Clinical trial NCT02402062
Conditions: Neuroendocrine Tumors Pancreatic Neoplasms
Keywords: pNET
Sponsor: Grupo Espanol de Tumores Neuroendocrinos
Start date: 2015-05-11; Completion date: 2020-01-10
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the safety and the efficacy of the combination of the drugs TH-302 and sunitinib in metastatic neuroendocrine tumours.

Detailed description:
The purpose of this study is to determine the safety and the efficacy of the combination of the drugs TH-302 and sunitinib in Treatment-naïve patients with well- and moderately-differentiated metastatic Pancreatic Neuroendocrine Tumours (pNET).

Arms: arm 1: TH-302 + Sunitinib. Single arm Study.
Interventions: intervention 1: TH-302 + Sunitinib
Intervention descriptions: intervention 1: Combination of the two drugs in cycles of 28 days, described as follows:

Sunitinib: 37,5 mg/day Oral everyday of each 28 day cycle.

TH-302: 340 mg/m2 IV on days 8, 15 and 22 of each cycle.

Protocol documents:
Prot_000.pdf: 
A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in patients 
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A phase II trial to assess the activity and safety of TH-302 in 
combination with sunitinib in patients with well- and moderately-
differentiated metastatic pancreatic neuroendocrine tumours (pNET) 
previously untreated.  
 
 
PROTOCOL CODE:  
 
GETNE-1408 
EudraCT No.:  
 
 
2014-004072-30 
 
VERSION: 
 
 
 
5.0 (23 November 2016) 
 
 
SPONSOR: 
 
 
 
Spanish Task Force Group For Neuroendocrine Tumours 
(Grupo Español de Tumores Neuroendocrinos - GETNE) 
INVESTIGATOR:  
 
 
Dr Enrique Grande (Hospital Universitario Ramón y Cajal) 
BIOMARKER STUDY:  
Dr José Palacios Calvo  
(Hospital Universitario Ramón y Cajal) 
Dr Cristina Rodríguez-Antona  
Spanish National Cancer Research Centre (CNIO) 
 
 
 
 
The information contained in this document is confidential and may not be disclosed to others without written authorisation from the 
investigators, with the exception of the use thereof to obtain informed consent from the subjects who are going to receive the 
investigational drug, as well as in communications to the health authorities, the clinical trial committees and/or those individuals who are 
going to carry out the study. 
 
 


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PROTOCOL SIGNATURE PAGE  
 
Protocol: GETNE-1408 
VERSION:  5.0 (23 November 2016) 
I have read this protocol and agree to direct this trial in accordance with all the stipulations of the 
protocol and the Declaration of Helsinki.  
Sponsor’s signature 
[signature] 
 
Dr Rocío García Carbonero 
 
Coordinating investigator’s signature 
[signature] 
 
Dr Enrique Grande 
I have read this protocol and agree to direct this trial in accordance with all the stipulations of the 
protocol and the Declaration of Helsinki.  
 
 
 
Principal Investigator at the Hospital ______________________ 
Name: 
 
 


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 . SUMMARY 
  
 1.1 Type of Application 
A phase II, open-label, non-controlled, multicenter prospective clinical trial in treatment-naïve patients 
with well- and moderately-differentiated advanced or metastatic pancreatic neuroendocrine tumours. 
The study includes analysis of serological and tumour tissue biomarkers. 
 
1.2 Sponsor details 
Spanish Task Force Group For Neuroendocrine Tumours (Grupo Español de Tumores 
Neuroendocrinos - GETNE) 
 
 
1.3 Trial Title 
A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in patients 
with well- and moderately-differentiated Metastatic Pancreatic Neuroendocrine Tumours (pNET) 
previously untreated. 
 
1.4 Protocol code: GETNE - 1408 
 
1.5 EudraCT No.: 2014-004072-30 
 
1.6. Coordinating investigator 
Dr Enrique Grande. Medical Oncology Department, Hospital Universitario Ramón y Cajal. Carretera 
de Colmenar Viejo km 9,100. 28034 Madrid, Spain. Tel./Fax: +34913368263. Email: 
egrande@oncologiahrc.com 
 
1.7 Principal Investigators 
The list of Principal Investigators and participating sites is provided in a separate document. 
 
1.8 Sites where the trial is to be conducted 
10 Spanish hospitals will participate in the study. 
 
1.9 Name of the Organisation responsible for Monitoring 
MFAR (Marketing Farmacéutico & Investigación Clínica) 
Secretari Coloma, 64-68, esc B, Entlo 5ª  
08024 - Barcelona  
Tel.: +34 93 434 44 12 Fax: +34 93 253 11 68 
investigacion@mfar.net / www.mfar.es 
 
 
 
 


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1.10 Trial treatment  
Single arm of TH-302 administered at 340 mg/m2 by intravenous infusion on days 8 and 22 in 
combination with sunitinib given orally at doses of 37.5 mg per day continuously in 28-day cycles. 
Pharmaceutical form:  
● Sunitinib: hard gelatin capsules of 25 and 12.5 mg. Oral administration. 
● TH-302: the dose will be adjusted according to body surface area and will be 
administered by intravenous infusion over 30 to 60 minutes. In the event of weight 
variation > 10%, the body surface area will be recalculated and the dose readjusted.   
The physical and chemical properties of sunitinib and TH-302, as well as the list of excipients, are 
included in the Investigator’s Brochure. 
 
1.11. Design and Phase of Clinical Trial  
Phase II, open-label, non-controlled, multicenter, prospective clinical trial. 
 
1.12 Primary and Secondary Objectives 
The main purpose of the study is to determine the safety and activity of TH-302 in combination with 
sunitinib in patients with a well- or moderately-differentiated metastatic pancreatic neuroendocrine 
tumour (pNET). Drug activity will be measured according to the objective response rate (ORR), as 
measured by RECIST criteria version 1.1, with assessments performed every 8 weeks, regardless of 
delays due to adverse events. ORR is defined as the percentage of patients with confirmed complete 
response (CR) or confirmed partial response (PR) according to RECIST criteria v1.1, relative to the 
total analysis population. Confirmed responses are those that persist in a repeat imaging study 
conducted ≥ 4 weeks after initial documentation of response.  
The secondary objectives of the study are:  
● Progression-free survival 
● Time to tumour progression 
● Duration of response 
● Overall survival 
● Safety of TH-302 treatment in combination with sunitinib. 
● Prognostic/predictive value of biomarkers analysed in peripheral blood and in 
paraffin-embedded tumour tissue. 
 
