational treatment 
21 
5.2.1 
Overview of lenvatinib 
21 
5.2.2 
Clinical Experience with Lenvatinib 
21 
5.3 
Trial Objectives 
22 
5.3.1 
Primary objective: 
22 
5.3.2 
Secondary objective: 
22 
5.3.3 
Exploratory objectives 
22 
6. 
Randomization process 
22 
7. 
Type of trial and trial design 
23 
7.1 
Overall study design and plan 
23 
7.2 
Screening phase 
24 
7.3 
Treatment phase 
25 
7.3.1 
End of Treatment Visit (Off Treatment Assessment) 
25 
7.4 
Follow up Phase 
25 
7.5 
Blinding techniques 
26 
8. 
Subject screening 
26 
8.1 
Inclusion criteria 
26 
8.2 
Exclusion criteria 
29 
9. 
Number of expected subjects 
30 
10. 
Recruitment period duration 
30 
11. 
Treatment description 
31 
11.1 
Description of dose, interval, route and dosing regiment 
31 
11.1.1 
Chemical name, structural formula of lenvatinib 
31 


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11.2 
Storage Conditions 
32 
11.3 
Administration of study treatment 
32 
11.4 
Selection of Doses in the Study 
32 
11.5 
Selection and Timing of Dose for Each Subject 
33 
11.6 
Prior and Concomitant Therapy 
33 
11.7 
Dose reduction and interruption instructions 
34 
11.8 
Unused drugs 
35 
11.9 
Drug-Drug Interactions 
35 
11.10 
Prohibited Concomitant Therapies and Drugs 
35 
11.11 
Treatment Compliance 
35 
11.12 
Drug Supplies and Accountability 
36 
12. 
Study Methods 
37 
12.1 
Demography and baseline characteristics 
37 
12.2 
Primary Efficacy assessments 
37 
12.3 
Secondary efficacy assessments 
39 
12.4 
Pharmacodynamic, and Pharmacogenomic Assessments for the substudy 40 
12.5 
Safety Assessments 
40 
13. 
Trial development 
42 
13.1 
Schedule of Visits and Procedures 
42 
13.2 
Screening period procedures 
46 
13.2.1 
Baseline period procedures 
48 
13.2.2 
Treatment phase assessments schedule 
49 
13.3 
Treatment cycle procedures 
49 
13.3.1 
End Off-treatment assessments 
54 
13.4 
Record survival data. Post study treatment follow-up period procedures 
54 
13.5 
Laboratory measurements 
54 
13.6 
Vital signs and weight measurements 
57 
13.7 
Electrocardiograms 
57 
13.8 
Echocardiograms 
57 
14. 
Adverse events 
58 
14.1 
Assessing severity of adverse events 
60 
14.2 
Assessing relationship to study treatment 
60 
14.3 
Serious adverse events and other events of interest 
60 
14.4 
Reporting Laboratory abnormalities 
61 
14.4.1 
Laboratory abnormality to be considered as SAE 
62 
14.5 
Reporting of SAEs, Pregnancy, and Other Events of Interest 
62 
14.5.1 
Reporting of SAEs 
62 
14.5.2 
Reporting of Pregnancy 
63 
14.5.3 
Reporting of Overdose 
63 
14.6 
Expedited reporting 
64 
14.7 
Regulatory reporting of adverse events 
64 
14.8 
Treatment Emergent Adverse Event 
64 


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14.8.1 
Management of hypertension 
64 
14.8.2 
Management of Proteinuria 
66 
15. 
Data quality assurance 
67 
15.1 
Data Collection 
67 
15.2 
Clinical Data Management 
67 
15.3 
Database Quality Assurance 
68 
16. 
Ethical aspects 
68 
16.1 
Ethics Committee 
68 
16.2 
Ethical Conduct of the Study 
68 
16.3 
Subject information and Consent 
69 
17. 
Administrative procedures 
70 
17.1 
Changes to the Protocol 
70 
17.2 
Adherence to the Protocol 
70 
17.3 
Monitoring Procedures 
70 
17.4 
Recording of Data 
71 
17.5 
Retention of Records 
71 
17.6 
Auditing Procedures and Inspection 
72 
17.7 
Handling of Study Drug 
72 
17.8 
Publication of Results 
72 
17.9 
Disclosure and Confidentiality 
73 
17.10 
Subject Insurance and Indemnity 
73 
18. 
Completion/Discontinuation of Subjects 
73 
18.1 
Removal of Subjects from Therapy or Assessment 
73 
18.2 
Completion/Discontinuation of Subjects 
74 
19. 
Confirmation of Medical Care by Another Physician 
74 
20. 
Statistical methods 
75 
20.1 
Statistical and Analytical Plans 
75 
20.2 
Analysis Sets 
75 
20.3 
Demographic and other baseline characteristics 
75 
20.4 
Prior and concomitant medications 
75 
20.5 
Efficacy Analyses 
75 
20.5.1 
Analysis of primary efficacy variable 
76 
20.6 
Sample Size and Accrual 
76 
20.7 
Data Analyses Plans 
76 
20.8 
Safety Analyses 
77 
20.9 
Extent of exposure 
77 
20.10 
Adverse events 
77 
20.11 
Laboratory values 
78 
20.12 
Vital signs 
78 
20.13 
ECG results 
78 
20.14 
Echocardiograms 
78 
21. 
References 
79 


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Appendix I Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
80 
Appendix II: Eastern Cooperative Oncology Group Performance Status 
81 
Appendix III Cockcroft and Gault Formula 
82 
Appendix IV: Common Terminology Criteria for Adverse Events (CTCAE v4.03) 
83 
Appendix V Drug-Drug Interactions 
84 
Appendix VI Pharmacogenomics 
85 
Appendix VII: Adverse event report form 
88 
 
 
 


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List of Figures 
Figure 1Study Design .........................................................................................................2426 
 
List of tables 
Table 1.-Groups of GEPNEN following the recent WHO classification GEPNEN ..... 2022 
Table 2: Dosage formulation and capsule strength of lenvatinib .................................. 3133 
Table 3. - Dose reduction and interruption instructions ................................................. 3436 
Table 4 Schedule of Visits and Procedures ..................................................................... 4244 
Table 5 Clinical laboratory tests .................................................................................... 5658 
Table 6.- Treatment for hypertension ................................................................................ 6668 
Table 6 Drugs That Affect the Activity of CYP3A4 .......................................................... 8486 
 
 
 


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3. Abbreviations 
AE 
Adverse Event 
ALT 
alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology  
AST 
aspartate aminotransferase 
BP 
Blood pressure 
CR 
Complete response 
CRA 
Clinical Research associate 
CRO 
Clinical research Organization 
CT 
Computerized tomography 
CTCAE 
 Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting Toxicity 
DNA 
Deoxyribonucleic acid 
DpR 
Deepness of Response 
EBRT 
external beam radiotherapy  
EC 
Ethics committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EOT 
End of treatment visit 
FVFP 
First Visit first patient 
g-CSF: 
Granulocyte colony-stimulating factor 
GEPNEN 
Gastroenteropancreatic neuroendocrine neoplasms  
GEPNETs 
Gastroenteropancreatic neuroendocrine tumors 
GETNE 
Grupo Español de Tumores Neuroendrocrinos) 
GPC 
Good Clinical Practice 
h 
hours 
HPMC 
hydroxypropyl methylcellulose 


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HR 
Hearth Rate 
ICF 
Informed Consent Form 
ICH 
International Conference Harmonization 
IGF 
insulin-like growth factor 
INR 
International Normalized Ratio 
IU 
International Units 
IUD 
Intrauterine Dispositive 
IV 
intravenous 
L 
liter 
LMWH 
low molecular weight heparin 
LP 
Last Patient 
LPLV 
Last Patient last visit 
LVEF 
left ventricular ejection fraction  
MedDRA  
Medical Dictionary for Regulatory Activities 
mg 
milligrams 
MRI 
magnetic resonance imaging 
msec 
milliseconds 
MTD 
Maximum tolerated dose 
Mtor 
mammalian target of rapamycin 
NE 
Non Evaluable  
NSAIDs 
nonsteroidal anti-inflammatory drugs  
NSE 
Neuron specific enolase 
ORR 
Overall response rate 
PD 
Progressive disease 
PDGFR 
PDGF receptors 
PDGFR 
Platelet-derived growth factor 
PET-CT 
Positron emission tomography–computed tomography 
PFS 
Progression-free survival 
PR 
Partial response 


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PT 
Preferred Term 
pTNM 
Classification of Malignant Tumors 
qd 
Once daily 
RA 
Regulatory authority 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RF 
Radiofrequency 
RNA 
Ribonucleic acid 
RR 
respiratory rate 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
System Organ Class 
SOP 
standard operating practices  
Surg 
surgical 
TEAE 
Treatment-emergent adverse event 
TEAV 
treatment-emergent abnormal laboratory values  
UK 
United Kingdom 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
VEGFR 
VEGF receptor 
vs. 
versus 
w/in 
within 
WHO 
World Health Organization 
 
 
 


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4. General information 
4.1 Trial identification 
Protocol number: GETNE1509 
Short study code: TALENT. 
EudraCT: 2015-001467-39 
Title: “TRIAL TO ASSESS THE EFFICACY OF LENVATINIB IN METASTATIC 
NEUROENDOCRINE TUMORS (TALENT STUDY).” 
4.2 Type of clinical trial 
Prospective, multi-center, open label, stratified, exploratory phase II study evaluating the 
efficacy and safety of lenvatinib. 
4.3 Description of study drugs 
Experimental drugs: 
Lenvatinib will be provided as #4-size hydroxypropyl methylcellulose (HPMC) capsules in 2 
strengths differentiated by color: 4-mg capsule (yellowish-red cap and body) and 10-mg 
capsule (yellowish-red cap with yellow body). 
Dosing schedule of 24 mg once a day (two 10-mg capsules + one 4-mg capsule) has been 
selected for continued lenvatinib development 
4.4 Sponsor 
GETNE (Grupo Español de Tumores Neuroendrocrinos) 
París 162, Pral. 1ª. 08036, Barcelona 
Telephone: 93 451 17 24; Fax: 93 451 43 66 
Contact: getne@getne.org  
4.5 Technician responsible for central radiology review 
Dr. Xavier Merino 
Radiology Department 
Vall d’Hebron University Hospital 
Pg Vall d’Hebron 119-129 
08035. Barcelona 
xavier.merino@idi-cat.org 
 


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4.6 CRO responsible for monitoring 
Experior, S.L. 
C/ Vicente Galmés, 1A 
46139 La Pobla de Farnals (Valencia) 
Tel: 902.105.255; Fax: 96.145.21.91 
4.7 Participating Sites 
It is planned to include approximately 25 sites in several countries in Europe (planned sites in 
Spain, Italy, United Kingdom, and Austria). 
4.8 Trial planned duration 
Start of Recruitment September 2015 
End of Recruitment Period March 2017 
3rd tumor assessment of the LP (primary analysis): July 2017 
Database Lock for Interim Analysis: October 2017 
End of Follow up Period: March 2019 
FPFV: September 2015 
LPLV: September 2018 
Clinical Study Report: September 2019 
5. Rationale and objectives 
5.1 Overview of gastroenteropancreatic neuroendocrine tumors 
Gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) constitute a heterogenic 
group of tumors derived from the Kultchitzky cells of the diffuse neuroendocrine system 
located in the gastrointestinal tract (origin of classical carcinoid tumors) and pancreatic islet 
cells (origin of pancreatic endocrine tumors). Although GEPNENs represent less than 2% of all 
gastrointestinal cancers, they constitute the second most prevalent advanced tumor of the 
gastrointestinal tract after colorectal cancer1. The biological behavior of GEPNENs depends 
mainly on their histological characteristics, mainly differentiation grade and Ki67 expression. 
The most recent 2010 WHO classification divides GEPNENs in three groups regarding Ki67 
value and mitotic count: gastroenteropancreatic neuroendocrine tumors (GEPNETs) that 
include grade 1(G1) and grade 2 (G2) with Ki67 value ≤20% and mitotic count ≤20 mitoses x 


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10 HPF, and neuroendocrine carcinomas that include grade 3 (G3) with Ki67>20% and/or 
mitotic count >20 mitoses x 10 HPF. 
Table 1.-Groups of GEPNEN following the recent WHO classification GEPNEN 
 
Grade 
Mitotic 
count 
(10 HPF) 
Ki-67 index (%)
G1 
2  
≤2 
G2 
2-20 
3-20 
G3 
20  
20  
 
The medical treatment of advanced GEPNETs has included somatostatin analogs, interferon 
and cytotoxic agents. The lack of effectiveness of conventional cytotoxic agents has prompted 
exploration of new targeted drugs exploiting phenotypical features of GEPNETs. GEPNETs 
are characterized by being remarkably vascular and expressing several growth factors, 
including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), 
insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming 
growth factor (TGF)- and -β. In addition, expression of several receptors of these growth 
factors and ligands has been described, including stem cell factor receptor (c-KIT), epidermal 
growth factor receptors (EGFR), VEGF receptors (VEGFR)-2 and 3, IGF receptors (IGF-R), 
and PDGF receptors (PDGFR). The (over)expression of some of these factors has been 
associated with poor prognosis and decreased progression-free survival (PFS), as well as with 
tumor growth, aggressiveness, and disease extent in patients with GEPNETs2. Several 
targeted agents have been studied in the treatment of GEPNETs including antiangiogenic 
compounds (such as bevacizumab), inhibitors of multiple receptors with kinase activity (such 
as sunitinib), and inhibitors of intracellular downstream effector proteins such as the 
mammalian target of rapamycin (mTOR), such as everolimus. Two phase III studies with 
everolimus and sunitinib have demonstrated efficacy in pancreatic neuroendocrine tumors 
becoming two new treatment options in the management of these patients. However, even 
there are several phase II clinical trials suggesting the efficacy of new targeted agents in 
gastrointestinal neuroendocrine tumors, currently, and with the exception of somatostatin 
analogues, no drug is approved for the antiproliferative therapy in non-pancreatic 
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5.2 Introduction of investigational treatment 
5.2.1 Overview of lenvatinib 
Lenvatinib is an orally available potent inhibitor of the split-kinase family of transmembrane 
growth factor receptors including Flt-1/VEGFR-1 and KDR/VEGFR-2. Receptor tyrosine kinase 
cell free assays demonstrate IC50 values of 22 (Flt-1/VEGFR-1) and 4 nM (KDR/VEGFR-2). 
Additionally, lenvatinib potently inhibits vascular endothelial growth factor receptor 3 (VEGFR-
3, IC50 5nM), fibroblast growth factor receptor (FGFR)-1 (IC50 46 nM), 2, 3, 4 and platelet-
derived growth factor receptor (PDGFR, IC50 39 nM) beta tyrosine kinases. Lenvatinib also 
inhibits (IC50 5.2 nM) SCF-driven tube formation of HUVEC, which express SCF receptor, 
KIT3,4. 
5.2.2 Clinical Experience with Lenvatinib 
A global Phase 1 program in patients with solid tumors has been conducted to determine the 
safety, tolerability and pharmacokinetics of three different regimens including continuous once-
daily dosing (Study E7080-E044-101), intermittent (Schedule 1) and continuous (Schedule 2) 
twice-daily dosing (Study E7080-A001-102), and an intermittent schedule of twice daily dosing 
for 2 weeks of a 3 week cycle (Study E7080-J081-103).Pharmacokinetic analysis has 
demonstrated that lenvatinib is rapidly absorbed with maximum concentrations observed from 
1 to 3 hours postdose. Lenvatinib elimination occurs with a bi-exponential decline composed of 
an initial rapid decline followed by a slower decline. The terminal half-life is approximately 30 
hours and steady state is achieved within 5 days. A dose dependent increase in soluble 
VEGF, consistent with an anti-angiogenic effect was observed during 2 weeks of continuous 
dosing. Hypertension and proteinuria were the most common dose limiting toxicities (DLT). A 
dose of 25 mg once daily was found to be the maximum tolerated dose (MTD) for the once 
daily continuous dosing schedule. A cohort of 24 patients treated at this dose level established 
the safety and tolerability of the lenvatinib 25 mg dose for once daily continuous dosing. To 
simplify drug administration, a dose of 24 mg (two 10 mg capsules + one 4 mg capsule) once 
daily has been selected for ongoing lenvatinib development5. 
Several clinical trials are currently in development for different tumor types with lenvatinib. 
Recently, an international, randomized, placebo-controlled, phase III trial with lenvatinib in 
advanced, 
radioactive-refractory 
differentiated 
thyroid 
cancer 
has 
been 
reported 
demonstrating a significant benefit in median progression-free survival (18.3 vs. 3.6 months, 
HR: 0.21, p<0.0001) and in response rate (65% vs. 2%, p<0.0001)6. Lenvatinib demonstrated 
significant benefit regardless previous antiangiogenic therapy and in all subgroups of patients 
included in the study. Main side effects included hypertension, diarrhea, fatigue, decreased 


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appetite, nausea-vomiting, decreased weight, stomatitis, palmar-plantar erythrodysesthesia 
syndrome, proteinuria, headache and dysphonia. 
5.3 Trial Objectives 
This two arm phase II clinical trial has been designed to analyze the antitumoral efficacy of 
lenvatinib 24 mg daily in two different cohorts of patients with advanced/metastatic G1/G2 
neuroendocrine tumors. 
5.3.1 Primary objective: 
 
To assess the efficacy of lenvatinib on tumor objective response rate (ORR) (complete 
(CR) and partial responses (PR) in two independent cohorts of patients with 
advanced/metastatic G1/G2 neuroendocrine tumors: patients with pancreatic 
neuroendocrine tumors after progression to a previous targeted agent (cohort A), and 
patients with neuroendocrine tumors of the gastrointestinal tract after failure to 
somatostatin analogues therapy (cohort B) 
5.3.2 Secondary objective: 
 
To determine the safety and tolerability of lenvatinib. 
 