1.13 Disease under study 
Patients with a well- or moderately-differentiated metastatic pancreatic neuroendocrine tumour 
(pNET) (grade 1-2 of histological differentiation and Ki67 ≤ 20%) who are naïve to systemic 
treatment, with the exception of somatostatin analogues. 
 
 
 


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1.14 Total Number of Patients 
It is estimated that 43 patients will be enrolled in the study. 
 
1.15 Duration of Treatment 
Treatment with TH-302 in combination with sunitinib will continue until disease progression, 
unacceptable toxicity, non-compliance with the protocol, the patient’s withdrawal of informed consent 
or at the discretion of the investigator. 
 
1.16. Schedule and planned end date 
Recruitment is expected to last for 24 months, followed by a 20-month follow-up period. 
● Date of submission to central IEC for research with medicinal products: November 
2014/January 2015. 
● Data of submission/AEMPS approval: November 2014/January 2015 
● Estimated date of enrolment of first patient: February 2015 
● Study end date: January 2019 
● Data analysis period: 4 months 
● Database closure: April 2019 
● Date for the final study report: June 2019 
● Publication date: June 2019 
 
1.17 Table of Trial Determinations  
Determinations outline: (ANNEX 1) 
 
 
 


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2. PROTOCOL TABLE OF CONTENTS 
Table of contents
1. SUMMARY 
3 
3. STUDY RATIONALE 
7 
4. STUDY OBJECTIVES 
17 
5. STUDY DESCRIPTION 
18 
6. TREATMENT 
21 
7. PATIENT SELECTION 
31 
8. METHODOLOGY 
34 
9. STATISTICAL ANALYSIS 
36 
10. ASSESSMENT CRITERIA 
37 
11. STUDY PROCEDURES 
45 
12. ETHICAL ASPECTS 
48 
13. STUDY DOCUMENTATION 
50 
14. REFERENCES 
52 
ANNEXES 
56
 
 
 
 
 
 
 
 
 
 


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 3. STUDY RATIONALE 
 
3.1. Epidemiology and classification of pancreatic neuroendocrine tumours (pNET) 
 
pNETs represent a heterogeneous tumour group classified according to their functional capacity and 
histological differentiation (1) (Annex 2). The prevalence of neuroendocrine tumours (NET) has 
increased in recent years at an estimated rate of 35/100,000/year, of which approximately 30% are 
pNET. In particular, the incidence of pNET is 0.32/100,000/year (2). Most are non-functioning 
tumours. Those that are functioning are identified according to the hormone secreted, and some are 
found outside the pancreas.  
 
The 5-year survival rate is 80%; 60-100% for localised disease, 40% for locally advanced disease and 
25% for metastatic disease (which can reach 60% in reference sites). 
 
3.2. Therapeutic options for managing metastatic pancreatic neuroendocrine tumours (pNET) 
 
Treatment goals in the management of pNETs are symptom control and limiting tumour growth in 
order to positively affect patient survival. 
 
In the context of cytotoxic drugs, it appears that pNETs are more sensitive to chemotherapy than other 
NETs, including carcinoid tumours. For decades, cytotoxic therapy was the only available treatment 
option, with streptozotocin as the first drug to demonstrate NET activity, being approved in 1976 by 
the FDA (Food and Drug Administration). Its combination with fluoropyrimidines, particularly 
doxorubicin, further increased its activity, and it became the standard treatment for well- and 
moderately-differentiated tumours. These combinations achieved a pNET response rate of between 35-
69%, with median overall survival of up to 26 months (3), (4). However, this goal was not always 
measured according to radiological assessments, but also clinical ones, so its interpretation was limited 
and no definite correlation was found between these data and those obtained in reviews of routine 
clinical practice (5). A second cytostatic agent that is key in the treatment of pNETs is temozolomide, 
an alkylating agent, the benefit of which appears to be correlated with MGMT enzyme deficiency. The 
combination of temozolomide and capecitabine studied in retrospective reviews, such as the one 
published in 2011 with 30 treatment-naïve patients with pNET (6), showed an objective response rate 
of 70%, a median progression-free survival (PFS) of 18 months and an overall 2-year survival rate of 
92%.  
 
In high-grade, poorly-differentiated tumours, the standard treatment regimen comprises the 
combination of platinum and etoposide, which, in retrospective reviews and prospective studies, 
achieves a high response rate of between 56-67%, but they are unfortunately not as durable as 
expected (7).  
 
The pNET population was represented in the CLARINET phase III study, which randomised 204 
patients with G1/G2 non-functioning GEP-NETs, to receive lanreotide Autogel 120 mg (N = 101) 
versus placebo (N = 103) (8). The first endpoint - PFS - was achieved by showing a 53% reduction in 
the risk of progression in favour of somatostatin analogues (HR 0.47; 95% CI 0.30-0.73, p = 0.0002). 
Subgroup analysis according to the location of the primary demonstrated a PFS for pNET patients (N 
= 91) that had not been achieved in the arm with lanreotide Autogel and 12.1 months in the placebo 
arm (HR 0.58; 95% CI 0.32-1.04, p = 0.0637).  
 
 
 


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In recent years, data from two phase III studies with targeted therapy against vascular endothelial 
growth factor receptor (VEGFR), sunitinib, and the mammalian target of rapamycin (mTOR), 
everolimus, in pNET patients, has broadened the therapeutic horizon for these patients. The improved 
PFS demonstrated led to the approval of both drugs by the EMA and the FDA. 
 
The PI3K/AKT/mTOR pathway is also key in tumour development, as it regulates the metabolism, 
growth, cell proliferation and angiogenesis, integrating multiple signalling pathways.  Its activation 
can be responsive to VEGFR, PDGFR and insulin-like growth factor receptor (IGFR) stimulation, and 
it is regulated through two tumour suppressor genes (TSG) - TSC2 and PTEN. As everolimus 
deregulates this molecular pathway in pNET, use of the drug should be developed against these 
tumours. Thus, based on the phase II results published in 2008 with two cohorts of 60 patients treated 
with octreotide and everolimus at doses of 5 and 10 mg daily, a response rate of 27% was observed in 
pNET patients with a median PFS of 63 weeks (9). Based on these results, a second phase II study was 
developed, called RADIANT-1, targeting pNET patients who had progressed during or after 
chemotherapy and who received everolimus 10 mg/day, being stratified according to prior treatment 
with octreotide (115 patients in monotherapy and 45 patients in combination) (10). The results for both 
strata showed a response rate of 9.6% and 4.4%, respectively, and PFS was 9.7 vs. 16.7 months, 
respectively, for both arms. In a third phase III study, RADIANT-3, 410 pNET patients were 
randomised to receive everolimus 10 mg/day vs. placebo (11). The results of the study demonstrated 
significantly improved PFS with everolimus of 11.4 months versus 5.4 months (HR 0.34; p<0.0001). 
 
Unfortunately, patients ultimately progress and the development of new active drugs, as well as the 
development of predictive biomarkers of progression, is vital. The first study to analyse the sequence 
of therapeutic targets was the PAZONET study, the results of which were presented at ESMO 2012 
(12). A total of 44 patients were enrolled who had previously received treatment with a tyrosine-kinase 
inhibitor (TKI) and/or mTOR inhibitor, and who were treated with pazopanib 800 mg/day allowing 
concomitance with somatostatin analogues. The results showed that pazopanib was active in this 
patient arm with a clinical benefit of 83% for those previously treated with TKI, 89% with an mTOR 
inhibitor and 60% with both drugs. The PFS in these three subgroups was 12.1 months, 6.8 months 
and 4.1 months, respectively. For the overall population it was 9.5 months.  
 
3.3. Sunitinib in Pancreatic Neuroendocrine Tumours 
 
In pNET, there is a high expression of VEGF and VEGFR2-3, PDGFR alpha and beta, cKIT and 
EGFR, and hypoxia is a key event in the regulation of tumour angiogenesis. This constitutes a strong 
rationale when it comes to developing anti-angiogenic drugs for these tumours. In clinical studies, the 
activity of sunitinib on NET was first demonstrated in a phase I study where the 3 enrolled NET 
patients, all of whom had been previously treated, showed reduced tumour lesions to varying degrees, 
being exceptional in one patient with a higher partial response (21 weeks) and two long-lasting minor 
responses (13). Thereafter, a multicenter, phase II study was conducted in patients with carcinoid 
tumours and pNET (14). Results from the 66 pNET patients showed an objective response rate of 
16.7% and a stable disease rate of 68%. The time to progression and overall survival at one year was 
7.7 months and 81.1%, respectively. To definitively confirm this benefit, a phase III study versus 
placebo was developed, in which 171 patients of the 340 initially estimated were finally randomised 
against independent data monitoring (15). The benefit in terms of PFS was 11.4 months for the 
sunitinib arm at a dose of 37.5 mg/day versus 5.5 months for the placebo arm (HR 0.42; p<0.001). 
Efficacy data on patients in routine clinical practice treated with sunitinib were consistent with those 
obtained on selected populations in clinical trials (16).  
 
 


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Figure 1. PFS results of the phase III study of sunitinib vs. placebo in pNET patients. 
 
 
 
 3.4. TH-302 (Preclinical and Clinical Development in Solid Tumours) 
● Introduction 
 
(1-methyl-2-nitro-1H-imidazole-5-yl)methyl N,N’-bis(2-bromoethyl) diamidophosphate (also known 
as TH-302) is a nitroimidazole-triggered prodrug of a brominated version of isophosphoramide 
mustard (Br-IPM) (17). TH-302 is able to diffuse into hypoxic tissues without activation by NADP(H) 
quinone oxidoreductase (DT-diaphorase). It is preferentially activated under severe hypoxic conditions 
that are unlikely to be present in healthy tissue but in solid tumours (18). 
 
The molecule TH-302 is activated by a process that involves a one electron reduction at the 2-
nitroimidazole site of the prodrug, mediated by ubiquitous cellular reductases such as the NADPH-
cytochrome P450, to generate a radical anion prodrug (RP). In the presence of oxygen (normoxia) the 
radical anion prodrug reacts rapidly with oxygen to generate the original prodrug and superoxide (SO). 
In these situations, TH-302 is relatively inert, remaining intact as a prodrug. However, under hypoxic 
conditions, (<0.5% O2), the radical anion prodrug can either fragment directly or undergo further 
reduction at the nitroimidazole site of the prodrug, causing Br-IPM to be released (Figure 2). Br-IPM 
can then act as a DNA alkylating agent and form DNA crosslinks, causing damage through the 
presence of γH2AX. Br-IPM can diffuse through normoxic tissues and act as a cytotoxic agent in these 
regions. Previously, other alkylating mustards such as ifosfamide or cyclophosphamide had already 
demonstrated activity in many tumours. 
 
 
 
 
 
 
 


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Tumours often contain highly hypoxic regions that are known to be resistant to chemotherapy and 
radiotherapy. These regions develop due to the creation of irregular and aberrant blood vessels that 
prevent adequate oxygenation and penetration of the majority of chemotherapy treatments, which act 
on highly proliferating cells adjacent to the blood vessels, but not on the relatively quiescent cells 
found in the hypoxic regions. For this reason, they are resistant to these regimens of cytostatic drugs 
(19). In contrast, the prodrug TH-302 is activated in conditions of severe hypoxia, and not in the 
majority of normal tissues with a similar structure (20). Recent preclinical findings support the 
hypothesis of the induction of hypoxia within the tumour developed by anti-angiogenic drugs, which 
could constitute a synergistic effect with TH-302. 
 
The molecular formula of TH-302 is C9H16Br2N5O4P and the molecular mass is 449 g/mol.  
 
Figure 2. TH-302 activation pathway diagram 
 
 
 
Figure obtained from Meng, F., et al. Molecular and cellular pharmacology of the hypoxia-activated 
prodrug TH-302. Mol Cancer Ther. 2012;11:740–51 
 
● Preclinical Data  
 
In preclinical investigations, TH-302 as monotherapy or in combination with numerous cytotoxic 
drugs has shown broad activity in murine models (21). In particular, TH-302 has shown consistent 
activity 
in 
cell 
lines 
from 
neural 
crest 
derived 
tumours 
such 
as 
melanoma 
and 
glioblastoma/astrocytoma (TH-302 Investigator’s Brochure). 
 