To estimate the early tumor shrinkage rate and the deepness of response of lenvatinib 
in each cohort of patients. 
 
To estimate progression-free survival in both cohorts of patients. 
5.3.3 Exploratory objectives 
 
To evaluate biochemical response (changes in CgA and NSE levels) and its 
association with response rate and progression-free survival. 
 
To assess whether baseline tumor and blood biomarkers may be predictive of 
response to lenvatinib. 
 
To explore additional hypotheses related to biomarkers and relationship to lenvatinib, 
neuroendocrine tumors, other endocrine disorders and/or cancer which may arise from 
internal or external research activities. 
6. Randomization process 
Not applicable, no randomization is done in this study; all patients will receive the same study 
treatment independently of the cohort of the study.  


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7. Type of trial and trial design 
Prospective, international, multi-center, open label, stratified, exploratory phase II study 
evaluating the efficacy and safety of lenvatinib. 
7.1 Overall study design and plan 
The patient recruitment period of the study will last approximately 18 months. The maximum 
treatment period for each subject on study is anticipated to be approximately 36 months. 
However, subjects will continue on treatment as long as they demonstrate clinical benefit.  
This study will be conducted in 3 phases: a screening phase, a treatment phase stratified by 
tumor origin and a follow up phase. An overview of the study design is presented in figure 1. 


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Figure 1Study Design 
 
7.2 Screening phase 
Screening will occur between Day -28 and Day -1. The purpose of the screening period is to 
establish protocol eligibility. Informed consent will be obtained up to 4 weeks prior to Cycle 1 
Day 1 and after the study has been fully explained to each subject and prior to the conduct of 
any screening procedures or assessments. Procedures to be followed when obtaining 
informed consent are detailed in Section 17.3 
Subjects must have a histological confirmed diagnosis of well-moderately differentiated G1/G2 
neuroendocrine tumor meeting the criteria for being progressive to other targeted agent within 
the prior 12 months in pancreatic origin and progressive to somatostatin analogues within the 
prior 12 months in gastrointestinal origin.  
The purpose of the baseline visit is to establish disease characteristics prior to treatment and 
allocation and to confirm protocol eligibility as specified in the inclusion/exclusion criteria. 
Results of baseline assessments must be obtained prior to the first dose of study drug (Cycle 
1/Day 1). Tumor assessments will be performed using CT/MRI of the abdomen and pelvis. A 
CT/MRI will only be performed in the other organs in case of lesions; otherwise, it will not be 
required (including neck and chest) (see Section 12.2). Baseline assessments may be 
performed on Day -1 or on Cycle 1/Day 1 prior to dosing. Clinical laboratory tests (Table 
4) including pregnancy test (where applicable) can be performed within 72 hours prior 
to the first dose of study drug. Subjects who complete the baseline visit and continue to 
meet the criteria for inclusion/exclusion (Section 8.1 and Section 8.2) will begin the treatment 
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7.3 Treatment phase  
The treatment phase will begin at the time of allocation of the first subject and will consist of 
the study treatment cycles. The treatment phase will end when the last patient discontinues 
the study drug. Prior to the completion of the final primary study analysis, an individual subject 
will remain in the treatment phase until documentation of disease progression. 
Subjects who discontinue study drug administration prior to disease progression will continue 
to be followed in the treatment phase according to the tumor assessment schedule listed in 
table 3 (performed at week 6 after the first dose of study drug and then, every 12 weeks or 
sooner if clinically indicated) until documentation of disease progression or start of another 
anticancer therapy.  
Subjects will be allocated in each primary tumor cohort to receive lenvatinib 24 mg by 
continuous once daily oral administration. Subjects will undergo safety and efficacy 
assessment as defined in Table 3. Other reasons for discontinuation of study drug different 
from disease progression include development of unacceptable toxicity, withdrawal of consent 
or sponsor discontinuation of lenvatinib development.  
7.3.1 End of Treatment Visit (Off Treatment Assessment) 
Whenever possible, the off treatment assessments should be performed within 28 days after 
subjects have discontinued study treatment. 
Subjects who discontinue study administration prior to disease progression will continue to 
undergo disease assessment every 12 weeks until documentation of disease progression or 
start of another anticancer therapy, at which time the subject will enter the follow-up period. 
7.4 Follow up Phase 
The follow-up period (see Section 14.1.6 and 14.1.7) for such subjects will begin immediately 
after the end of treatment visit and will continue as long as the study subject is alive or until 
discontinuation of survival follow-up by sponsor. 
All subsequent anticancer therapies received will be recorded during the follow-up phase.  
Data cut-off for the study primary analysis will take place after the last patient enrolled in the 
study has performed the second tumor assessment (week 12 after first dose of study drug, 
given that the first assessment will be performed 6 weeks after the first dose). Subsequent 
tumor assessments will be performed starting on week 12every 12 weeks until documentation 
of disease progression or start of another anticancer therapy. The sponsor may choose to 
discontinue survival follow-up at some point following the performance of the primary study 
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7.5 Blinding techniques 
Not applicable, open label study. 
8. Subject screening 
Approximately 110 patients will be enrolled and allocated in a balanced manner into either the 
pancreatic or gastrointestinal cohorts at approximately 25 sites in Europe (Spain,  UK, Italy, 
and Austria). Subjects who meet all of the inclusion criteria and none of the exclusion criteria 
and are willing to participate will be eligible to receive study drug. 
8.1 Inclusion criteria 
Subjects must meet all of the following criteria to be included in this study: 
1. Subjects must have histologically confirmed diagnosis of one of the following 
advanced/metastatic neuroendocrine tumor types:  
a) WHO Classification G1/G2 (Ki67<20% and mitotic count ≤20 mitoses x 
10 HPF) pancreatic neuroendocrine tumor 
b) WHO Classification G1/G2 (Ki67<20% and mitotic count ≤20 mitoses x 
10 HPF) gastrointestinal neuroendocrine tumor (including stomach, 
small intestine and colorectal origins). 
2. Subjects must have evidence of measurable disease meeting the following criteria: 
a)  At least 1 lesion of ≥ 1.0 cm in the longest diameter for a non-lymph 
node, or ≥ 1.5 cm in the short-axis diameter for a lymph node, which is 
serially measurable according to RECIST 1.1 (Appendix I) using 
computerized tomography/magnetic resonance imaging (CT/MRI). If 
there is only one target lesion and it is a non-lymph node, it should have 
a longest diameter of ≥ 1.5 cm. 
b) Lesions that have had external beam radiotherapy (EBRT) or loco-
regional therapies such as radiofrequency (RF) ablation or liver 
embolization must show evidence of progressive disease based on 
RECIST 1.1 to be deemed a target lesion. 
3. Subjects must show evidence of disease progression by radiologic image 
techniques within 12 months (an additional month will be allowed to accommodate 
actual dates of performance of scans, i.e., within ≤ 13 months) prior to signing 
informed consent, according to RECIST 1.1 (Appendix I). 
4. Subjects must meet the following inclusion criterion regarding primary tumor site: 


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a) Pancreatic origin: progression after a previous targeted agent 
(including mTOR inhibitors, such as everolimus or antiangiogenic 
therapies, such as sunitinib, sorafenib, axitinib, bevacizumab within 
others). Combination therapies in the same treatment line (such as 
sorafenib plus bevacizumab, chemotherapy plus antiangiogenic drugs) 
are considered one treatment line and are allowed to be included in 
the study. Patients must be treated with only one previous line of 
targeted agent(s)-based therapy. Previous therapy with somatostatin 
analogues and/or interferon is allowed and is not considered as a 
previous targeted agent therapy.  
b) Gastrointestinal origin: progression after therapy with antitumoral 
doses of somatostatin analogs (octreotide LAR 30 mg every 28 days or 
Lanreotide 120 mg every 28 days) and/or interferon treatment. 
5.  Only for patients with pancreatic origin neuroendocrine tumors, one previous line 
with chemotherapy is allowed. 
6. Concomitant somatostatin analogues are allowed in both cohorts during the study. 
7. Patients with known brain metastases who have completed whole brain 
radiotherapy, stereotactic radiosurgery or complete surgical resection, will be 
eligible if they have remained clinically stable, asymptomatic and off of steroids for 
at least one month. 
8. All prior chemotherapy or radiation-related toxicities must have resolved to < Grade 
2 (following CTCAE V 4.03 grade levels), except alopecia and infertility. 
9. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Status of 0 − 1 (Appendix II). 
10. Previous 
liver 
locoregional 
therapies, 
such 
as 
(chemo) 
embolization, 
radiofrequency or liver-directed radioembolization, or systemic peptide-receptor 
radionucleotide therapy are allowed if the procedure was performed at least 6 
months previous the informed consent form signature. 
11. Adequately controlled blood pressure with or without antihypertensive medications, 
defined as BP < 150/90 mmHg at screening and no change in antihypertensive 
medications within 1 week prior to the Screening Visit. 
12. Adequate renal function defined as calculated creatinine clearance ≥ 30 mL/min per 
the Cockcroft and Gault formula (Appendix III). 


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13. Adequate bone marrow function, defined as:  
a) Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 × 103/µL). 
b) Platelets ≥ 100,000/mm3 (≥ 100 × 109/L). 
c) Hemoglobin ≥ 9.0 g/dL. 
14. Adequate blood coagulation function as evidenced by an International Normalized 
Ratio (INR) ≤ 1.5. Prophylactic low molecular weight heparin therapy is allowed. 
15. Adequate liver function:  
a) Bilirubin ≤ 1.5 × the upper limit of normal (ULN) except for unconjugated 
hyperbilirubinemia or Gilbert’s syndrome. 
b) Alkalin phosphatase, alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤ 3 × the ULN (≤ 5 × ULN if subject has liver 
metastases). 
16. Males or females age ≥ 18 years at the time of informed consent. 
17.  All females must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of beta human chorionic gonadotropin (β-
hCG) at the baseline visit (and/or within 72h prior to the first dose of study drug). 
Females of childbearing potential must agree to use a highly effective method of 
contraception (e.g., total sexual abstinence*, an intrauterine device, a double-
barrier method such as condom + spermicide or condom + diaphragm with 
spermicide or have a vasectomized partner with confirmed azoospermia) 
throughout the entire study period and for 30 days after study drug administration. 
The only subjects who will be exempt from this requirement are postmenopausal 
women (defined as women who have been amenorrheic for at least 12 consecutive 
months, in the appropriate age group, without other known or suspected primary 
cause) or subjects who have been sterilized surgically or who are otherwise proven 
sterile (i.e., bilateral tubal ligation with surgery at least 1 month prior to dosing, 
hysterectomy, or bilateral oophorectomy with surgery at least 1 month prior to 
dosing). The women using oral hormonal contraceptives should add an additional 
barrier method as there is unknown whether lenvatinib may reduce the 
effectiveness of the hormonal contraceptives. All women who are of reproductive 
potential and who are using hormonal contraceptives must have been on a stable 
dose of the same hormonal contraceptive product for at least 4 weeks prior to 


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dosing and must continue to use the same contraceptive during the study and for 
30 days after study drug discontinuation. 
* Sexual abstinence will be acceptable only when this is in line with the preferred 
and usual lifestyle of the subject. 
18. Male subjects who are partners of women of childbearing potential must use or 
their partners must use a highly effective method of contraception (e.g., condom + 
spermicide, condom + diaphragm with spermicide, IUD) beginning at least 1 
menstrual cycle prior to starting study drug(s), throughout the entire study period, 
and for 30 days after the last dose of study drug, unless they are sexually abstinent 
or have undergone a successful vasectomy. Those with partners using hormonal 
contraceptives must also be using an additional approved method of contraception, 
as described previously. 
19. Voluntary provision of written informed consent and the willingness and ability to 
comply with all aspects of the protocol. 
8.2 Exclusion criteria 
Subjects who meet any of the following criteria will be excluded from this study:  
1. WHO Classification G3 neuroendocrine tumors of the pancreas and gastrointestinal 
tract. 
2. Two or more prior lines of targeted agents-based therapy in pancreatic origin and any 
previous line of targeted therapy for gastrointestinal origin or any ongoing 
antiproliferative treatment for advanced/metastatic neuroendocrine tumors, with the 
exception of somatostatin analogues therapy. 
3. More than one previous line of chemotherapy in pancreatic neuroendocrine tumors. 
4. Previous chemotherapy in gastrointestinal neuroendocrine tumors. 
5. Prior treatment with lenvatinib. 
6. Subjects who have received any anti-cancer treatment within 21 days or any 
investigational agent within 30 days prior to the first dose of study drug and should 
have recovered from any toxicity related to previous anti-cancer treatment. This does 
not apply to the use of somatostatin analogues for symptomatic therapy. 
7. Major surgery within 3 weeks prior to the first dose of study drug. 
8. Subjects having > 1+ proteinuria on urine dipstick testing will undergo 24h urine 
collection for quantitative assessment of proteinuria. Subjects with urine protein ≥ 1 
g/24h will be ineligible. 


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9. Gastrointestinal malabsorption, or any other condition in the opinion of the investigator 
that might affect the absorption of lenvatinib. 
10. Significant cardiovascular impairment: history of congestive heart failure greater than 
New York Heart Association (NYHA) Class II, unstable angina; myocardial infarction or 
stroke within 6 months prior to the first dose of study drug, or cardiac arrhythmia 
requiring medical treatment. The left ventricular ejection fraction in the echocardiogram 
must be of at least 50%. 
11. Prolongation of QTcF interval to > 480 msec. 
12. Bleeding or thrombotic disorders or use of anticoagulants, such as warfarin, or similar 
agents requiring therapeutic international normalized ration (INR) monitoring. 
Treatment with low molecular weight heparin (LMWH) is allowed. 
13. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the 
first dose of study drug. 
14. Active infection (any infection requiring treatment). 
15. Active malignancy within the past 5 years (except for melanoma in-situ, basal or 
squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix). 
16. Known intolerance or hypersensitivity to the active substance (or any of the excipients). 
17. Any medical or other condition which, in the opinion of the investigator, would preclude 
participation in a clinical trial. 
18. Females who are pregnant or breastfeeding. 
19. Documented active alcohol or drug abuse. 
20. Patients with a prior history of non-compliance with medical regimens. 
9. Number of expected subjects 
It is expected to include 110 patients in the study. 
The study will enroll 55 patients in each cohort. Patients who meet study eligibility criteria will 
be stratified in cohort A or cohort B in function of primary tumor origin. 
10. Recruitment period duration 
The patient recruitment period of the study will begin on approximately September 2015 and 
will end on or before March 2017 (18 months approximately). The maximum treatment period 
for each subject on study is anticipated to be approximately 36 months. However, subjects will 
continue on treatment as long as they demonstrate clinical benefit. 