TH-302 is very active in vitro, as demonstrated in proliferation studies of H460 lung carcinoma cells 
(22), where TH-302 activity is related to dose-exposure and oxygen dependence, which practically 
achieves linearity (23). This activity is also observed in H69 small-cell lung cancer cells (SCLC), B16-
F10 melanoma, SKMEL-5 melanoma, HT-29 colon cancer, HCT116 colon cancer, MES-SA uterine 
cancer, DX5 uterine cancer, ACHN renal cancer and PC-3 prostate cancer in anoxic conditions (CI50 
from 0.1 to 10 µM) and weakly cytotoxic in the presence of air (CI50 > 80 µM). Consistent results are 
obtained in clonogenic models. 
 
 
 
 
 
 
 
 
 


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In vivo studies demonstrate activity both as monotherapy and in combination with other cytostatic 
drugs (cisplatin, paclitaxel or 5-fluorouracil) (22). 
 
The effect of TH-302 has been studied in many murine xenograft models (H82 small-cell lung cancer, 
H460 and Calu-6 non-small cell lung cancer, A375 and Stew2 melanoma, 786-0 renal cell and 
PLC/PRF/5, Hs766t and BxPC-3 pancreatic cancer). The cytotoxic activity of TH-302 increases in 
vivo in hypoxic conditions, as shown by excision methods and tumour growth models. Acute (single 
dose) or chronic (for 2 weeks) treatment with TH-302 demonstrates selective reduction in tumour 
volume of the hypoxic regions in xenograft models, with their corresponding increase in necrotic 
compartments (20). TH-302 achieves a significantly greater benefit in combination with 
chemotherapy, and even the complete eradication of some tumours, including metastatic ones (24). 
 
With regard to the combination with anti-angiogenic drugs, the rationale starts from the knowledge of 
hypoxia induced by these agents that, in tumour progression, provide a more aggressive phenotype. 
The study of murine xenograft models in human 786-O renal cell carcinoma, melanoma A375, H460 
non-small cell lung cancer and hepatocellular carcinoma PLC/PRF/5, investigated the synergistic 
activity of TH-302 in combination with sunitinib or sorafenib (25). Both anti-angiogenic drugs 
increased hypoxia detected in the tumour tissue, and was time and dose-dependent. In the 786-O renal 
cell model, the activity of sunitinib (40 mg/kg) increased when combined with TH-302 (50 mg/kg) in 
terms of tumour growth control, from 38% to 75%. In addition, no significant weight loss was 
identified when combining anti-angiogenic drugs with TH-302, which is an indicator of toxicity. In 
conclusion, the synergism reached in terms of the anti-tumour efficacy of the combination of sunitinib 
or sorafenib with TH-302 by selective action on hypoxic tissue induced by anti-angiogenic drugs, 
forms the basis for the future clinical development of this combination.  
 
● Pharmacokinetic data and preclinical safety 
 
TH-302 does not act as a substrate for the clinically relevant efflux pumps studied: MDR1 (ABCB1), 
MRP1 (ABCC1) and BCRP (ABCG2). Reductase expression and homologous recombination-
dependent repair (HRD) affect in vitro cytotoxicity caused by TH-3026. 
 
The first pharmacokinetic data for TH-302 and its active metabolite Br-IPM in preclinical studies were 
obtained from mice, rats, dogs and monkeys (26). The drug was delivered as a single oral, intravenous 
and intraperitoneal dose, and the safety of the drug was subsequently analysed by repeated doses. 
Following intravenous administration of the drug, rapid distribution throughout the body was 
identified, with a volume of distribution similar to or greater than total body water (0.542 l/kg in mice 
vs. 1.67 – 5.09 l/kg in rats, 1.98 l/kg in dogs and 2.92 l/kg in monkeys), as well as rapid clearance 
(3.28 – 7.66 l/h/kg) with an effective half-life of between 10 and 50 minutes. TH-302 remained stable 
when incubated with liver microsomes from mice, rats, dogs, monkeys and humans.  TH-302 is mainly 
eliminated renally and faecally, based on observations in rats and dogs. A tissue distribution study on 
rats demonstrated that TH-302 distributes quickly to tissues following intravenous administration. The 
highest concentrations of radioactivity related to TH-302 were found in the kidneys and the small 
intestine. However, low but quantifiable radioactivity levels were observed in the brain and spinal 
cord. Protein binding was low (< 55%) and independent of plasma concentration. 
 
 
 
 
 
 


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The first toxicity data after one or multiple doses of TH-302 were gathered from rats and dogs. As the 
preclinical efficacy data indicated that the Cmax might be important for anti-tumour activity, a 30-
minute intravenous infusion was chosen for these toxicity studies, in order to obtain rapid drug 
concentration peaks and support the use of the 30 minute infusion in clinical practice. Toxicity at non-
fatal doses was mainly haematological, accompanied in male rats by moderate weight loss. All of these 
changes were fully reversible within 2 weeks during the recovery period.  
 
Based on these results, TH-302 was administered in rats in multiple doses of 12.5, 25 and 50 mg/kg, 
according to Good Laboratory Practice (GLP), where each rat received a 30-minute infusion once a 
week for 3 weeks. The primary toxicity was haematological and reversible, and was only significant at 
the 50 mg/kg dose. Dry and flaky skin was also observed at this dose on the top and soles of the feet, 
as well as excessive salivation. None of these results was present at the end of the recovery period. The 
histopathology showed bone marrow hypocellularity in the high-dose group and tongue epithelial 
dysplasia in the mid-, and especially the high-dose groups. These changes disappeared completely. In 
the study with dogs treated intravenously with 4, 8 or 16 mg/kg of TH-302, leukopenia and 
neutropenia were observed, in particular at the highest dose. These changes were completely 
reversible. In the study with rats treated intravenously with 12.5 mg/kg or 50 mg/kg of TH-302, the 
main toxicities were haematological and reversible.  
 
● Clinical data in solid tumours 
 
The first phase I study in humans was conducted in 57 patients treated with TH-302 administered 
intravenously in 2 different regimens (17). The first regimen, involving 37 patients, was weekly for 3 
weeks with 1 week rest, and a dose escalation of 7.5 to 575 mg/m2. The second regimen, involving 20 
patients, was introduced subsequently and independently, with doses administered tri-weekly and a 
dose escalation of 670 to 940 mg/m2. The maximum tolerated dose (MTD) of TH-302 was 575 mg/m2 
for the weekly regimen, or 670 mg/m2 for the tri-weekly regimen. The most common adverse events in 
the weekly treatment regimen (>= 20%) were fatigue, nausea, skin rash, constipation, anorexia, 
vomiting, stomatitis and dyspnoea. Haematological toxicity was rarely significant, 3 events were grade 
> 0 anaemia (6%), thrombocytopenia (5%) and neutropenia (4%). From the 240 mg/m2 dose, anti-
emetic prophylaxis was required for moderately emetogenic models. Dose-limiting toxicity (DLT) was 
mucosal and cutaneous toxicity, as well as dehydration. In the weekly regimen, the DLT was grade 3 
mucosal and cutaneous toxicity at a dose of 670 mg/m2. In the tri-weekly regimen, the DLT was grade 
3 fatigue and joint pain in one patient, and grade 3 vaginitis/proctitis, stomatitis and pain in another 
patient at a dose of 940 mg/m2. The pharmacokinetic data showed that plasma concentrations of TH-
302 and its active metabolite Br-IPM increased in proportion to the administered dose. The elimination 
half-life was 0.81 hours for TH-302 and 0.70 hours for Br-IPM. The low plasma concentrations of the 
active metabolite (1% - 2% of the concentration of TH-302) are explained by the rapid distribution of 
TH-302 one hour after administration and not being susceptible to activation by liver enzymes or DT-
diaphorase. Two partial responses were identified in a patient with metastatic small-cell lung cancer 
and another patient with melanoma at doses of 480 and 670 mg/m2 in weekly regimen. Disease 
stability was identified in 18 patients treated with the weekly regimen, and in 19 patients treated with 
the tri-weekly regimen. 
 
 
 
 
 
 


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Administration of TH-302 in combination with different chemotherapy regimens - docetaxel, 
pemetrexed and gemcitabine - was investigated in a triple-arm, phase I/II dose escalation study (TH-
CR-402) with an expansion cohort that included patients with castration-resistant prostate cancer 
(CRPC) (docetaxel), non-small cell lung cancer (NSCLC) (pemetrexed) and pancreatic cancer 
(gemcitabine). 
 
The starting dose of TH-302 in each of the treatment arms was 240 mg/m2.  
 
In the phase I/II study with docetaxel, after the determination of the MTD, the cohort was expanded to 
26 patients with CRPC and NSCLC after first line progression, who received TH-302 on days 1 and 8 
plus docetaxel 75 mg/m2 on day 1 for 21-day cycles (27). The MTD of TH-302 in combination with 
75 mg/m2 docetaxel was 340 mg/m2. DLTs at higher doses of TH-302 were: afebrile grade 4 
neutropenia, grade 3 infection (pneumonia) with grade 3 neutropenia and febrile grade 3 neutropenia 
and diarrhoea. The recommended dose of TH-302 was 340 mg/m2. In terms of responses achieved, of 
the 4 evaluable CRPC patients, one partial response was observed and two disease stabilisations. Of 
the two evaluable NSCLC patients, 1 achieved partial response and the other achieved stable disease. 
 
In the case of the combination with pemetrexed, after reaching the MTD, patients with NSCLC in 
second line were enrolled, receiving TH-302 on days 1 and 8 with pemetrexed 500 mg/m2 on day 1 of 
each 21-day cycle (28). The 29 patients enrolled showed a DLT that was grade 4 thrombocytopenia or 
grade 3 oral stomatitis. The recommended dose of TH-302 for the combination was 400 mg/m2. Of the 
26 patients eligible for response assessment, 35% showed a partial response and another 35% showed 
stable disease. 
 
In the third gemcitabine arm, the 38 patients enrolled were treated with TH-302 followed by 
gemcitabine 1000 mg/m2 on days 1, 8 and 15 of each 28-day cycle (29). The DLTs were grade 4 
thrombocytopenia and grade 4 neutropenia, as well as grade 3 pain caused by perianal rash and 
oesophagitis. The MTD was 340 mg/m2. The 17 patients with a pancreatic tumour who received first-
line treatment had a partial response rate of 35% and a stable disease rate of 59%. 
 
The TH-302 study was expanded to include 214 patients with adenocarcinoma of the pancreas in phase 
II (TH-CR-404), with 2 different TH-302 doses (240 mg/m2 – N = 71- or 340 mg/m2 – N = 74- on 
days 1, 8, 15) in combination with gemcitabine (1000 mg/m2) versus gemcitabine as monotherapy (N 
= 69) in 28-day cycles (1:1:1) (30). Crossover to the combination of TH-302 with gemcitabine arm 
was permitted after progression in randomised patients. The first endpoint - PFS - was 3.6 months for 
the gemcitabine arm vs. 5.5 months for the gemcitabine with TH-302 240 mg/m2 arm (HR 0.64; 95% 
CI: 0.43, 0.96; p = 0.031) vs. 6.0 months for the gemcitabine with TH-302 340 mg/m2 arm (HR 0.58; 
95% CI: 0.39, 0.87; p = 0.008). The response rate was 12% for the gemcitabine arm, 17% for the 
gemcitabine with TH-302 240 mg/m2 arm, and 27% for the gemcitabine with TH-302 340 mg/m2 arm. 
Based on the safety and efficacy data in this phase II study, a phase III study (MAESTRO) is currently 
in progress, evaluating TH-302 in the same regimen and dosage (340 mg/m2 of TH-302 on days 1, 8, 
and 15 of a 28-day cycle with gemcitabine), and on the same patient population evaluated in the 
randomised phase II study (study TH-CR-404) (NCT01746979). 
 
 
 
 
 


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Based on hypoxia markers detected in metastatic soft tissue sarcomas and its significant resistance to 
chemotherapy, the phase I study TH-CR-403 was conducted for this population (31). Patients were 
administered a starting dose of TH-302 of 240 mg/m2 on days 1 and 8 in the dose escalation phase 
with doxorubicin 75 mg/m2 on day 1 of every 21-day cycle.  16 patients were enrolled. Although there 
was no DLT with the starting dose, 3 patients experienced transient grade 4 neutropenia and were 
therefore permitted to add prophylaxis with granulocyte colony-stimulating factor (G-CSF) on day 8 
of each cycle. The MTD was 300 mg/m2 and the DLTs at 340 mg/m2 were grade 4 thrombocytopenia 
and febrile grade 4 neutropenia with grade 3 infection. Five patients (33%) had a partial response 
according to RECIST criteria. Data from the expansion cohort showed the following response rates (N 
= 89): complete response (2%), partial response (34%), disease stability (48%) and disease progression 
(DP) (16%).  
 