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11. Treatment description 
11.1 Description of dose, interval, route and dosing regiment 
The sponsor will package the study drug. Lenvatinib will be provided as #4-size hydroxypropyl 
methylcellulose (HPMC) capsules in 2 strengths differentiated by color: 4-mg capsule 
(yellowish-red cap and body) and 10-mg capsule (yellowish-red cap with yellow body). Dosage 
formulation and capsule strength of lenvatinib are presented in table 2. 
Lenvatinib should be stored in accordance with the labeled storage conditions (room 
temperature).  
Oral lenvatinib will be administered as follows: lenvatinib 24 mg (two 10-mg capsules + one 4-
mg capsule). 
 
Table 2: Dosage formulation and capsule strength of lenvatinib 
 
11.1.1 Chemical name, structural formula of lenvatinib 
Study drug code: E7080  
Generic name: lenvatinib 
Chemical 
name: 
4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate 
Molecular formula: C21H19ClN4O4•CH3SO3H  
Molecular weight: 522.96  


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Structural formula: 
 
11.2 Storage Conditions  
Study drug will be stored in accordance with the labeled storage conditions (room 
temperature). Temperature monitoring is required at the storage location to ensure that the 
study drug is maintained within an established temperature range. The investigator (if 
regionally required, the head of the medical institution) or designee is responsible for ensuring 
that the temperature is monitored throughout the total duration of the trial and that records are 
maintained; the temperature should be monitored continuously by using either an in-house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required. 
11.3 Administration of study treatment 
This is an open-label study for study patients, investigator site personnel and sponsor. The 
patient will receive on Day 1 of each cycle enough treatment for a whole treatment cycle, i.e. 3 
packages: 2 packages containing 30 capsules of 10-mg and 1 package containing 30 
capsules of 4 mg. 
Study subjects will be administered 3 capsules of the study drug (two 10-mg capsules and one 
4-mg capsule) to be taken once daily each morning during 28 days from Cycle 1 onward. 
Study drug should be taken at approximately the same time each morning. Study drug may be 
taken in a fasting state or following a meal. Criteria for interruption of treatment, dose 
reduction, and resumption of treatment dose reduction and interruption instructions for 
subjects who experience treatment-related toxicity are presented in Table 3. 
11.4 Selection of Doses in the Study  
Three Phase 1 studies were conducted examining escalating doses of lenvatinib administered 
once or twice daily on continuous and interrupted dosing schedules. The 25-mg dose 
administered in the continuous once daily schedule was identified as the MTD. This dosing 


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schedule appeared to provide an optimal balance of safety and efficacy in a multivariate 
analysis of these studies. To simplify drug administration in this study, a dosing schedule of 24 
mg once a day (two 10-mg capsules + one 4-mg capsule) has been selected for continued 
lenvatinib development. 
11.5 Selection and Timing of Dose for Each Subject  
Study drug capsules are to be taken orally once a day at approximately the same time in the 
morning without regard to food intake for 28 days from Cycle 1 onward. The starting dose will 
be 24 mg per day. If a subject misses a dose, it may be taken within the 12 hours following the 
usual time of the morning dose. If more than 12 hours have elapsed from the time of the usual 
daily dose, study drug should be taken the next day at the usual time in the morning. In the 
event a subject vomits after study drug administration, the subject should not take another 
dose until the next scheduled dose.  
11.6 Prior and Concomitant Therapy  
All prior medications (including over-the-counter medications) administered 30 days prior to 
the first dose of study drug and any concomitant therapy administered to the subject during the 
course of the study (starting at the date of informed consent) until 30 days after the final dose 
of study drug will be recorded. Additionally, all diagnostic, therapeutic, or surgical procedures 
relating to malignancy should be recorded. Any medication which is considered necessary for 
the subject’s health and which is not expected to interfere with the evaluation of or interact with 
study drug may be continued during the study.  
Treatment of complications or adverse events or therapy to ameliorate symptoms (including 
blood products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs, etc.) 
may be given at the discretion of the investigator, unless it is expected to interfere with the 
evaluation of (or to interact with) study drug.  
Concomitant somatostatin analogues are allowed in both cohorts during the study 
Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and low molecular weight heparin 
(LMWH) are permissible but should be used with caution. Granulocyte colony-stimulating 
factor (g-CSF) or equivalent may be used in accordance with American Society of Clinical 
Oncology (ASCO), institutional, or national guidelines. Erythropoietin may be used according 
to ASCO, institutional, or national guidelines, but the subject should be carefully monitored for 
increases in red blood cell (RBC) counts. 
If concomitant medication/therapy is administered for an adverse event, investigators will 
record that adverse event on the Adverse Events eCRF.  
 
 


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11.7 Dose reduction and interruption instructions 
In case of treatment related toxicity please follow the dose reduction and interruption 
instructions provided in Table 3.  
For details about the instructions for dose reduction and interruption in case of hypertension 
and proteinuria, please see Sections 14.8.1 and 14.8.2 of the protocol. In case of doubts 
regarding other specific cases, see the study reference information (Investigator Brochure 
and/or Summary of Product Characteristics) provided by the study sponsor. 
Table 3. - Dose reduction and interruption instructions 
 
 
Note: For grading see CTCAE v.4.03 (Appendix IV). Collect all CTC grades of AE, decreasing and increasing 
grade. 
a) 
A delay of study treatment for more than 28 days (due to treatment-related toxicities) will require a 
discussion with the sponsor before treatment can be resumed 
b) 
Initiate optimal medical management for nausea, vomiting, and/or diarrhea prior to any study treatment 
interruption or dose reduction 
c) 
Applicable only to Grade 2 toxicities judged by the subject and physician to be intolerable. 
d) 
Excluding laboratory abnormalities judged to be non-life threatening, in which case manage as Grade 3. 


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11.8 Unused drugs 
All used and unused study drugs, including empty containers are to be returned to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) by the subject and ultimately to the sponsor’s designated contractor or depot by 
the conclusion of the study, unless approval is given by the sponsor for destruction of supplies 
and containers at the investigational site. 
Upon completion of drug accountability and reconciliation procedures by investigational site 
personnel and documentation procedures by the sponsor’s personnel, study drug that is to be 
returned to the sponsor’s approved contract vendor must be boxed and sealed and shipped 
back to the sponsor’s approved contract vendor following all local regulatory requirements. In 
some regions, study drugs may be removed from the site and hand delivered to the sponsor’s 
specified location by sponsor representatives. Drug accountability will be reviewed during 
investigational site visits and at the completion of the study. 
11.9 Drug-Drug Interactions 
There have been no completed human studies, at present, specifically evaluating drug-drug 
interactions with lenvatinib. The weak inhibitory effect on CYP P450 enzymes (in vitro) 
exhibited by lenvatinib suggests a low risk of lenvatinib interference with the pharmacokinetics 
of other drugs co-administered in usual clinic practice. However, preliminary preclinical studies 
identify CYP3A4 as an important enzyme responsible for human hepatic metabolism of 
lenvatinib. Caution should be exercised when administering drugs metabolized by CYP3A4 or 
drugs that are inhibitors or inducers of CYP3A4 (including herbal supplements or grapefruit), 
as administration of such drugs could affect the metabolism of lenvatinib. Please refer to 
Appendix V and http://medicine.iupui.edu/flockhart/table.htm for the most current information.  
11.10 Prohibited Concomitant Therapies and Drugs 
Subjects should not receive other anti-tumor therapies while on study. If subjects receive 
additional anti-tumor therapies 
such 
as 
chemotherapy, 
palliative radiotherapy, or 
immunotherapy, this will be judged to represent evidence of disease progression and study 
drug will be discontinued. These subjects should complete all off treatment assessments and 
continue to be followed for survival in the Follow-Up Period. 
11.11 Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study. Clinical 
research associates (CRAs) will review treatment compliance during monitoring visits and at 
the completion of the study. 


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11.12 Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:  
 
A signed and dated confidentiality agreement;  
 
A copy of the final protocol signature page signed and dated by both the sponsor and 
investigator;  
 
Written proof of approval of the protocol, the informed consent form(s) (ICFs), and any 
other information provided to the subjects by the Ethics Committee (EC) for the 
institution where the study is to be conducted;  
 
The EC membership list; 
 
A copy of the regulatory authority (RA) approval for the country in which the study is 
being conducted (if required), and the Import License (if required);  
 
A signed and dated curriculum vitae (CV) for the Principal Investigator (PI); 
 
Financial Disclosure Form(s); 
 
A signed and dated clinical trials agreement. 
 
An insurance policy contracted for the clinical trial. 
The investigator and study staff (if regionally required, the head of the medical institution or the 
designated pharmacist) will be responsible for the accountability of all clinical supplies 
(dispensing, inventory, and record keeping) following the sponsor’s instructions and adherence 
to Good Clinical Practice (GCP) guidelines as well as local and/or regional requirements. 
Under no circumstances will the investigator allow the study drug to be used other than as 
directed by this protocol. Clinical supplies will not be dispensed to any individual who is not 
enrolled in the study. An accurate and timely record of the receipt of all clinical supplies, 
dispensing of study drug to the subject, collection of unused supplies returned by the subject, 
and subsequent return of unused study drug to the sponsor must be maintained. This 
includes, but may not be limited to: (a) documentation of receipt of clinical supplies, (b) study 
drug dispensing/return reconciliation log, (c) study drug accountability log, (d) all shipping 
service receipts, and (e) documentation of drug returned to the sponsor. All forms will be 
provided by the sponsor. Any comparable forms that the investigational site wishes to use 
must be approved by the sponsor.  
The supplies and inventory records must be made available, upon request, for inspection by 
the designated representative of the sponsor, a representative of the Regulatory Authorities 
and/or Ethics Committee. 


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12. Study Methods 
12.1 Demography and baseline characteristics 
Demographic information and baseline characteristics will be collected at the screening visit. 
Standard demography parameters include age, sex, and race/ethnicity (recorded in 
accordance with prevailing regulations). Baseline characteristics will include ECOG 
performance status, Medical and surgical histories will be obtained during the screening 
phase, along with a record of prior and concomitant medications. Physical examinations 
(comprehensive or symptom-directed) will be performed as specified in the schedule of visits 
and procedures (table 4). A comprehensive physical examination will include evaluations of 
the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), abdomen, limbs, 
skin, and a complete neurological examination. A urogenital examination will only be required 
in the presence of clinical symptoms related to this region. Documentation of the physical 
examination will be included in the source documentation at the investigational site. Significant 
findings prior to the start of study drug will be recorded on the Medical History and Current 
Medical Conditions eCRF. Changes from screening physical examination findings that meet 
the definition of an AE will be recorded on the Adverse Events eCRF. Clinical laboratory tests 
and pregnancy test will be done according to Table 5 
12.2 Primary Efficacy assessments 
The primary efficacy endpoint is overall response rate (ORR) by RECIST v1.1 
 
ORR is the proportion of subjects who have best overall response of CR or PR. 
Tumor assessments 
 
Tumor assessments will be performed using RECIST 1.1. (Appendix I) Investigator 
determined response assessments will be performed at each assessment time point 
and entered onto the eCRF. Copies of all tumor imaging studies will be sent to an 
imaging core laboratory (Central Review) for prospective on-study primary efficacy 
assessment. Tumor assessments will be carried out following the guidelines provided 
by the study sponsor. Tumor assessments (CT of abdomen, and pelvis, and of all other 
known sites of disease) will be performed during the screening phase and, the first 
assessment will be performed 6 weeks after the first dose, the second assessment will 
be performed 12 weeks after the first dose, then every 12 weeks during study 
treatment cycles in the treatment phase or sooner if clinically indicated until 
documentation of disease progression.  
 
A brain CT/MRI will be performed at screening, as clinically indicated. In addition, for 
subjects with history of treated brain metastases, brain scans must be performed at 
screening and every tumor assessment time point.  


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 
Data from somatostatin receptor schintigraphy or PET-CT (octreoscan) with specific 
radiolabeled agents for neuroendocrine tumors (such as Ga68, 5-HTP or F-Dopa) will 
be collected if available and performed within the 6 months prior to the first dose of 
study drug but are not acceptable as tumor assessment techniques during treatment 
phase.  
 
Data from bone scan will be collected, if available and performed within 6 months prior 
to first dose of study drug and every 24 weeks after first dose of study drug, and at the 
final visit unless the last scan was performed less than 24 weeks before.  
 
Somatostatin schintigraphy, PET and bone scan are not compulsory. They will be 
collected, if performed. 
 
A chest x-ray or skeletal x-ray that clearly demonstrates a new metastatic lesion may 
be used to document progression in lieu of the CT/MRI scans.  
 
Subjects who discontinue study drug prior to disease progression must continue to 
undergo tumor assessments every 12 weeks in the follow-up period, until disease 
progression is documented or another anti-cancer therapy is initiated. 
 
A dynamic study of multiphasic imaging, at least biphasic imaging, with arterial and 
venous/portal phases must be performed using CT and/or MG, since one or other 
technique may be recommended depending on different clinical characteristics. As a 
general rule, TCs will be performed. Although, for example, for patients allergic to 
iodinated contrast (in the CT), a MR with a dynamic study would be better. 
 
The preferred type of CT scan is a diagnostic quality spiral or multidetector CT with oral 
and iodinated IV contrast, and the preferred MRI scan is performed with IV gadolinium 
chelate, unless there is a medical contraindication to contrast. Scans of the neck, 
abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but 
evaluation of the chest should be done with CT. If iodinated IV contrast is 
contraindicated, the chest evaluation should be done with non-contrast CT, and the 
abdomen and pelvis evaluation should be performed using either CT with oral contrast 
(without IV contrast) or MRI with gadolinium chelate IV contrast (the latter is preferred). 
It is recommended that spiral/multidetector CT be performed with a 5-mm contiguous 
slice reconstruction algorithm. If body MRI scans are performed, contiguous slices of 5 
mm are also recommended. 
 
The same imaging modality and image-acquisition protocol (including use or nonuse of 
IV contrast) should be used consistently across all time points to allow consistent 
comparison of lesions. Low-dose non-contrast CT transmission scans from a positron 
emission tomography-CT (PET-CT) combination scanner are not acceptable. 


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Ultrasound should not be used for radiographic tumor assessment. A chest x-ray or 
skeletal x-ray which clearly demonstrates a new metastatic lesion may be used to 
document progression in lieu of the CT/MRI scans.  
 
To be considered a target lesion at baseline, the minimum size of non-lymph nodes 
should be 1.0 cm in the longest diameter. If this is the only target lesion, the longest 
diameter should be ≥ 1.5 cm. (However, if a slice thickness > 5 mm is used, the 
minimum lesion size should be twice the slice thickness.) For a lymph node to be 
considered a target lesion at baseline, the minimum lesion size should be ≥ 1.5 cm in 
the short-axis.  
 
Brain scans should be performed with and without contrast-enhanced CT or MRI with 
5-mm contiguous slices recommended (maximum inter-slice gap of 1 mm on MRI). 
 
The recommended bone scan technique is 99m-technetium-methylene diphosphonate 
(99m-Tc MDP) scintigraphy or whole body-bone MRI, although 18F-sodium fluoride 
PET (NaF PET) may be used if the 99m-Tc MDP tracer is not available. If an 
alternative scanning method is used, it should be continued throughout the rest of the 
study. The same methodology and scan acquisition techniques used at screening 
should be used throughout the study to ensure comparability.  
 
If a bone lesion is to be followed as a non-target lesion, it is preferable that this be 
done using CT/MRI. For bone non-target lesions that can be followed only on bone 
scans, a time point response other than Not Evaluable (NE) will be allowed despite an 
individual lesion assessment of NE for weeks when bone scans are not required.  
 
If subcutaneous masses or nodes are palpable (e.g., bulky) and are assessable by 
both clinical and radiographic techniques, the radiographic (CT/MRI) technique should 
be used for the assessment of target and non-target lesions.  
 
Assessments are to be performed at the site by appropriately qualified personnel and 
results of the site interpretation are to be recorded on the appropriate eCRF page. 
12.3 Secondary efficacy assessments 
 
Progression-free survival (PFS) is defined as the time from the date of treatment start 
(C1D1) to the date of first documentation of disease progression or death (whichever 
occurs first) using RECIST 1.1. PFS censoring rules will follow FDA guidance in 20077. 
 
Early tumor shrinkage (ETS) rate defined as 20% reduction in target lesions after the 
first 6 weeks of treatment (first tumor assessment)  
 
Deepness of response (DpR) defined as percentage of maximum tumor shrinkage 
observed at the nadir compared with baseline. 