Survival rate to 6 months was 62%. Median overall survival was 17.5 months (95% CI: 16.1 months 
until an unattained upper limit) and the overall survival rate at 1 year was 70%.  
 
With these encouraging results (better than doxorubicin as monotherapy), a randomised phase III study 
(TH-CR-406) was conducted to assess the administration of TH-302 at doses of 300 mg/m2 weekly in 
combination with a routine doxorubicin regimen (NCT01440088). 
 
From the work which identified an increase in the hypoxic fraction with sunitinib at 40 mg/m2 in 786-
0 renal cell carcinoma murine models, and the activity of TH-302 in hypoxic tissues, its research in 
humans began with the conduct of a phase I dose-escalation clinical trial (32). This study combined 
TH-302 with sunitinib in patients with renal cell carcinoma, gastrointestinal stromal tumour (GIST) 
and pancreatic neuroendocrine tumour (pNET) in first line or successive. GIST and pNET were only 
included in the dose escalation phase. The recommended dose of sunitinib was 50 mg daily for 28 days 
in 42-day cycles (6 weeks) in combination with TH-302 at a dose 340 mg/m2 by intravenous infusion 
on days 8, 15 and 22 of each 42-day cycle (6 weeks). There was no DLT at a dose of 240 mg/m2 (N = 
4), 1 DLT was observed at 340 mg/m2 (N = 6), which was a grade 2 stomatitis. Grade 3/4 neutropenia 
and thrombopenia was observed in 3 and 5 patients, respectively. The most common adverse events 
associated with TH-302 were nausea and mucositis. Preliminary data showed synergistic activity of 
sunitinib plus TH-302 in patients with renal cell carcinoma progressing to sunitinib (figure 3).  
 
Figure 3. Change in tumour volume with the combination therapy sunitinib+TH-302. 
 
 
 
 
 
 
 


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3.5. Biomarkers 
To date, no validated predictive marker has been identified in pancreatic neuroendocrine tumours. The 
importance of this research lies in being able to identify patients optimally to ensure as personalised a 
global approach as possible. 
 
Although VEGF is considered to be the driving force behind angiogenesis in pNET, many studies have 
proven the involvement of other molecules such as PDGF, cKIT or mTOR. Initial data from patients 
with neuroendocrine tumours treated with sunitinib (33), (34) has been obtained by measuring 
circulating biomarker levels in the plasma, such as VEGF, soluble VEGF receptor-2 (sVEGFR-2), 
interleukin-8 (IL-8) and sVEGFR-3. In one of the studies, sVEGFR-2 and sVEGFR-3 levels dropped 
significantly by 30% after the first cycle, in 60% and 70% of patients, respectively. The reduction in 
sVEGFR-3 levels in the first cycle was greater in the subgroup of patients with partial response (N = 
11). Elevated IL-8 levels were also identified in those patients with reduced tumour size.  
 
Recently, a phase II study in pNET patients in first line or after progression and treated with pazopanib 
at a dose of 800 mg/24h, also included a biomarker expression analysis (35). Patients with some 
degree of VEGFR-2 expression tended towards longer PFS compared to those who did not express this 
protein (median 12.18 vs. 11.56 months; HR 0.95). 
In 101 patients with a renal cell carcinoma treated with sunitinib, 16 SNPs (single nucleotide 
polymorphisms) have been evaluated, belonging to 9 genes that affect the pharmacodynamics 
[VEGFR2 (rs2305948, rs1870377), VEGFR3 (rs307826, rs448012, rs307821), PDGFR-α 
(rs35597368) and VEGF-A (rs2010963, rs699947, rs1570360) and IL8 (rs1126647), and 
pharmacokinetics [CYP3A4 (rs2740574), CYP3A5 (rs776746)], transport [ABCB1 (rs1045642, 
rs1128503, rs2032582] and [ABCG2 (rs2231142)] and metabolism [CYP3A5*1, CYP3A4] of 
sunitinib. The results defined a possible group of patients with VEGFR3 and CYP3A5*1 
polymorphisms who had a lower response and worse tolerance to sunitinib (36).  
 
The HIF-1 pathway is a crucial angiogenesis regulator involving other molecules such as VEGF, 
PDGF, angiopoietins (Ang-1 and Ang-2), DLL4 and metalloproteinases (37). Carbonic anhydrase 
(CAIX) is another factor associated with the activity of HIF-1α and which regulates tumour pH and 
cell survival, together with cell adhesion. The expression of these key proteins in tumour hypoxia and 
their determination in pNET patients where this phenomenon is widely described, may contribute 
predictive information for incorporation in clinical practice. 
 
 
 
 


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Finally, TH-302 has been associated with hypoxia, which is why hypoxia markers (vascular 
microdensity, carbonic anhydrase IX, etc.) are potential candidates to predict which patients will be 
more likely to respond and which are not. 
 3.6. Rationale for the Clinical Development of this Study 
NETs are highly vascular tumours exhibiting a high expression of proangiogenic molecules, such as 
VEGF. Many inhibitors of this pathway, such as monoclonal antibodies (bevacizumab) or tyrosine 
kinase inhibitors (sunitinib, sorafenib, pazopanib) have shown activity in pNET. 
 
Despite these advances, a wider range of treatment options and the complexity of the treatment 
algorithm for pNET, the tumours may exhibit primary or acquired resistance after an initial response 
that make them insensitive to treatment with these drugs (38), (39).  
 
Primary resistance to anti-angiogenic drugs may develop by the expression of proangiogenic factors 
that are relatively insensitive to VEGF-mediated inhibition (including c-MET, fibroblast growth factor 
(FGF), angiopoietins, and ephrins), or by the formation of blood vessels by other molecular pathways 
or the prior infiltration by inflammatory cells that express pro-inflammatory factors and cytokines that 
promote angiogenesis and which protect the blood vessel from VEGF-mediated inhibition. Acquired 
resistance may develop through the hypoxia-induced activation of alternative proangiogenic pathways 
such as angiopoietins, ephrins or FGF, or increase mesenchymal marker levels. These new receptors 
and molecular pathways seem to continue signalling through PI3K/AKT/mTOR (a finding that could 
potentially suggest secondary sensitivity to mTOR inhibitors), the recruitment of cells from bone 
marrow that contribute to VEGF-independent tumour vascularisation, pericyte-mediated protection or 
the invasion of non-tumour tissue with vessels that are more mature and less responsive to anti-VEGF 
therapy. 
 
The mechanisms described that lead to an increase in the release of pro-angiogenic factors include 
accumulation of intratumoral HIF-1α. (40).  
 
In conclusion, pancreatic neuroendocrine tumours (pNET), which exhibit significant vascularisation, 
are sensitive to anti-angiogenic therapy, although with poor responses. In contrast, the chemotherapy 
regimens achieve a high objective response rate, although they are not sustainable over time. 
Therefore, the development of therapeutic targets against hypoxia, including reducible prodrugs, 
targets against HIF-1 and genetic engineering with anaerobic bacteria gives cause for optimism in 
overcoming resistance mechanisms of cell survival in hypoxic areas versus conventional 
chemotherapy. 
 
Based on all the data presented above, the purpose of this study is to demonstrate the activity of TH-
302 under hypoxic conditions, such as in neuroendocrine tumours, after sunitinib-induced response, 
which may be consolidated and prolonged to overcome an established resistance mechanism. The 
study shall try to determine the synergism and safety of this combination, in order to achieve improved 
and longer-lasting responses in unresectable, locally advanced or metastatic well- or moderately-
differentiated pNET in first-line therapy.  
 
 
 
 


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4. STUDY OBJECTIVES 
 4.1. Primary Objective 
Objective response rate (ORR). 
 4.2 Secondary Objectives 
Progression-free survival (PFS) 
Time to progression (TTP) 
Response duration (RD) 
Overall survival (OS) 
Safety 
Serological and tumour tissue biomarkers  
 
  
 
 


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 5. STUDY DESCRIPTION 
  
 5.1. Design 
 
This is a prospective, non-randomised, open-label, single-arm, phase II study that will assess the 
efficacy and safety of TH-302 plus sunitinib in patients with well- and moderately-differentiated 
metastatic pancreatic neuroendocrine tumours (pNET) who are naïve to systemic treatment other than 
somatostatin analogues. The study will include a serological biomarker analysis to investigate its 
clinically beneficial prognostic and predictive role. 
 
The study will be conducted at 10 Spanish university sites belonging to the Spanish Task Force Group 
for Neuroendocrine Tumours (GETNE) network. GETNE will act as the study sponsor. 
 
Once the patient has signed the informed consent form, he/she should be registered in the study, 
regardless of whether he/she meets the eligibility criteria, using the electronic data collection platform 
provided for the trial, at the following web address: 
 
https://www.e-crd.net/getne1408/ 
 
In the event that the patient meets all of the inclusion criteria and none of the exclusion criteria, an 
enrolment confirmation email will be sent with the corresponding patient number. The trial treatment 
may only be initiated once this confirmation has been received. 
If any problems are detected with the tool during the enrolment process, or if the confirmation email is 
not received, please contact as soon as possible: 
 
Marketing Farmacéutico & Investigación Clínica [Pharmaceutical Marketing & Clinical Research] 
Tel.: +34 93 434 44 12 
email: investigacion@mfar.net 
 
For more information concerning the enrolment procedure, please refer to the enrolment procedure 
available in the site’s investigator files. 
 
The tumour sample must be found and sent to the Hospital Ramón y Cajal to perform the 
determinations detailed in this protocol. In addition, for patients who give their consent for the 
translational sub-study, blood samples (peripheral blood) must be collected prior to administration of 
the study medication and within the time limits defined in this protocol. These must be processed as 
laid out in section 8.1. 
 
For more information about the shipment of the biological samples, please refer to the biological 
sample shipment procedure available in the site’s investigator files. 
 
The study treatment is TH-302, administered at doses of 340 mg/m2 by intravenous infusion on days 8 
and 22 in combination with sunitinib given orally at 37.5 mg per day continuously from day 1 through 
to day 28 of a 28-day treatment cycle. Patients will receive the study treatment until radiological 
progression is confirmed according to RECIST criteria version 1.1, or until treatment discontinuation 
is considered to be in the best interests of the patient, at the discretion of the investigator (these 
decisions will balance maximum benefit with acceptable tolerability). Patients will continue taking the 
study treatment at the discretion of the investigator should they experience clinical benefit. 


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Tumour response will be assessed every 8 weeks, regardless of any delay which may arise due to 
toxicity. To prevent the introduction of bias associated with treatment duration, compliance with the 
assessment schedule is essential. 
 
 5.2. Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
5.3. Study Duration and Schedule 
Patient enrolment will take place over a period of 24 months, and a follow-up period of 20 months. 
 
It is estimated that the study schedule will be as follows: 
● Date of submission to central IEC for research with medicinal products: 
November:November 2014/January 2015. 
● Data of submission/AEMPS approval: November 2014/January 2015 
● Estimated date of enrolment of first patient: February 2015 
● Study end date: January 2019 
● Data analysis period: 4 months 
● Database closure: April 2019 
● Date for the final study report: June 2019 
● Publication date: June 2019 
5.4. Sample Size 
It is estimated that a total of 43 eligible patients will be enrolled in the study (having received at least 
one dose of treatment). The design will follow Simon’s two-stage design for phase II studies, with a 
baseline number of 18 patients. The combination of TH-302 with sunitinib will be considered as 
inactive in terms of the response rate if less than 5% of patients are responders, with a response rate 
threshold of 20%. These figures are based on the results shown with other drugs for the treatment of 
pNET.  
 
 
- Pancreatic NET 
- Unresectable/Metastatic 
- Well/moderately 
differentiated 
- Naïve to systemic 
treatment (except 
somatostatin analogues) 
TH-302  
+  
Sunitinib 
Biomarkers 
- Serological 
- Tumour tissue 
Radiological Progression 
(RECIST 1.1) 
Unacceptable toxicity 
Withdrawal of Consent 


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Should a response be identified in at least 3 out of every 18 patients treated, recruitment will continue 
up to 43 patients in order to be able to better estimate the response rate. If the study shows a response 
in at least 8 patients, the treatment is likely to continue its research development. 
 