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12.4 Pharmacodynamic, and Pharmacogenomic Assessments for the substudy  
Blood samples for the development of exploratory predictive biomarkers will be collected from 
all subjects prior to the first dose of study drug, and on Cycle 2/Day 1 and after documented 
disease progression. Biomarker discovery and validation will be performed to identify blood or 
tumor biomarkers which may be useful to predict subject response, as determined by 
evaluation of primary or secondary efficacy endpoints. Plasma samples from study subjects 
will undergo global proteomic and/or enzyme-linked immunosorbent assay (ELISA)-based 
analyses or multiplex bead-based immunoassay in an effort to identify protein biomarkers. In 
addition, DNA and RNA analyses will be performed in search of predictive or prognostic 
biomarkers and also biomarkers identified in other lenvatinib clinical studies may also be 
assessed in samples collected from subjects enrolled in this study.  
Archived, fixed tumor tissue from will be collected for all subjects for confirmation of histology 
and assessment of somatic mutations of genes which may be important in the development 
and progression of neuroendocrine tumors. Gene-expression profiling (GEP), proteomic, or 
immunohistochemical (IHC) analysis will be performed based on the amount of tumor tissue 
available for analysis. All analyses will be limited to correlations relevant to neuroendocrine 
tumors and clinical outcomes related to treatment with lenvatinib.  
Blood and tumor samples collected during the study will be stored at the study sites until the 
initial primary efficacy and safety analyses of the study will be completed and results will be 
available. Then, the study sponsor will decide whether to perform all or part of the 
pharmacogenetic/pharmacogenomics assessments. 
A specific and optional patient information sheet and Informed consent will be obtained for the 
collection of blood and tumor samples for the pharmacogenetic/pharmacogenomics 
assessments. Patient could participate in the study even if they do not sign this specific 
consent for the collection of blood and tumor samples, this will not be considered as protocol 
deviation. 
Data obtained will only be used for research, to assist in developing safer and more effective 
treatments, and will not be used to change the diagnosis of the subject or alter the therapy of 
the subject. Any DNA derived from the sample may be stored for up to 15 years to assist in 
any research scientific questions related to lenvatinib. Instructions for the processing, storage, 
and shipping of samples will be provided in the Laboratory Manual. For details about samples 
see Appendix VI Pharmacogenomics. 
12.5 Safety Assessments  
Safety will be assessed by monitoring and recording all AEs including all CTCAE grades (for 
both increasing and decreasing severity) and serious adverse events (SAEs); regular 


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monitoring of hematology, clinical chemistry, and urine values; physical examinations; and 
regular measurement of vital signs, and electrocardiograms (ECGs) and detailed in the 
schedule of visits and procedures (Table 4). 
 


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13. Trial development 
13.1 Schedule of Visits and Procedures 
Table 4 Schedule of Visits and Procedures 
This table presents the schedule of visits and procedures for the screening, treatment and follow-up phases of this study. 
Phase 
Screening Phase 
Treatment Phase 
FU 
Phase 
Period 
Screeninga,
b 
Baselinea,
b 
Study Treatment 
Follow 
up 
Visit 
v1 
-28 TO -2 
V2 
DAY -1 
V3 
C1D1 
V4
C1 D7 
V5 
C1D15
v6 
C2D1 
v7
C2D15
W6 
v8 
C3D1 
v9 
C3D15
V10
C4D1 
CXD1 
EOT
+28D 
LD 
Every 6 
months
Informed consent 
X 
  
  
 
  
  
  
  
  
  
  
  
Inclusion/exclusion 
X 
X 
  
 
  
  
  
  
  
  
  
  
Allocation 
  
X 
  
 
  
  
  
  
  
  
  
  
Demographic data 
X 
  
  
 
  
  
  
  
  
  
  
  
ECOG PSc  
X 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
  
pTNM staging 
X 
  
  
 
  
  
  
  
  
  
  
  
Med/Surg history 
X 
X 
  
 
  
  
  
  
  
  
  
  
Vitals signsd 
X 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
  
Physical examf 
X 
Xe 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
  
12-lead ECGg 
X 
  
  
 
  
X 
  
  
  
  
X 
  
Echocardiogramh 
X 
  
  
 
Performed every 24 weeks following the first dose of study 
drug or sooner, if clinically indicated 
  
Biochemistry and 
hematologyh 
X 
Xh 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
  
Urinalysis 
X 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
  
Pregnancy testi 
X 
X 
 Xb 
 
  
  
  
  
  
  
  
  


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Phase 
Screening Phase 
Treatment Phase 
FU 
Phase 
Period 
Screeninga,
b 
Baselinea,
b 
Study Treatment 
Follow 
up 
Visit 
v1 
-28 TO -2 
V2 
DAY -1 
V3 
C1D1 
V4
C1 D7 
V5 
C1D15
v6 
C2D1 
v7
C2D15
W6 
v8 
C3D1 
v9 
C3D15
V10
C4D1 
CXD1 
EOT
+28D 
LD 
Every 6 
months
Dispense Study 
Treatment 
  
  
x 
 
  
x 
  
x 
  
x 
  
  
Accountability Study 
Treatment 
  
  
x 
 
 
x 
 
x 
 
x 
x 
 
Tumor assessments 
(CT/MRI)j 
X 
  
 
CT/MRI of abdomen/pelvis and other areas of known disease at 
screening plus any areas of newly suspected disease should be 
performed at week 6 after the first dose of treatment, 12 weeks after 
the first treatment dose and then, every 12 weeks or sooner if clinically 
indicated until documentation of disease progression 
 
Survivalk 
  
  
x 
x 
x 
x 
x 
x 
Biomarkersl 
  
x 
  
 
  
x 
  
  
  
  
x 
  
Archival tumor blocks or 
slidesm 
  
x 
  
 
  
  
  
  
  
  
  
  
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
AEs/SAEsp 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
 
AEs = adverse events, BP = blood pressure, CT = computerized tomography, ECG = electrocardiogram, ECOG = Eastern Cooperative 
Oncology Group, HR = heart rate, LD = last dose, MRI = magnetic resonance imaging, PET = positron-emission tomography, RECIST = 
Response Evaluation Criteria In Solid Tumors, RR = respiratory rate, SAEs = serious adverse events, surg = surgical, 99m-Tc MDP = 
99m-technetium-methylene diphosphonate,  
a. 72 hours before Cycle 1 Day 1 (C1D1). The baseline assessment can be performed on C1D1, prior to treatment. Informed consent may be 
taken up to 4 weeks prior to C1D1. A physical examination is not mandatory for C1D1, if performed at baseline (day -1); however, a symptom-
directed physical examination will be performed on Cycle 1/Day 1 and at any time during the study, as clinically indicated. 


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b. Efforts should be made to conduct study visits on the day scheduled (± 1 day). Clinical laboratory assessments may be conducted anytime 
within 72 hours prior to the scheduled visit.  
c. ECOG will be performed at the Screening and Baseline Visits and at every subsequent treatment visit thereafter. For ECOG see Appendix II.  
d. Assessments will include vital signs (supine BP, HR, RR, and body temperature), weight, and height. Height will be measured at the Screening 
Visit only. Elevated BP (≥140/90 mmHg) should be confirmed by 3 measurements (at least 5 minutes apart). If systolic BP is ≤ 140 mmHg to <160 
mmgHg or dyastolic BP ≤90 mmHg to 100 mmHg, BP should be confirmed by repeat measurements after an hour.  
e. Required if screening physical examination was performed > 7 days prior C1D1.  
f. A comprehensive physical examination (including a neurological examination) will be performed at the Screening or Baseline Visit, on each visit 
of the Treatment phase, and at the off-treatment assessment. A symptom-directed physical examination will be performed on Cycle 1/Day 1 and at 
any time during the study, as clinically indicated.  
g. Single 12-lead ECG. Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.  
h. Baseline Assessments scheduled may be performed within 72 hours prior to the visit. Repeat complete full blood count with differential and AEs 
assessment will be performed as per the investigator judgment (until improvement to < Grade 3). A delay of study treatment for more than 28 days 
(due to AE) will require a discussion with the sponsor and probably will be discontinued. 
i. A serum or urine pregnancy test will be performed at the Screening Visit, at the Baseline Visit (or within 72 hours prior to the first dose of study 
medication) 
j. Screening tumor assessments using CT of the abdomen/pelvis and other areas of known disease or newly suspected disease should be 
performed within 28 days prior to C1D1. Scans of the abdomen, pelvis and other areas of the body may be done with MRI instead of CT, but 
evaluation of the chest should be done with CT. CT scans should be performed with oral and iodinated IV contrast and MRI scans with IV 
gadolinium chelate unless there is a medical contraindication to contrast. If iodinated IV contrast is contraindicated, chest CT should be done 
without IV contrast. Treatment phase: tumor assessments of the abdomen/pelvis and other areas of known disease or newly suspected disease 
should be performed after 6 weeks of first dose of study treatment, the second assessment will be performed 12 weeks after the first dose, and 
then every 12 weeks (or sooner if there is evidence of progressive disease) and should utilize the same methodology (CT or MRI) and scan 


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acquisition techniques (including use or nonuse of IV contrast) as were used for the screening assessments. Brain metastases assessment should 
be performed every 12 weeks and bone lesions every 24 weeks, only when clinically indicated. 
Screening CT/MRI of the brain and bone scan should only be performed in patients with known or suspected brain or bone lesions. During 
treatment phase evaluation of brain metastases should be performed every 12 weeks and bone lesions every 24 weeks.  
A dynamic study of multiphasic imaging, at least biphasic imaging, with arterial and venous/portal phases must be performed using CT and/or MG, 
since one or other technique may be recommended depending on specific clinical characteristics of the patient. As a general rule, TCs will be 
performed. Although, for example, a MR with a dynamic study would be indicated for patients allergic to iodinated contrast (in the CT).k. Survival 
data will be collected every 4 weeks until end of treatment is declared. All anticancer therapies will be collected. Survival data and other cancer 
treatments received will be collected every 6 months until close of the study database. The study sponsor may elect to discontinue survival follow-
up. 
l Collection of blood sample to obtain plasma, serum, or other components to be used for biomarker studies. Samples will be obtained at baseline, 
Cycle 2/Day 1, and at end-of-treatment visit.  
m. All subjects will have collection of most recent archived, tumor-biopsy sections for identification of predictive biomarkers. 
n. Throughout the study from the signature of Informed Consent. SAE irrespective of relationship to study treatment must be reported within 24 
hours since awareness of the SAE. AEs and concomitant meds collected 28 days from last dose.  


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13.2 Screening period procedures 
Day -28 to Day -1 (Visit 1)  
Prior to performing any procedures or assessments, the nature of the study and the potential risks 
associated with the trial will be explained to all subject candidates and written informed consent will 
be obtained. Once informed consent has been obtained (within 4 weeks of first dose of study 
drug), the following procedures and evaluations will be performed:  
• 
Verify inclusion/exclusion criteria, including: 
o Histological confirmed diagnosis of one of the following neuroendocrine tumor 
subtypes:  
 
 G1/G2 pancreatic neuroendocrine tumor (Ki67<20% and mitotic count ≤20 
mitoses x 10 HPF). 
 
G1/G2 gastrointestinal neuroendocrine tumor including stomach, small 
intestine and colorectal origins (Ki67<20% and mitotic count ≤20 mitoses x 
10 HPF). 
o Patients must show evidence of disease progression within 12 months (an 
additional month will be allowed to accommodate actual dates of performance of 
scans, i.e., within ≤ 13 months) prior to signing informed consent, according to 
RECIST 1.1 criteria (Appendix I). 
 
In case of patients with tumors of pancreatic origin, progression after 
previous treatment with targeted agent should be verified (including mTOR 
inhibitors, such as everolimus or antiangiogenic therapies, such as sunitinib, 
sorafenib, axitinib, bevacizumab within others). Combination therapies in the 
same treatment line (such as sorafenib plus bevacizumab, chemotherapy 
plus antiangiogenic drugs) are considered one treatment line and are 
allowed to be included in the study. Patients must be treated with only one 
previous line of targeted agent(s)-based therapy. Previous therapy with 
somatostatin analogues and/or interferon treatment is allowed and is not 
considered as a previous targeted agent therapy. 
 
In case of patients with tumors of Gastrointestinal origin: progression after 
therapy with antitumoral doses of somatostatin analogs (octreotide LAR 30 
mg every 28 days or Lanreotide 120 mg every 28 days) and/or interferon 
should be verified. 
o Measurable disease: 
 
 At least 1 lesion of ≥ 1.0 cm in the longest diameter for a non-lymph node or 
≥ 1.5 cm in the short-axis diameter for a lymph node (lymph node 


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enlargement) which is serially measurable according to RECIST 1.1 using 
computerized tomography/magnetic resonance imaging (CT/MRI).  
 
NON-lymph node measurable lesion/ non-lymph node > 10 mm in maximum 
axis.  
 
In case of a SINGLE NON-lymph node measurable LESION, the size 
must be > 15 mm in the maximum axis. 
 
 
 
 Lesions that have had external beam radiotherapy (EBRT) or loco-regional 
therapies such as radiofrequency (RF) ablation must show evidence of 
progressive disease based on RECIST 1.1 to be deemed a target lesion; 
o Record demographic data; 
o Evaluate ECOG performance status (subjects must register 0 or 1 on the ECOG 
scale for study eligibility) (Appendix II); 
o Establish pTNM staging and diagnosis; 
o Record medical and surgical history; 
o Obtain vital signs (systolic and diastolic BP, HR, RR, and body temperature), 
weight, and height. Height will be measured at the Screening Visit only. BP, HR, 
and RR will be obtained after subjects have been resting for 5 minutes. For subjects 
with an elevated BP (≥140/90 mmHg), confirmation should be obtained by 
performing 3 measurements (at least 5 minutes apart) to yield a mean value. 
Systolic BP ≥140 mmHg to <160 mmgHg or dyastolic BP ≥90 mmHg to 100 mmgHg 
should be confirmed by repeat measurements after an hour; 
o Perform a comprehensive physical examination (including a neurological 
evaluation); 
o Perform a single, 12-lead electrocardiogram (ECG); 
o Perform an echocardiogram any time during the screening phase; 
o Collect blood samples for biochemistry and hematology analysis including INR (see 
Table 5 for the tests to be performed); 
o Collect urine sample and perform urinalysis (see Table 5 for the tests to be 
performed); Samples for hematology, urinalysis and chemistry laboratory testing 
may be collected at any time within 72 hours prior to first dose of study drug; 
o Collect urine sample for β-hCG pregnancy testing from all premenopausal and any 
postmenopausal women who have been amenorrheic for < 12 months; 
o Perform CT/MRI tumor assessments; If CT/MRI of abdomen/pelvis are available 
within 28 days previous to the first dose of the study drug it is not need to repeat 
them and they will be used as a baseline tumor assessment; 