The likelihood of terminating the study after the first part with 18 patients enrolled is 0.42 if the 
response rate is 10%, and 0.06 if the response rate is 25%. 
 
The likelihood of not accepting the null hypothesis and considering the combination of TH-302 with 
sunitinib active with a response rate less than 5% is 5% (Type I or alpha error).  
 
The likelihood of not rejecting the null hypothesis and considering the combination of TH-302 with 
sunitinib inactive with a response rate greater than 5% is 20% (Type II or beta error). The statistical 
power of the study will be 0.80. 
 
  
 
 


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 6. TREATMENT 
 6.1 Treatment Administration 
 
6.1.1. Sunitinib 
Sunitinib will be provided by the Trial Sponsor. Sunitinib will be administered at a dose of 37.5 mg 
per day (1 capsule of 25 mg and 1 capsule of 12.5 mg) orally for 28 days on an ongoing basis. It must 
always be taken at the same time every day (or as close as possible) and capsules must be swallowed 
whole. Food does not appear to affect the bioavailability of the drug. A 37.5 mg dose was chosen 
based on the approved dose of sunitinib for the treatment of pancreatic neuroendocrine tumours 
(pNET). If the patient requires a sunitinib dose reduction, the dose adjustment stated in section 6.3 will 
be followed.  
 
On days when TH-302 is also administered, sunitinib must be taken 2 hours before, or at least 2 
hours after TH-302 infusion. Given its hypoxia-inducing ability in highly vascular tumour tissue 
and its TH-302-enhancing effect, sunitinib will be administered as monotherapy in the first week 
of treatment. 
 
If, for any reason, the patient skips a dose or vomits after ingestion, a double dose should not be taken 
the following day. Treatment will resume on the following day with the usual daily dose. In contrast, if 
for any reason an additional dose is taken, the following day’s dose should be skipped. 
 
The study drug will be supplied in 25 mg and 12.5 mg capsules. The study drug must be handled and 
stored safely and as specified on the label. The label on the bottles will indicate the study protocol 
number, the medication or bottle number, the contents, instructions for use, storage instructions, the 
clinical trial declaration and the name of the sponsor. The patient number will be allocated to a bottle 
upon hand over. 
 
Patients will be instructed as to its correct administration and that it must be kept at room temperature 
(15-25 ºC) and out of the reach of children. Site staff must ensure that the patient understands the 
instructions for correct outpatient use of the drug. 
 
Patients will receive enough medication until the next visit, and must return the containers with any 
surplus medication for it to be accounted for. This will take place on day 1 of each cycle prior to 
dispensation of medication for the next cycle. Any surplus medication returned by the patient for it to 
be accounted for will not be dispensed again, and the number of surplus sunitinib tablets will be 
recorded. If the dose is modified during a medical visit, the patient will return all surplus prior 
medication.  
 
The patient will be questioned about treatment compliance at each study visit. For a patient to be 
deemed to adequately comply with the study treatment, at least 80% of the prescribed doses must be 
administered. The recording of these activities will comply with current regulations and guidelines. 
 
 


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6.1.2 TH-302 
TH-302 will be provided by the Sponsor. The TH-302 dose administered will be 340 mg/m2 by 
intravenous infusion over 30-60 minutes, on days 8 and 22 of each cycle. The dose should be adjusted 
according to body surface area. In the event of patient weight variation > 10%, the body surface area 
will be recalculated and the TH-302 dose readjusted. If the patient requires a TH-302 dose reduction, 
the dose adjustment stated in section 6.3 will be followed.  
 
The TH-302 medicinal product is supplied in a 10 ml glass bottle and must be diluted prior to 
administration with a 5% commercial glucose solution (containing 278 mmol/L dextrose) for injection 
to a total volume of 500 ml (1000 ml for a total dose ≥ 1000 mg) per infusion to obtain the final 
desired concentration. The 5% glucose solution will not be provided. 
 
Each dose of TH-302 will be prepared in an infusion bag without di-(2-ethylhexyl) phthalate (DEHP) 
with 5% glucose solution for clinical use and administered intravenously using an infusion pump and 
DEHP-free IV delivery system. 
 
TH-302 should be administered under free-flow intravenous fluid, preferably through a central venous 
catheter, especially in the presence of extravasation risk factors. Administration through the small 
vessels in the hands or feet is not recommended. 
 
Detailed instructions on dilution and administration are included in the pharmacy files. Preventive 
treatment will be added prophylactically for nausea or vomiting, following a regimen for moderately 
emetogenic chemotherapy.  
 
Cases of perivascular erythema and hyperpigmentation at the infusion site have been reported. Severe 
cellulitis and tissue necrosis may manifest due to TH-302 extravasation during its administration. The 
necessary recommended and preventive measures should be taken for the administration of cytostatic 
drugs, thereby preventing complications during infusion. If any signs or symptoms of extravasation 
appear, the TH-302 infusion should be stopped and continued in another vein. The patient should be 
monitored closely to assess the evolution of the skin lesion given the progressive nature of 
extravasation lesions, and a plastic surgeon should be consulted if necessary. 
 
Infusion reactions have also been observed during the administration of TH-302 characterised by 
swelling of the lips and urticaria, which respond to treatment with steroids and antihistamines. Include 
a steroid (such as dexamethasone or equivalent) in the pre-infusion antiemetic regimen is 
recommended. Signs and symptoms of hypersensitivity include fever, myalgia, headache, rash, 
pruritus, urticaria, angioedema, chest discomfort, dyspnoea, cough, cyanosis and hypotension. If the 
nature and severity of the reaction require the infusion to be discontinued, it should be determined 
whether it is an IgE-mediated process. If symptoms such as obstruction of the upper airways or 
hypotension are presented that suggest anaphylaxis or an anaphylactoid reaction, the investigator will 
assess whether to administer an antihistamine (such as slow intravenous or intramuscular 
diphenhydramine 25-50 mg orally, or equivalent) and a low-dose steroid (such as intravenous 
hydrocortisone 100 mg or equivalent). If the event is clearly anaphylactic, the administration of 
epinephrine (1/1000, 0.3-0.5 ml subcutaneously, or equivalent) should be considered, in addition to the 
standard treatments. In the case of bronchospasm, the administration of inhaled β