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Scans of the abdomen, pelvis and other areas of the body may be done with MRI 
instead of CT, but evaluation of the chest should be done with CT. CT scans should 
be performed with oral and iodinated IV contrast and MRI scans with IV gadolinium 
chelate unless there is a medical contraindication to contrast. If iodinated IV contrast 
is contraindicated, chest CT should be done without IV contrast; 
o Record somatostatin receptor schintigraphy (octreoscran/ PET-CT) if available 
within the last 6 months previous C1D1; 
o CT or MRI of the brain and bone scan if indicated; 
o Record all prior and concomitant medication use (prescription and non-prescription 
medications as well as transfusions); 
o Record any AEs or SAEs; 
The screening form must be completed for all subjects screened, providing reasons for screen 
failure when applicable. 
13.2.1 Baseline period procedures  
Day 0 (Visit 2) 
The results of all screening assessments and evaluations must be completed and reviewed by the 
Principal Investigator prior to the Baseline Visit. Baseline assessments can be performed either on 
Day -1 or on Cycle 1/Day 1 prior to treatment, although the hematology, clinical chemistry, and 
pregnancy assessments may be performed within 72 hours prior to the first dose of study drug 
(Cycle 1/Day 1). Only those subjects who continue to meet all of the inclusion and none of the 
exclusion criteria are eligible to continue in the study. 
Reasonable efforts should be made to conduct all baseline and subsequent evaluations in the 
same test order at each visit. This is intended to minimize variability in subject response. It is 
further recommended, whenever possible, that subjects be evaluated at approximately the same 
time of the day (e.g., morning or afternoon) at each subsequent visit. 
At the Baseline Visit, the following evaluations will be conducted: 
• 
Reconfirm inclusion/exclusion criteria; 
• 
Allocation to cohort A or Cohort B, no randomization needed for this study as all patients 
included will receive the same study treatment; 
• 
Evaluate ECOG performance status; 
• 
Update medical and surgical history; 
• 
Obtain vital signs and weight; 
• 
Perform a comprehensive physical examination if the Screening Visit physical examination 
was performed more than 7 days prior to Cycle 1/Day 1 A symptom-directed physical 
examination will be performed on Cycle 1/Day 1 and at any time during the study, as 
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• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed). Screening results may be used if collected within 72 hours pre-dose; 
• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed); 
• 
Collect urine sample from all premenopausal and any postmenopausal women who have 
been amenorrheic for < 12 months for β-hCG pregnancy testing. Screening pregnancy test 
results may be used if obtained within 72 hours pre-dose; 
• 
Collect blood samples for biomarker analysis; 
• 
Collect most recently archival tumor-biopsy sections or blocks for identification of predictive 
biomarkers; 
• 
Record all concomitant medication use; 
• 
Record any AEs or SAEs; 
In case of any altered parameter of the screening/baseline parameters, these assessments could 
be repeated during the screening period (-28 to day -1) to check their stability/recovering. Other 
cases should be confirmed by the Sponsor prior to be considered as screening failure. 
Subjects who complete the Baseline Period and remain eligible for the study will continue into the 
treatment phase. 
13.2.2 Treatment phase assessments schedule 
13.3 Treatment cycle procedures 
Efforts should be made to conduct study visits on the day scheduled (window ± 1 day). Clinical 
laboratory assessments may be conducted anytime within 72 hours prior to the scheduled visit, 
unless otherwise specified in the Schedule of Visits and Procedures. Whenever possible, subjects 
should be evaluated at approximately the same time of the day (e.g., morning or afternoon) at each 
visit, and reasonable efforts should be made to conduct all evaluations in the same test order at 
each visit. 
Cycle 1/Day 1 (Visit 3) 
Baseline assessments may be performed on Day -1 or on Cycle 1/Day 1 prior to dosing. 
Clinical laboratory tests for hematology, biochemistry and urine tests (see Table 4) including 
pregnancy test (where applicable) can be performed within 72 hours prior to the first dose of study 
drug. No need to repeat them if previously obtained at basal visit. 
• 
Obtain vital signs (resting BP, HR, RR, body temperature) and weight; 
• 
Evaluate ECOG performance status. No need to repeat it if previously obtained at Baseline 
visit (72 hours before C1D1).; 
• 
Physical examination is not mandatory if performed at baseline (day -1) however a 
symptom-directed physical examination will be performed on Cycle 1/Day 1 and at any time 


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during the study, as clinically indicated. No need to repeat it if previously obtained at 
Baseline visit; 
• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed). Screening/baseline results can be used if they have been obtained 72 
hours before the first dose of study drug; 
• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed) 
Clinical laboratory tests including pregnancy test (where applicable) can be performed 
within 72 hours prior to the first dose of study drug; 
• 
Administer/dispense study drug: 
• 
Study drug (oral, QD). First dose to be taken at the site; 
• 
Instruct the subject not to take the Day 7 dose of study drug before coming to the site; 
• 
Record all concomitant medication use; 
• 
Record any AEs or SAEs; 
• 
Record the accountability of the study drug; 
Cycle 1/Day 7 (Visit 4) 
• 
Obtain vital signs (BP, HR, RR and body temperature at rest) and weight 
• 
Evaluate ECOG performance status. 
• 
Perform a comprehensive physical examination (including a neurological evaluation). A 
symptom-directed physical examination will be performed at any time during the study, as 
clinically indicated. 
• 
Instruct the subject not to take the Day 15 dose of study drug before coming to the site. 
• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed). 
• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed). 
Repeat complete full blood count with differential and perform AEs assessment as per the 
investigator judgment (until improvement to < Grade < 3). A delay of study treatment for 
more than 28 days (due to AE) will require a discussion with the sponsor who will probably 
determine to discontinue the subject. 
• 
Record concomitant medication use. 
• 
Record any AEs or SAEs. 
Cycle 1/Day 15 (Visit 5) 
• 
Obtain vital signs (resting BP, HR, RR, body temperature) and weight; 
• 
Evaluate ECOG performance status; 
• 
Perform a comprehensive physical examination (including a neurological evaluation). A 
symptom-directed physical examination will be performed at any time during the study, as 
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• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed). 
• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed). Repeat complete full blood count with differential and AEs assessment 
will be performed as per the investigator judgment (until improvement to < Grade 3). A 
delay of study treatment for more than 28 days (due to AE) will require a discussion with 
the sponsor and probably will be discontinued; 
• 
Instruct the subject to bring back the unused study drug (blister, boxes) for the following 
study visit; 
• 
Record all concomitant medication use; 
• 
Record any AEs or SAEs; 
Cycle 2/Day 1(Visit 6) 
• 
Evaluate ECOG performance status; 
• 
Obtain vital signs (supine BP, HR, RR, body temperature) and weight; 
• 
Perform a comprehensive physical examination (including a neurological evaluation). A 
symptom-directed physical examination will be performed at any time during the study, as 
clinically indicated; 
• 
Perform a single, 12-lead electrocardiogram (ECG); 
• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed). Repeat complete full blood count with differential and AEs assessment 
will be performed as per the investigator judgment (until improvement to < Grade 3). A 
delay of study treatment for more than 28 days (due to AE) will require a discussion with 
the sponsor and probably will be discontinued; 
• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed)  
• 
Administer/dispense study drug; 
• 
Unused study drug return and review the accountability of the study drug; 
• 
Collect blood samples for biomarker analysis; 
• 
Record all concomitant medication use; 
• 
Record any AEs or SAEs; 
• 
Record survival data; 
Cycle 2/Day 15 (Visit 7) 
• 
Evaluate ECOG performance status; 
• 
Obtain vital signs (supine BP, HR, RR, body temperature) and weight; 
• 
Perform a comprehensive physical examination (including a neurological evaluation). A 
symptom-directed physical examination will be performed at any time during the study, as 
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• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed) Repeat complete full blood count with differential and AEs assessment will 
be performed as per the investigator judgment (until improvement to < Grade 3). A delay of 
study treatment for more than 28 days (due to AE) will require a discussion with the 
sponsor and probably will be discontinued; 
• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed); 
• 
Tumor assessment by CT/MRI of neck/chest/abdomen/pelvis and other areas of known 
disease at screening plus any areas of newly suspected disease should be performed at 
week 6 after the first dose of treatment; 
• 
Instruct the subject to bring back the unused study drug (Blister/boxes) for the following 
study visit; 
• 
Record all concomitant medication use; 
• 
Record any AEs or SAEs; 
Cycle 3/Day 1 (Visit 8) 
• 
Evaluate ECOG performance status; 
• 
Obtain vital signs (supine BP, HR, RR, body temperature) and weight; 
• 
Perform a comprehensive physical examination (including a neurological evaluation). A 
symptom-directed physical examination will be performed at any time during the study, as 
clinically indicated; 
• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed). Repeat complete full blood count with differential and AEs assessment 
will be performed as per the investigator judgment (until improvement to < Grade 3). A 
delay of study treatment for more than 28 days (due to AE) will require a discussion with 
the sponsor and probably will be discontinued; 
• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed); 
• 
Administer/dispense study drug; 
• 
Unused study drug return and review the accountability of the study drug; 
• 
Record all concomitant medication use; 
• 
Record any AEs or SAEs; 
• 
Record survival data; 
Cycle 3/Day 15 (Visit 9) 
• 
Evaluate ECOG performance status; 
• 
Obtain vital signs (supine BP, HR, RR, body temperature) and weight; 
• 
Perform a comprehensive physical examination (including a neurological evaluation). A 
symptom-directed physical examination will be performed at any time during the study, as 
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• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed). Repeat complete full blood count with differential and AEs assessment 
will be performed as per the investigator judgment (until improvement to < Grade 3). A 
delay of study treatment for more than 28 days (due to AE) will require a discussion with 
the sponsor and probably will be discontinued; 
• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed); 
• 
Instruct the subject to bring back the unused study drug (Blister/boxes) for the following 
study visit; 
• 
Record all concomitant medication use; 
• 
Record any AEs or SAEs. 
Cycle 4 Through Last Cycle/Day 1 (Visit 10 and subsequent until PD) 
• 
Evaluate ECOG performance status; 
• 
Obtain vital signs (supine BP, HR, RR, body temperature) and weight; 
• 
Perform a comprehensive physical examination (including a neurological evaluation). A 
symptom-directed physical examination will be performed at any time during the study, as 
clinically indicated; 
• 
Perform an echocardiogram every 24 weeks following the first dose of study drug or sooner 
if clinically indicated; 
• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed); 
• 
Repeat complete full blood count with differential and AEs assessment will be performed as 
per the investigator judgment (until improvement to < Grade 3). A delay of study treatment 
for more than 28 days (due to AE) will require a discussion with the sponsor and probably 
will be discontinued; 
• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed); 
• 
Administer/dispense study drug; 
• 
Unused study drug return and review the accountability of the study drug. Instruct the 
subject to bring back the unused study drug (Blister/boxes) for the following study visit; 
• 
Perform tumor assessments at time points indicated in the Schedule of Visits and 
Procedures (Table 4). Assessments should utilize the same methodology and acquisition 
techniques as were used for the screening assessments: 
o Perform follow-up tumor assessments every 12 weeks or sooner, if clinically 
indicated) until documentation of disease progression. 
• 
Record all concomitant medication use; 
• 
Record any AEs or SAEs; 
• 
Record survival data. 


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13.3.1 End Off-treatment assessments  
Whenever possible, the following assessments should be performed within 28 days after subjects 
have discontinued study treatment:  
• 
Obtain vital signs (supine BP, HR, RR, body temperature) and weight; 
• 
Evaluate ECOG performance status; 
• 
Perform a comprehensive physical examination (including a neurological evaluation). A 
symptom-directed physical examination will be performed at any time during the study, as 
clinically indicated; 
• 
Perform a single, 12-lead electrocardiogram (ECG); 
• 
Collect blood samples for biochemistry and hematology analyses (see Table 5 for the tests 
to be performed); 
• 
Collect urine sample and perform urinalysis (see Table 5 for the tests to be performed); 
• 
Record survival 
• 
Collect blood samples for biomarker analysis; 
• 
Unused study drug return and review the accountability of the study drug Record all 
concomitant medication use. Concomitant medications should be collected for 28 days after 
the last dose of study medication; 
• 
Record any AEs or SAEs. AEs should be collected for 28 days after the last dose of study 
medication. SAEs, regardless of causality assessment, must be collected through the off-
treatment assessment and for 28 days following study drug discontinuation, whichever is 
longer. Any SAE judged by the investigator to be related to the study treatment should be 
reported to the sponsor regardless of the length of time that has passed since study 
completion. 
13.4 Record survival data. Post study treatment follow-up period procedures  
After study drug discontinuation, subjects will be followed for survival during the Post Study 
Treatment Follow-Up Period. Survival data and other cancer treatments received will be collected 
every 6 months until close of the study database. The study sponsor may elect to discontinue 
survival follow-up at any time. 
13.5 Laboratory measurements 
Clinical laboratory tests and urinalysis will be performed at the investigational site. The schedules 
of visits and procedures (Table 4) show the visits at which blood and urine will be collected for 
clinical laboratory tests. A Laboratory Manual will be provided to detail handling, processing, and 
shipping procedures. Regarding sample handling, Law 14/2007 of Biomedical Research will be 
complied with. All hematology, clinical chemistry (including pregnancy test, where applicable), and 
urinalysis samples are to be obtained prior to study drug administration and results reviewed prior 


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to administration/dispensing of study drug at the beginning of Cycle 1 and within 24 hours after 
Day 1 of all subsequent cycles. Please refer to Study Drug Dose Reduction and Interruption 
Instructions (Table 3) for the management of clinically significant laboratory abnormalities. A 
laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol and 
the eCRF Completion Instructions. In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event eCRF. Table 5 presents the clinical laboratory 
tests to be performed. 
 
 


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Table 5 Clinical laboratory tests 
 
Category 
Tests 
Hematology 
 Hematocrit, hemoglobin, RBC, platelet count, 
WBC with differential (bands, basophils, 
eosinophils, lymphocytes, monocytes, 
neutrophils), MCH, MCHC, MCV 
 INRa 
Clinical Chemistry 
 
Screening visit 
 Pregnancy test (serum or urine β-hCG)b 
 Bicarbonate, chloride, potassium, sodium, BUN 
or urea, creatinine, glucose, magnesium, 
phosphorus, calcium, albumin, total protein, alkaline 
phosphatase, ALT, AST, conjugated (direct) 
bilirubin, total bilirubin 
 TSH 
 Chromagranin A (pancreatic origin patients) 
 Chromagranin A +5 HIAA (only for 
gastrointestinal origin patients)  
 Levels of NSEe 
Treatment visits 
without tumor 
assessment 
 Bicarbonate, chloride, potassium, sodium, BUN 
or urea, creatinine, glucose, magnesium, 
phosphorus, calcium, albumin, total protein, 
alkaline phosphatase, ALT, AST, conjugated 
(direct) bilirubin, total bilirubin 
Treatment visits with 
tumor assessment 
 
 Bicarbonate, chloride, potassium, sodium, BUN 
or urea, creatinine, glucose, magnesium, 
phosphorus, calcium, albumin, total protein, 
alkaline phosphatase, ALT, AST, conjugated 
(direct) bilirubin, total bilirubin 
 TSH 
 Chromagranin A (pancreatic origin patients) 
 Chromagranin A +5 HIAA (only for 
gastrointestinal origin patients) 
 Levels of NSEe 
Urine analysis c 
glucose, hemoglobin (or blood), ketones, pH, 
protein specific gravityd 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = 
beta human chronionic gonadotropin; BUN = Blood urea nitrogen; 
CPK=creatine phosphokinase; INR=International Normalized Ratio; LDH= lactate 
deshidrogenase; MCH=mean corpuscular hemoglobin; MCHC= mean corpuscular 
hemoglobin concentration; MCV=mean corpuscular volume; NSE = neuron-
specific enolase; RBC=red blood cells; T4=thyroxine; TSH=thyroid stimulating 
hormone; WBC=White blood cells 
a) INR should only be performed as part of the screening (baseline) 
assessment and when clinically indicated. 
b) Pregnancy test should be performed during 72 hours prior to the study 
drug administration. 
c) If urinanalysis suggests a urinary tract infection, or if clinically indicated, a 
urine microscopy, culture and sensitivity should be performed at the 


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institution laboratory. 
d) If the urine protein is ≥2+ on urinalysis, then a 24-hour urine collection 
should be done to quantify the 24-hour urine protein excretion. 
e) Levels of NSE will be obtained based on local availability to perform the 
test at each site. 
 
For laboratory abnormalities meeting criteria as SAEs (Section 15.3), the study site must send the 
SAE report including the laboratory report to the SAE fax number or email address provided in the 
Investigator File.  
13.6 Vital signs and weight measurements 
Vital sign measurements (systolic blood pressure, diastolic blood pressure, heart rate [HR], 
respiratory rate [RR], body temperature [°C]), and weight will be obtained at the visits designated in 
the schedule of visits and procedures (Table 4). Height will be measured at the screening visit only. 
Blood pressure, HR, and RR will be obtained after subjects have been resting for 5 minutes. For 
subjects with an elevated BP (≥ 140/90 mmHg), confirmation should be obtained by performing 3 
measurements (at least 5 minutes apart) to yield a mean value. Systolic BP ≥ 140 mmHg or 
diastolic BP ≥ 90 mmHg should be confirmed by repeat measurements after an hour.  
13.7 Electrocardiograms  
Electrocardiograms will be complete, standardized, 12-lead recordings that permit all 12 leads to 
be displayed on a single page with an accompanying lead II rhythm strip below the customary 3 x 4 
lead format. In addition to a rhythm strip, a minimum of 3 full complexes should be recorded from 
each lead simultaneously. Subjects should be in the recumbent position for a period of 5 minutes 
prior to the ECG. An ECG abnormality may meet the criteria as an AE as described in this protocol 
(Section 15) and the CRF instructions. In case of basal ECG abnormality but does not involve any 
risk to the patient by the judgment of the investigator, the patient may be included in the study and 
need not be repeated ECG otherwise indicated by the investigator. 
In these instances, the AE corresponding to the ECG abnormality will be recorded on the Adverse 
Events CRF. For ECG abnormalities meeting criteria as SAEs (Section 14.3), the study site must 
fax the SAE report including the ECG report to the number indicated in the Investigator File using 
the SAE reporting form.  
13.8 Echocardiograms 
An echocardiogram to assess left ventricular ejection fraction (LVEF) will be performed during the 
screening phase and every 6 months following the first dose of study drug while the subject is on 
treatment or sooner, if clinically indicated. Echocardiograms should be performed following the 
local protocol to assess LVEF. LVEFs as assessed by the institution will be entered onto the 
eCRF. Investigator assessment will be based upon institutional reports.  


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14. Adverse events 
An adverse event is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product. An AE does not necessarily have a causal relationship 
with the study drug. For this study, the study drug is lenvatinib. The criteria for identifying adverse 
events are:  
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  
 
Any new disease or exacerbation of an existing disease.  
 
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (e.g., ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation from study drug.  
 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline.  
Reporting Laboratory abnormalities 
An abnormal laboratory test result may be considered as an adverse event if the identified 
laboratory abnormality leads to any type of intervention whether prescribed in the protocol or not.  
A laboratory result should be considered by the investigator to be an adverse event if it: 
 
Results in the withdrawal of study treatment.  
 
Results in withholding of study treatment pending some investigational outcome.  
 
Upon medical evaluation, results in the initiation of an intervention (e.g., potassium 
supplement for hypokalemia).  
 
Is an out-of-range laboratory value that, in the investigator’s judgment, fulfills the definition 
of an AE with regard to the subject’s medical profile. 
 
 Increases in severity compared to baseline by ≥ 2 CTCAE grades (see Appendix IV for 
CTCAE v4.03), with the exception of lymphocytes, albumin, cholesterol, glucose, and 
phosphate. For these tests, a change of ≥ 2 grades will be evaluated by the investigator to 
determine if they are of clinical significance and, if so, will be considered an adverse event.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE. Any laboratory abnormality considered to 
constitute an adverse event should be reported on the Adverse Event CRF.  
It is the responsibility of the investigator to review all laboratory findings in all subjects and 
determine if they constitute an AE. Medical and scientific judgment should be exercised in deciding 
whether an isolated laboratory abnormality should be classified as an adverse event.  


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Regarding the Laboratory abnormalities only should be notified as SAE those abnormalities that 
meet Grade 3 or above following the CTCAE criteria (v.4.03), taking into account the following 
situations: 
 
Laboratory abnormality is within normal limits at baseline and has increased in severity to meet 
CTCAE (v4.03) criteria of Grade 3 or above and it is considered by the investigator to meet 
serious criteria should be reported as SAE. i.e. laboratory abnormality is within normal limits at 
baseline and has increased in severity to meet CTCAE (v4.03) criteria of Grade 3 or above 
and it is not considered by the investigator to meet serious criteria should not be reported as 
SAE. 
 
Laboratory abnormality is outside normal limits at baseline and increases in severity to CTCAE 
(v4.03) Grade 4 or above. These abnormalities are automatically considered to be serious and 
should be reported as SAE. 
 
Significant laboratory abnormalities should not be listed as separate AEs or SAEs if they are 
considered to be part of the clinical syndrome that is being reported as an AE or SAE. 
An abnormal ECG result, if not otherwise considered part of a clinical symptom that is being 
reported as an AE, should be considered an AE if either there is worsening by ≥ 2 CTCAE v4.03 
grade levels from baseline or a QTc increase of ≥60 msec from baseline. Any ECG abnormality 
that the investigator considers to be an adverse event should be reported as such. In case of basal 
ECG abnormality but does not involve any risk to the patient by the judgment of the investigator, 
the patient may be included in the study and need not be repeated ECG otherwise indicated by the 
investigator. 
Adverse events in clinical investigation subjects include any change in the subject’s condition. This 
includes symptoms, physical findings, or clinical syndromes. All AEs encountered during the 
clinical study will be reported on the CRF. All AEs, regardless of relationship to study drug or 
procedure, should be collected beginning from the time the subject signs the study consent 
through the last visit and for 28 days following study drug discontinuation. 
Progression of malignant disease should not be recorded as an adverse event in studies where it 
is included as an endpoint for underlying disease. If the progression leads to an untoward medical 
occurrence (increased pain, pleural effusion, etc.), then this medical occurrence should be the 
adverse event.  
All AEs must be followed until resolution or for 28 days after the subject’s last study visit, whichever 
comes first.  
Every effort must be made by the investigator to categorize each AE according to its severity and 
its relationship to the study treatment. 


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14.1 Assessing severity of adverse events 
AEs will be graded on a 5-point scale according to CTCAE v4.03 (Appendix IV) as follows:  
 
Grade 1 = Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
 
Grade 2 = Moderate: minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL).  
 
Grade 3 = Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.  
 
Grade 4 = Life-threatening consequences: urgent intervention indicated.  
 
Grade 5 = Death related to AE.  
Investigators will collect all CTCAE grades (Appendix IV) for AEs (for both increasing and 
decreasing severity). All adverse events reported using CTCAE classification and graded as 4 or 5 
are to be considered serious. The criteria for assessing severity are different from those used for 
seriousness (see Serious Adverse Events and Other Events of Interest). 
14.2 Assessing relationship to study treatment  
Items to be considered when assessing the relationship of an AE to the study treatment are:  
 
Temporal relationship of the onset of the event to the initiation of the study treatment.  
 
The course of the event, considering especially the effect of discontinuation of study 
treatment or reintroduction of study treatment, as applicable.  
 
Whether the event is known to be associated with the study treatment or with other similar 
treatments.  
 
The presence of risk factors in the study subject known to increase the occurrence of the 
event.  
 
The presence of non-study treatment-related factors which are known to be associated with 
the occurrence of the event.  
Classification of causality 
 
Not Related: A causal relationship between the study treatment and the AE is not a 
reasonable possibility.  
 
Related: A causal relationship between the study treatment and the AE is a reasonable 
possibility. The investigator must further qualify the degree of certainty as “possible” or 
“probable.” 
14.3 Serious adverse events and other events of interest 
A serious adverse event is any untoward medical occurrence that at any dose:  


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 
Results in death;  
 
Is life-threatening (i.e., the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death);  
 
Requires inpatient hospitalization or prolongation of existing hospitalization;  
 
Results in persistent or significant disability/incapacity; or  
 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the study 
drug). 
 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization, but when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered serious adverse events. Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in 
such situations.  
In addition to the above, other events of interest which include pregnancy and overdose. All events 
of these types are to be reported on the eCRF whether or not they meet the criteria for an SAE. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization:  
 
Hospitalizations for respite care;  
 
Planned hospitalizations required by the protocol;  
 
Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration);  
 
Hospitalization for administration of study drug or insertion of access for administration of 
study drug.  
14.4 Reporting Laboratory abnormalities 
An abnormal laboratory test result may be considered as an adverse event if the identified 
laboratory abnormality leads to any type of intervention whether prescribed in the protocol or not.  
A laboratory result should be considered by the investigator to be an adverse event if it: 
 
Results in the withdrawal of study treatment.  
 
Results in withholding of study treatment pending some investigational outcome.  
 
Upon medical evaluation, results in the initiation of an intervention (e.g., potassium 
supplement for hypokalemia).  
 
Is an out-of-range laboratory value that, in the investigator’s judgment, fulfills the definition 
of an AE with regard to the subject’s medical profile. 


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 
 Increases in severity compared to baseline by ≥ 2 CTCAE grades (see Appendix IV for 
CTCAE v4.03), with the exception of lymphocytes, albumin, cholesterol, glucose, and 
phosphate. For these tests, a change of ≥ 2 grades will be evaluated by the investigator to 
determine if they are of clinical significance and, if so, will be considered an adverse event.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE. Any laboratory abnormality considered to 
constitute an adverse event should be reported on the Adverse Event CRF.  
It is the responsibility of the investigator to review all laboratory findings in all subjects and 
determine if they constitute an AE. Medical and scientific judgment should be exercised in deciding 
whether an isolated laboratory abnormality should be classified as an adverse event.  
14.4.1 Laboratory abnormality to be considered as SAE 
Regarding the Laboratory abnormalities only should be notified as SAE those abnormalities that 
meet Grade 3 or above following the CTCAE criteria (v.4.03), taking into account the following 
situations: 
 
Laboratory abnormality is within normal limits at baseline and has increased in severity to meet 
CTCAE (v4.03) criteria of Grade 3 or above and it is considered by the investigator to meet 
serious criteria should be reported as SAE. i.e. laboratory abnormality is within normal limits at 
baseline and has increased in severity to meet CTCAE (v4.03) criteria of Grade 3 or above 
and it is not considered by the investigator to meet serious criteria should not be reported as 
SAE. 
 
Laboratory abnormality is outside normal limits at baseline and increases in severity to CTCAE 
(v4.03) Grade 4 or above. These abnormalities are automatically considered to be serious and 
should be reported as SAE. 
Significant laboratory abnormalities should not be listed as separate AEs or SAEs if they are 
considered to be part of the clinical syndrome that is being reported as an AE or SAE. 
14.5 Reporting of SAEs, Pregnancy, and Other Events of Interest  
14.5.1 Reporting of SAEs  
All serious adverse events (SAEs), irrespective of relationship to study treatment, must be reported 
on a completed SAE form by email (farmacovigilancia@experior.es) or fax (0034 96 145 21 91) as 
soon as possible within 24 hours since awareness of the SAE. Serious adverse events, 
regardless of causality assessment, must be collected from the signature of the ICF by the patient 
through the termination visit and for 28 days following study drug discontinuation, whichever is 
longer. All SAEs must be followed to resolution, or if resolution is unlikely, to stabilization. Any SAE 
judged by the investigator to be related to the study treatment should be reported to the sponsor 


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regardless of the length of time that has passed since study completion. Deaths and life-
threatening events should be reported immediately by telephone. The immediate report should be 
followed-up within 24 hours since awareness of such information by emailing or faxing the 
completed SAE form. The detailed contact information for reporting of SAEs is provided in the 
Investigator File. 
For urgent safety issues, please ensure all appropriate medical care is administered to the subject 
and contact the appropriate study team member listed in the Investigator File. It is very important 
that the SAE report form be filled out as completely as possible at the time of the initial report. This 
includes the investigator’s assessment of causality. 
Any follow-up information received on SAEs should be forwarded within 24 hours of its receipt. If 
the follow-up information changes the investigator’s assessment of causality, this should also be 
noted on the follow-up SAE form.  
The investigator should notify his/her EC of the occurrence of the SAE, in writing, in accordance 
with local requirements. A copy of this communication must be forwarded to the CRO monitor and 
filed in the Trial Master File.  
14.5.2  Reporting of Pregnancy  
Any pregnancy where the estimated date of conception occurs either prior to the study termination 
visit or within 28 days of the last study treatment must be reported. If an adverse outcome of a 
pregnancy is suspected to be related to study drug exposure, this should be reported regardless of 
the length of time that has passed since the exposure to study treatment.  
An induced abortion or a spontaneous abortion is considered to be an SAE and should be reported 
in the same timeframe and in the same format as all other SAEs. Pregnancies must be reported 
within 24 hours since awareness of it by fax (0034 96 145 21 91) or email 
(farmacovigilancia@experior.es). The contact information for the reporting of pregnancies is 
provided in the Investigator File. The Pregnancy Report Form must be used for reporting. All 
pregnancies must be followed to outcome. The outcome of the pregnancy must be reported within 
24 hours since awareness of it.  
A subject who becomes pregnant must be withdrawn from the study.  
14.5.3 Reporting of Overdose 
Study drug overdose is the accidental or intentional use of the drug in the amount higher than 
the dose being studied. Any study drug overdose during the study should be noted on the study 
medication CRF. 
All AEs associated with an overdose should both be entered on the Adverse Event CRF and 
reported using the procedures detailed in Reporting of SAEs even if the events do not meet 
serious criteria. If the AE associated with an overdose does not meet serious criteria, it must still be 


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reported using the SAE form and in an expedited manner but should be noted as non-serious on 
the SAE form and the Adverse Event CRF. 
14.6 Expedited reporting 
The sponsor must inform investigators (or, as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable regulatory 
requirements, on an expedited basis (i.e., within specific timeframes). For this reason, it is 
imperative that investigational sites provide complete SAE information in the manner described 
above. 
14.7 Regulatory reporting of adverse events  
Adverse events will be reported to regulatory authorities in compliance with local and regional law 
and established guidance by the sponsor, or a third party acting on behalf of the sponsor. The 
format of these reports will be dictated by the local and regional requirements and will comply with 
the European Clinical Trial Directive 2005/28/EC. All suspected unexpected serious adverse 
reactions (SUSARs) will be reported as required to the Competent Authorities of all involved 
European member states. 
14.8 Treatment Emergent Adverse Event 
 TEAE is defined as any event not present prior to the initiation of the study drug or any event 
already present that worsens in either intensity or frequency following exposure to the study drug. 
TEAE provides more relevant and useful information than a general AE to the investigators. 
Therefore, most AE tables in statistical reports should be based on TEAE. In this sense, any 
unfavorable and unintended sign prior to dosing 3 but not worsening during the treatment will be 
automatically excluded from the analysis. The programming practice to code a TEAE is comparing 
AEs onset date/time and first study drug administration date/time. If the AE has the same intensity 
before and after the first drug administration, then it is not counted as TEAE. Note that a TEAE is 
not necessarily a drug related AE. 
14.8.1 Management of hypertension 
Hypertension is a recognized side-effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that subjects enrolled to receive treatment with lenvatinib 
have BP < 150/90 mmHg at the time of study entry and, if known to be hypertensive, are on 
antihypertensive therapy before they start treatment with lenvatinib. The early detection and 
effective management of hypertension are important to minimize the need for lenvatinib dose 
interruptions and reductions. Antihypertensive agents should be started as soon as the BP is 
confirmed to be ≥ 140/90 mmHg on 3 measurements performed every 5 minutes after the first 
measurement, and a last measurement performed in an hour. The choice of antihypertensive 


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treatment should be individualized to the subject’s clinical circumstances and follow standard 
medical practice. For previously normotensive subjects, monotherapy with one of the classes of 
anti-hypertensives should be started when BP ≥ 140/90 mmHg is first observed. For those subjects 
already on antihypertensive medication, the dose of the current agent may be increased, if 
appropriate, or one or more agents of a different class of antihypertensive should be added. For 
subjects with hypertension and proteinuria, treatment with an angiotensin-converting enzyme 
inhibitor or angiotensin-II receptor antagonist is preferred. 
Study drug should be withheld in any instances where a subject is at imminent risk to develop a 
hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (e.g., BP ≥ 160/100 mmHg, significant risk factors for cardiac disease, intracerebral 
hemorrhage, or other significant co-morbidities). Once the blood pressure is controlled, study drug 
should be resumed as described below.  
The following guidelines should be followed for the management of systolic BP ≥ 140 mmHg to 
<160 mmgHg or diastolic BP ≥ 90 mmHg to 100mmgHg confirmed on repeat measurements after 
an hour: 
 
Continue study drug and institute antihypertensive therapy for subjects not already 
receiving this.  
 
For those subjects already on antihypertensive medication, the dose of the current agent 
may be increased, if appropriate, or one or more agents of a different class of 
antihypertensive should be added.  
 
 If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg persists despite maximal 
antihypertensive therapy, then study drug administration should be interrupted and 
restarted at a dose of 20 mg once daily when BP ≤ 150/95 mmHg and the patient has 
received a stable dose of antihypertensive drugs within at least 48 hours. (Refer to Table 3 
for instruction regarding duration of the interruption of drug administration and decision of 
reintroduction) 
o If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg recurs on the 20-mg once 
daily dose despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then study drug administration should be interrupted and 
restarted at a dose of 14 mg once daily when BP ≤ 150/95 mmHg.  
o If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg recurs on the 14-mg once 
daily dose despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then study drug administration should be interrupted and 
restarted at a dose of 10 mg once daily when BP ≤ 150/95 mmHg.  


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o Additional dose reduction should be discussed with the sponsor.  
The following guidelines should be followed for the management of Grade 4 hypertension (life-
threatening consequences):  
 
Institute appropriate medical management.  
 
Discontinue of study drug 
A summary table of treatment for hypertension is shown below. 
Table 6.- Treatment for hypertension 
Level of blood pressure (BP) 
Recommended action 
Systolic BP ≥140mmHg to <160 mmHg or 
Diastolic BP ≥90 mmHg to <100 mmHg 
Continue with treatment with lenvatinib and 
start antihypertensive treatment, if it has not 
been administered yet 
OR 
Continue with treatment with lenvatinib and 
increase the dose of current antihypertensive 
drug or start and additional antihypertensive 
treatment 
Systolic BP ≥160 mmHg or 
Diastolic BP ≥100 mmHg 
despite the administration of a treatment 
optimal antihypertensive 
1. Discontinue the administration of 
lenvatinib 
2. If systolic BP is ≤150 mmHg, diastolic BP is 
≤95 mmHg and the patient has received a 
stable dose of antihypertensive medication 
during at least 48 hours, resume the 
administration of lenvatinib to a reduced dose. 
Life-threatening consequences (malignant 
hypertension, neurological damage or 
hypertensive crisis) 
An immediate action is required. Discontinue 
treatment with lenvatinib and start appropriate 
medical treatment  
 
14.8.2 Management of Proteinuria 
Regular assessment for proteinuria should be conducted as detailed in the schedule of visits and 
procedures (table 4). Guidelines for assessment and management of proteinuria are summarized 
as follows:  
 
Initial episode of proteinuria: if proteinuria ≥ 2+ is detected on urinalysis, study drug will be 
continued and a 24-hour urine collection for total protein will be obtained as soon as 
possible within 72 hours to verify the grade of proteinuria. Grading according to the National 
Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE v4.03, 
Appendix IV) will be based on the 24-hour urinary protein result. Management of study drug 


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administration will be based on the grade of proteinuria according to the dose reduction and 
interruption instructions provided in Table 3.  
 
Urinalysis should be performed every 4 weeks subsequent to cycle 2 during the treatment 
phase and any increases in the level of proteinuria on urinalysis up to 3+ needs to be 
confirmed with a 24-hour urinary protein test which will be assessed and graded according 
to the dose reduction and interruption instructions provided in Table 3.  
15. Data quality assurance  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating practices (SOPs), working practice documents, and applicable regulations and 
guidelines. Site visit audits will be made periodically by the sponsor’s or CRO’s qualified 
compliance auditing team, which is an independent function from the study conduct team.  
15.1 Data Collection  
Data required by the protocol are collected on an electronic Case Report Form (eCRF) and 
entered into a validated data management system which is compliant to all regulatory 
requirements. As defined by ICH Guidelines, ‘the Case Report Form (CRF) is a printed, optical, or 
electronic document designed to record all of the protocol required information to be reported to 
the sponsor on each trial subject’. In this study, CRF should refer to electronic data collection form. 
Data collected on the CRF must follow the instructions described in the CRF Completion 
Guidelines. The Investigator has ultimate responsibility for the collection and reporting of all 
clinical, safety and laboratory data entered on the CRF. 
The primary objective of the study will be ORR by central radiology review. Images of tumor 
assessments will be anonymized correctly identified with trial number patient (code dissociated) 
and send to Vall d’Hebron University Hospital for revision by an independent experienced 
radiologist. 
15.2 Clinical Data Management 
All software applications used in the collection and validation of data must be properly validated 
following standard computer system validation and must be compliant to all regulatory 
requirements.  
The Data Management Plan (DMP) defines and documents the procedures necessary to ensure 
data quality. These activities must be followed to ensure data are properly entered, validated, 
coded, integrated, reconciled and reviewed.  
Data cut-off for the study primary analysis will take place after the last patient enrolled in the study 
has performed the second tumor assessment (week 12 after the first dose of study drug) given that 
the first assessment will be performed 6 weeks after the first dose). Subsequent tumor 


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assessments will be performed starting on week 12 every 12 weeks until documentation of disease 
progression or start of another anticancer therapy. 
15.3 Database Quality Assurance  
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures. Data queries requiring 
clarification will be generated and addressed by the investigational site. Only authorized personnel 
will make corrections to the clinical database, and all corrections will be documented in an audit 
trail.  
16. Ethical aspects 
16.1 Ethics Committee 
The protocol, ICF, and appropriate related documents must be reviewed and approved by an EC 
constituted and functioning in accordance with ICH E6, Section 3, and any local regulations. Any 
protocol amendment and/or revision to the ICF will be resubmitted to the EC for review and 
approval, except for changes involving only logistical or administrative aspects of the study (e.g., 
change in CRA[s] or change of telephone number[s]). Documentation of EC compliance with ICH 
and any local regulations regarding constitution and review conduct will be provided to the 
sponsor.  
A signed letter of study approval from the EC Chairman must be sent to the Principal Investigator 
(if regionally required, the heads of the medical institutions) with a copy to the sponsor prior to 
study start and the release of any study drug to the site by the sponsor or its designee (ICH E6, 
Section 4.4). If the EC decides to suspend or terminate the study, the investigator (if regionally 
required, the heads of the medical institutions) will immediately send the notice of study 
suspension or termination by the EC to the sponsor. Study progress is to be reported to the EC 
annually (or as required) by the investigator or sponsor, depending on local regulatory obligations. 
If the investigator is required to report to the EC, he/she will forward a copy to the sponsor at the 
time of each periodic report. The investigator(s) or sponsor will submit, depending on local 
regulations, periodic reports and inform the EC (if regionally required, the heads of the medical 
institutions) of any reportable adverse events per ICH guidelines and local EC standards of 
practice. Upon completion of the study, the investigator will provide the EC with a brief report of the 
outcome of the study, if required. 
16.2 Ethical Conduct of the Study  
This study will be conducted in accordance with the standard operating practices of the sponsor (or 
designee), which are designed to ensure adherence to GCP guidelines as required by the 
following: 


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• 
In accordance to the principle of World Medical Association Declaration of Helsinki, 2013;  
• 
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation 
of Medicinal Products, Committee for Proprietary Medicinal Products, International 
Conference on Harmonization of Pharmaceuticals for Human Use;  
• 
European Clinical Trial Directive 2005/28/EC, for studies conducted within any EU country. 
All SUSARs will be reported, as required, to the Competent Authorities of all involved EU 
member states; 
• 
And other applicable regulatory authorities.  
16.3 Subject information and Consent 
As part of administering the informed consent document, the investigator must explain to each 
subject (or guardian/legally authorized representative) the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved, and any 
potential discomfort. Each subject must be informed that participation in the study is voluntary and 
that he/she may withdraw from the study at any time and that withdrawal of consent will not affect 
his/her subsequent medical treatment or relationship with the treating physician. This informed 
consent should be given by means of a standard written statement, written in non-technical 
language. The subject should understand the statement before signing and dating it and will be 
given a copy of the signed document. If a subject is unable to read or if a legally acceptable 
representative is unable to read, an impartial witness should be present during the entire informed 
consent discussion. After the written informed consent form and any other written information to be 
provided to subjects is read and explained to the subject or the subject’s legally acceptable 
representative, and after the subject or the subject’s legally acceptable representative has orally 
consented to the subject’s participation in the trial and, if capable of doing so, has signed and 
personally dated the ICF, the witness should sign and personally date the consent form. The 
subject will be asked to sign an informed consent at the Screening Visit prior to any study-specific 
procedures being performed. No subject can enter the study before his/her informed consent has 
been obtained. An unsigned copy of an EC and sponsor-approved written informed consent must 
be prepared in accordance with ICH E 6, Section 4, and all applicable local regulations and 
provided to the sponsor. Each subject must sign an approved informed consent prior to study 
participation. The form must be signed and dated by the appropriate parties. The original, signed 
ICF for each subject will be verified by the sponsor and kept on file, according to local procedure, 
at the study center. 
The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the trial. The communication of this information should be documented. 


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17. Administrative procedures 
17.1 Changes to the Protocol  
There are to be no changes to the protocol without written approval from the sponsor. Protocols 
will be followed as written. Any change to the protocol requires a written protocol amendment or 
administrative change that must be approved by the sponsor before implementation. Amendments 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the study 
require submission to health or regulatory authorities as well as additional approval by the 
applicable EC of all investigational sites and, in some countries, by the regulatory authority. These 
requirements should in no way prevent any immediate action from being taken by the investigator, 
or by the sponsor, in the interest of preserving the safety of all subjects included in the study. If an 
immediate change to the protocol is felt by the investigator to be necessary for safety reasons, the 
sponsor’s appropriate study team member must be notified promptly and the EC for the site must 
be informed immediately. A protocol change intended to eliminate an immediate hazard may be 
implemented immediately, provided that the Regulatory Authorities are subsequently notified by 
protocol amendment.  
Changes affecting only administrative aspects of the study do not require formal protocol 
amendments or EC approval, but the EC (if regionally required, the heads of the medical 
institutions) must be kept informed of such changes. In these cases, the sponsor will send a letter 
to the EC (if regionally required, the heads of the medical institutions) detailing such changes. 
17.2 Adherence to the Protocol  
The investigator will conduct the study in strict accordance with the protocol (refer to ICH E6, 
Section 4.5).  
17.3 Monitoring Procedures  
The sponsor’s or CRO’s CRA will maintain contact with the investigator and designated staff by 
telephone, and/or letter, and/or email between study visits. Monitoring visits to each investigational 
site will be conducted by the assigned CRA as described in the monitoring plan. The investigator (if 
regionally required, the heads of the medical institutions) will allow the CRA to inspect the clinical, 
laboratory, and pharmacy facilities to assure compliance with Good Clinical Practices and local 
regulatory requirements. The eCRFs and subject’s corresponding original medical records (source 
documents) are to be fully available for review by the sponsor’s representatives at regular intervals. 
These reviews verify adherence to the study protocol and data accuracy in accordance with federal 
regulations. All records at the investigational site are subject to inspection by the local regulatory 
agency.  
In accordance with ICH E6, Section 6.10, source documents include but are not limited to the 
following: 


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• 
Clinic, office, hospital charts;  
• 
Copies or transcribed healthcare provider notes which have been certified for accuracy 
after production;  
• 
Recorded data from automated instruments such as x-rays, and other imaging reports: e.g., 
sonograms, 
CT scans, MRIs, 
nuclear medicine 
scans, ECGs, 
rhythm strips, 
electroencephalograms 
(EEGs), 
polysomnographs, 
and 
pulmonary 
function 
tests 
(regardless of how these images are stored, including microfiche and photographic 
negatives); 
• 
Records of telephone contacts;  
• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel;  
• 
Laboratory results and other laboratory test outputs: e.g., urine pregnancy test result 
documentation;  
• 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the EC;  
17.4 Recording of Data  
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel. All data on the eCRF must reflect the corresponding source document. Any corrections 
to entries made on the CRF must be documented in a valid audit trail where the corrections must 
be dated, initialed, the reason for change stated, and original data not obscured. Only data 
required by the protocol for the purposes of the study should be collected.  
17.5 Retention of Records  
The circumstances of completion or termination of the study notwithstanding, the investigator (if 
regionally required, the heads of the medical institutions) has the responsibility to retain all study 
documents, including but not limited to the protocol, the Investigator's Brochure, regulatory agency 
registration documents, ICFs, and EC correspondence. The investigational site should plan to 
retain study documents until at least 2 years after the last approval of a marketing application in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH region 
or at least until 3 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  
It is requested that at the completion of the required retention period or, should the investigator 
retire or relocate, the investigator contact the sponsor, allowing the sponsor the option of 
permanently retaining the study records. 


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17.6 Auditing Procedures and Inspection  
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance department 
conducts audits of clinical research activities in accordance with the sponsor’s Standard Operating 
Procedures (SOPs) to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations. A government regulatory authority may also wish to conduct an inspection (during the 
study or after its completion). If an inspection is requested by a regulatory authority, the 
investigator must inform the sponsor immediately that this request has been made.  
17.7 Handling of Study Drug  
All study drugs will be supplied to the Principal Investigator (or a designated pharmacist) by the 
sponsor. Drug supplies must be kept in an appropriate secure area (e.g., locked cabinet) and 
stored according to the conditions specified on the drug label. The investigator (a designated 
pharmacist) must maintain an accurate record of the shipment and dispensing of the study drug in 
a drug accountability ledger, a copy of which must be given to the sponsor at the end of the study. 
An accurate record of the date and amount of study drug dispensed to each subject must be 
available for inspection at any time. Once study drug has been received by the investigational site, 
the assigned CRA will review these documents along with all other study conduct documents at 
appropriate intervals during investigational site visits.  
All drug supplies are to be used only for this protocol and not for any other purpose. The 
investigator (a designated pharmacist) must not destroy any drug labels or any partly used or 
unused drug supply prior to approval to do so by the sponsor. At the conclusion of the study and as 
appropriate during the course of the study, the investigator (a designated pharmacist) will either 
return all used and unused drug containers, drug labels, and a copy of the completed drug 
disposition form to the sponsor’s designated contractor or, where approval is given by the sponsor, 
will destroy supplies and containers at the investigational site.  
17.8 Publication of Results  
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the sponsor in advance of submission. The review is 
aimed at protecting the sponsor’s proprietary information existing either at the date of the 
commencement of the study or generated during the study. The detailed obligations regarding the 
publication of any data, material results or other information, generated or created in relation to the 
study shall be set out in the agreement between each investigator and the CRO or the sponsor, as 
appropriate. 


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17.9 Disclosure and Confidentiality  
The contents of this protocol and any amendments and results obtained during the course of this 
study will be kept confidential by the investigator, the investigator’s staff, and the EC and will not be 
disclosed in whole or in part to others or used for any purpose other than reviewing or performing 
the study without the written consent of the sponsor. No data collected as part of this study will be 
utilized in any written work, including publications, without the written consent of the sponsor. 
These obligations of confidentiality and non-use shall in no way diminish such obligations as set 
forth in the Confidentiality Agreement between the sponsor and the investigator.  
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the Confidentiality Agreement between the investigator and 
sponsor (provided by the sponsor). 
17.10 Subject Insurance and Indemnity  
The sponsor will provide the insurance in accordance with local guidelines and requirements as a 
minimum for the subjects participating in this study. 
18. Completion/Discontinuation of Subjects 
18.1 Removal of Subjects from Therapy or Assessment  
The sponsor reserves the right to discontinue the study for medical reasons or for any other reason 
at any time. If the study is prematurely terminated or suspended, the sponsor will promptly inform 
the investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension. The IEC should also be informed promptly and 
provided with the reason(s) for the termination or suspension by the sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s).  
The investigator may discontinue treating a subject with the study drug or withdraw the subject 
from the study at any time for safety or administrative reasons. The subject may decide to 
discontinue study drug or withdraw from the study at any time for any reason. The reason for 
discontinuation will be documented. If a subject discontinues study treatment, the subject will enter 
the follow-up period and be required to complete protocol-specified end of treatment visits, 
procedures, and survival follow-up unless the subject withdraws consent. The investigator should 
confirm whether a subject is withdrawing from study treatment but agreeing to continue protocol-
specified, end of treatment study visits, procedures, and survival follow-up, or whether the subject 
is withdrawing consent. If a subject withdraws consent, the date will be documented in the source 
documents.  
Subjects who have discontinued study treatment without progression should have disease 
assessments every 12 weeks from the date of the last assessment until disease progression is 
documented or another anti-cancer therapy is initiated.  


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All subjects will be followed for survival and all post disease progression cancer treatments 
administered will be recorded until death, except where a subject withdraws consent or the 
sponsor chooses to halt survival follow-up following completion of the primary study analysis. 
18.2 Completion/Discontinuation of Subjects  
A subject may elect to discontinue study drug at any time for safety, medical, or personal reasons. 
Patients who choose to discontinue study drug prior to disease progression will be followed in the 
post study treatment follow up period and continue to undergo regularly scheduled disease 
assessment until documentation of disease progression or start of an alternative anticancer 
therapy. All subjects who discontinue study drug will be followed for overall survival and all post 
progression cancer treatments administered will be recorded. Subjects may at any time withdraw 
consent for further study participation. No further data will be collected on subjects once consent 
has been withdrawn. All subjects who discontinue study drug are to complete the study 
discontinuation procedures indicated in the Schedule of Visits and Procedures (Table 4). The 
investigator will promptly explain to the subject involved that the study drug will be discontinued for 
that subject and provide appropriate medical treatment and other necessary measures for the 
subject. A subject who has ceased to return for visits will be followed up by mail, phone, or other 
means as much as possible to gather information such as the reason for failure to return and the 
status of treatment compliance, presence or absence of adverse events, and clinical courses of 
signs and symptoms, and the information will be recorded in the CRF. 
Subjects who discontinue early from the study or treatment will be discontinued for 1 of these 
primary reasons: adverse event(s), lost to follow-up, subject choice, progressive disease, or 
administrative/other. In addition to the primary reason, the subject may have indicated 1 or more of 
these reasons as secondary reasons for discontinuation. Study disposition information will be 
collected on the appropriate CRF. A subject removed from the study for any reason may not be 
replaced. 
19. Confirmation of Medical Care by Another Physician 
The investigator will instruct the subject to tell beforehand when the subject is going to receive 
medical care by another physician. At each visit, the investigator will ask the subject whether the 
subject has done so since the last visit or is planning to do so in the future. When the subject is 
going to receive medical care by another physician, the investigator, with the consent of the 
subject, will inform the other physician that the subject is participating in the clinical study. 
 
 


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20. Statistical methods  
Statistical programming and analyses will be performed using R statistical software and/or other 
statistical software.  
20.1 Statistical and Analytical Plans  
The statistical analyses described in this section will be performed as further outlined in the 
Statistical Analysis Plan, which will be included in the clinical study report for this protocol.  
20.2 Analysis Sets  
The analysis sets will be defined as follows:  
• 
Full Analysis Set will include all allocated subjects. This will be primary analysis set for the 
efficacy endpoints.  
• 
Per Protocol Analysis Set will include those subjects who were allocated and received at 
least one dose of the assigned study drug and had no major protocol deviations. The 
subjects will complete both baseline and at least one post-baseline tumor assessments 
(week 6).  
• 
Safety Analysis Set will include all subjects who were allocated and received at least one 
dose of the study drug and had at least one post-baseline safety evaluation (week 6). This 
will be the analysis set for all safety evaluations. 
• 
Pharmacodynamic Analysis Set: All the subjects who have received at least one dose of 
study drug and have evaluable pharmacodynamic data. 
20.3 Demographic and other baseline characteristics  
Demographic and other baseline characteristics will be summarized and listed. For continuous 
demographic/baseline variables including age, weight, and vital signs, results will be summarized 
and presented as n, number of not available data (NA), mean, standard deviation, median, and 
minimum and maximum values. For categorical variables such as race/ethnicity, the number and 
percentage of subjects will be used.  
20.4 Prior and concomitant medications  
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary (WHO DD) drug codes. Concomitant medications will be further coded to the 
appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating therapeutic classification. 
Prior and concomitant medications will be summarized and listed by drug and drug class. 
20.5 Efficacy Analyses  
All efficacy analyses will be based primarily on the Full Analysis Set and secondarily on the Per 
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Data cut-off for the study primary analysis will take place after the last patient enrolled in the study 
has performed the second tumor assessment (week 12 after the first dose of study drug, given that 
first evaluation will be performed 6 weeks after the first dose. Subsequent tumor assessments will 
be performed every 12 weeks until documentation of disease progression or start of another 
anticancer therapy. 
20.5.1 Analysis of primary efficacy variable 
The analysis of ORR will be performed independently for each study cohort when the last patient 
included in the corresponding cohort of the study will have at least two tumor assessments (12 
weeks after the last patient recruited). The primary objective of the study will be based on the 
independent central radiology review. 
20.6 Sample Size and Accrual 
Sample size has been calculated using single stage design. For considering Lenvatinib as an 
effective treatment, a success rate of ORR of at least 25% is expected. However, a success rate of 
10% or less would be considered unacceptable. With 90% power and a 5% level of significance, a 
total of 55 patients for each cohort are required. 
20.7 Data Analyses Plans 
Summary tables (descriptive statistics and/or frequency tables) will be provided for all baseline 
variables, efficacy variables, and safety variables, as appropriate. Continuous variables will be 
summarized with descriptive statistics (n, NA, mean, standard deviation, median and minimum and 
maximum values). Ninety-five (95) percent confidence intervals may also be presented, as 
appropriate. Frequency counts and percentage of subjects within each category will be provided 
for categorical data. 
Missing data will be ignored. 
Secondary endpoints will be summarized with descriptive statistics. Continuous variables will be 
summarized with n, NA, mean, standard deviation, median and range. Frequency counts and 
percentage of subjects within each category will be provided for categorical data. Multivariate 
regression models may be used to study relations between explanatory variables and primary 
endpoint. Survival analysis will be performed to analyze PFS, Kaplan & Meyer curves will be 
presented and possible comparisons will be tested using the log-rank test or the Cox proportional 
hazard model for multivariate analysis.  
Patients with lost of follow-up or treatment discontinuation will be included in the final analysis of 
primary endpoint if they have at least one tumor assessment and considered as censored data for 
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20.8 Safety Analyses  
Safety analyses will be based on the Safety Analysis Set. All safety analyses will be summarized 
separately by cohort. Adverse events and serious adverse events, laboratory test results, physical 
examination findings, vital signs, and echocardiogram results (including LVEF), and their changes 
from baseline will be summarized using descriptive statistics. Abnormal values will be flagged.  
20.9 Extent of exposure  
The number of cycles/days on treatment, quantity of study drug administered, and the number of 
subjects requiring dose reductions, treatment interruption, and treatment discontinuation due to 
adverse events will be summarized.  
20.10 Adverse events  
Adverse events will be graded using CTCAE v4.3. Investigators will collect all adverse event 
CTCAE grades (for both increasing and decreasing severity). Adverse events will be classified into 
standardized medical terminology from the verbatim description (investigator term) using the 
Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will be presented by 
preferred term (PT) nested within system organ class (SOC). Verbatim descriptions and MedDRA 
SOC and PT for all adverse events will be contained in the data listings of the clinical study report 
for this protocol. 
An overview table, including the incidence of and the number of subjects with TEAEs, SAEs, 
deaths, and those TEAEs that led to study drug discontinuation, dose modification, or dose 
interruption will be provided. The incidence of TEAEs will be summarized by SOC, PT, CTCAE 
grade, and relatedness to study drug. All summaries will be performed by cohort. Although a 
MedDRA term may be reported more than once for a subject, that subject will be counted only one 
time in the incidence count for that MedDRA term with the highest CTCAE grade (in the summary 
by CTCAE grade) or with the closest relationship to study treatment (in the summary by 
relatedness to study treatment). TEAEs will be defined as adverse events that emerge during 
treatment, having been absent pretreatment (at baseline) or those that:  
• 
Reemerge during treatment, having been present at baseline but stopped prior to 
treatment, or 
• 
Worsen in severity during treatment relative to the pretreatment state, when the adverse 
event is continuous.  
Separate summary tables will be provided for: all TEAEs, treatment-emergent SAEs, TEAEs 
reported as treatment-related, treatment-emergent SAEs reported as treatment-related, and 
TEAEs leading to treatment discontinuation.  


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20.11 Laboratory values 
Clinical laboratory values will be evaluated for each laboratory parameter by subject. Abnormal 
laboratory values will be identified as those outside (above or below) the normal range. Reference 
(normal) ranges for laboratory parameters will be included in the clinical study report for this 
protocol. Descriptive summary statistics for laboratory parameters and their changes from baseline 
will be calculated. Laboratory parameters that are graded in CTCAE v4.03 will be summarized by 
CTCAE grade. 
20.12 Vital signs 
Vital sign values will be evaluated on an individual basis by subject. Abnormal vital sign values will 
be identified as those outside (above or below) the reference range. Reference ranges for vital sign 
parameters will be included in the clinical study report for this protocol. Descriptive summary 
statistics for vital sign parameters and their changes from baseline will be calculated. 
20.13 ECG results  
ECG results will be evaluated on an individual basis by subject. Abnormal readings will be 
identified as those outside the reference range. ECG findings will be summarized.  
An abnormal ECG result, if not otherwise considered part of a clinical symptom that is being 
reported as an AE, should be considered an AE if either there is worsening by ≥ 2 CTCAE v4.03 
grade levels from baseline or a QTc increase of ≥60 msec from baseline. Any ECG abnormality 
that the investigator considers to be an adverse event should be reported as such. 
20.14 Echocardiograms  
Echocardiograms (including LVEFs) will be assessed. Summary statistics (mean plus/minus 
standard deviation, median, and range) for echocardiograms and their changes from baseline will 
be calculated and summarized for each treatment arm. 
 
 


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21. References 
1. 
Yao JC, Hassan M, Phan A, et al. One Hundred Years After "Carcinoid": 
Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the 
United States. J Clin Oncol 2008;26:3063-72. 
2. 
Fjällskog ML, Lejonklou MH, Oberg KE, Eriksson BK, Janson ET. Expression of 
Molecular Targets for Tyrosine Kinase Receptor Antagonists in Malignant Endocrine 
Pancreatic Tumors. Clinical Cancer Research 2003;9:1469-73. 
3. 
Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets 
multiple kinases, has potent antitumor activities against stem cell factor producing human 
small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008;122:664-
71. 
4. 
Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase 
inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast 
tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 
and VEGF-R3 kinase. Clin Cancer Res 2008;14:5459-65. 
5. 
Yamada K, Yamamoto N, Yamada Y, et al. Phase I dose-escalation study and 
biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res 
2011;17:2528-37. 
6. 
Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in 
Radioiodine refractory thyroid cancer. New England J Ned 23015;372:621-30. 
 
 
 


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Appendix I Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
 
Tumor response assessments in this clinical trial will utilize Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) based on the 2009 article by Eisenhauer et al entitled, New Response 
Evaluation Criteria in Solid Tumors: revised RECIST guideline (version 1.1). The sole modification 
to RECIST 1.1 to be implemented in this trial is that chest x-rays may not be used to follow 
disease; only CT scans may be used to follow chest disease. As required by RECIST 1.1, the 
protocol states that the minimum duration of stable disease is 7 weeks following the date of first 
dose of study drug. The Eisenhauer article, published in the European Journal of Cancer, is 
available online at: http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733. 
 
 


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Appendix II: Eastern Cooperative Oncology Group Performance Status  
 
 
 
 


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Appendix III Cockcroft and Gault Formula 
 
 
 


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Appendix IV: Common Terminology Criteria for Adverse Events (CTCAE 
v4.03) 
 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE v4.03 
published 14 June 2010) provides descriptive terminology to be used for adverse event reporting in 
clinical trials. A brief definition is provided to clarify the meaning of each AE term. To increase the 
accuracy of AE reporting, all adverse event terms in CTCAE version 4.03 have been correlated 
with single-concept, Medical Dictionary for Regulatory Activities (MedDRA®) terms.  
CTCAE v4.03 grading refers to the severity of the AE. CTCAE grades 1 through 5, with unique 
clinical descriptions of severity for each AE, are based on this general guideline: 
 
 
 


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Appendix V Drug-Drug Interactions  
Preliminary preclinical studies identify CYP3A4 as an important enzyme responsible for human 
hepatic metabolism of E7080. Caution should be exercised when administering drugs metabolized 
by CYP3A4 or drugs that are inductors or inhibitors of CYP3A4 (including herbal supplements, or 
large amounts of grapefruit juice), as administration of such drugs could affect the metabolism of 
E7080 (see table below).  
Table 6 Drugs That Affect the Activity of CYP3A4 
 
 
 


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Appendix VI Pharmacogenomics  
All research performed with the samples during this study is ruled by the provisions of Law 14/2007 
of biomedical research and RD 1716/2011 of November 18 which sets the basic requirements for 
authorization and running of biobanks for purposes of biomedical research y handling of human 
biological samples. 
Subjects enrolled in this clinical study will have samples collected for pharmacogenomic and 
biomarker analysis. The aim of the analysis is to identify genetic factors that may influence a 
subject’s exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential adverse events related to study treatment, and to explore the role of genetic 
variability in response. Samples may be analyzed to determine a subject’s genotypes or sequence 
for a number of genes or non-coding regulatory regions. The research may include the 
investigation of polymorphisms in genes that are likely to influence the study drug 
pharmacokinetics or therapeutic response.  
Collection of the samples for pharmacogenomic analysis will be bound by the sample principles 
and processes outlined in the main study protocol. Sample collection for pharmacogenomic and 
biomarker analysis is required as per the study protocol unless the collection and use of the 
samples is prohibited by specific country laws.  
The patients will sign a specific Informed Consent form for the sample pharmacogenomic 
collection. 
SAMPLE COLLECTION AND HANDLING  
The samples will be collected according to the study flow chart and laboratory manual.  
The sponsor of the study may decide not to conduct any pharmacogenomics analysis of the 
samples collected during the study if its primary efficacy endpoint is not achieved and there are not 
clinically relevant safety issues that raise additional interest. This decision will be notified to all IEC 
and regulatory authorities. 
SECURITY OF THE SAMPLES, USE OF THE SAMPLES, RETENTION OF THE SAMPLES  
Sample processing, including DNA/RNA extraction and genotyping, sequencing or other analysis 
will be performed by a laboratory under the direction of the study sponsor. Processing, analysis, 
and storage will be performed at a secure laboratory facility to protect the validity of the data and 
maintain subject privacy.  
The laboratory in charge of processing, storing and destroying the samples is Laboratory of 
Hospital Vall Hebrón; Paseo de la Vall Hebrón, nº 119-129, 08035 Barcelona. 
Samples will only be used for the purposes described in this protocol by the study sponsor. 
Laboratories contracted to perform the analysis on behalf of the study sponsor will not retain rights 
to the samples beyond those necessary to perform the specified analysis and will not transfer or 
sell those samples. The study sponsor will not sell the samples to a third party and will not 


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transfer them. Samples will be stored for up to 15 years after the completion of the study (defined 
as submission of the clinical study report [CSR] to the appropriate regulatory agencies). At the end 
of the storage period, samples will be destroyed. Samples may be stored longer if a Health 
Authority (or medicinal product approval agency) has active questions about the study. In this 
special circumstance, the samples will be stored until the questions have been adequately 
addressed. 
It is possible that future research and technological advances may identify genomic variants of 
interest, or allow alternative types of genomic analysis not foreseen at this time. Because it is not 
possible to prospectively define every avenue of future testing, all samples collected will be single- 
or double-coded (according to the ICH15 guidelines) in order to maintain subject privacy.  
RIGHT TO WITHDRAW  
If, during the time the samples are stored, a participant would like to withdraw his/her consent for 
participation in this research. The study sponsor will destroy the samples, if they can still be 
identified (not anonymized). Once samples have been anonymized, it will not be possible to 
identify which samples have come from a particular individual. Therefore, it will not be possible to 
destroy subject samples after anonymization. Information from any assays that have already been 
completed at the time of withdrawal of consent will continue to be used as necessary to protect the 
integrity of the research project.  
SUBJECT PRIVACY AND RETURN OF DATA  
No subject-identifying information (e.g., initials, date of birth, government identifying number) will 
be associated with the sample. Samples that are processed for analysis (DNA/RNA extracted) may 
be double-coded. Double-coding involves removing the initial code and replacing with another 
code such that the subject can be re-identified by use of 2 code keys. The code keys are usually 
held by different parties. The key linking the sample ID to the subject number will be maintained 
separately from the sample. At this point, the samples will be double-coded (the first code being 
the subject number) as long as the initial tube does not carry any personal identifiers or the random 
code assigned by the central laboratory or biorepository. 
Laboratory personnel performing genetic analysis will not have access to the “key.” Clinical data 
collected as part of the clinical trial will be cleaned of subject identifying information and linked by 
use of the sample ID “key.”  
Sample anonymization may occur by destruction of the “key.” Once the “key” is destroyed, it will 
not be possible to trace the pharmacogenomics assay results back to an individual. The sponsor 
will take steps to ensure that data are protected accordingly and confidentiality is maintained as far 
as possible. Data from subjects enrolled in this study may be analyzed worldwide, regardless of 
location of collection.  


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The sponsor and its representatives and agents may share anonymized data with persons and 
organizations involved in the conduct or oversight of this research. These include:  
• Clinical research organizations retained by the sponsor;  
• Independent ethics committees or institutional review boards that have responsibility for this 
research study;  
• National regulatory authorities or equivalent government agencies 
At the end of the analysis, results may be presented in a final report which can include part or all of 
the anonymized data, in listing or summary format. Other publication (e.g., in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of the 
population in the study, and no identified individual results will be disclosed.  
Given the research nature of the planned analysis, it will not be possible to return individual data to 
subjects participating in the pharmacogenomics analysis.  


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Appendix VII: Adverse event report form 
Please see attached form 

SAP_001.pdf: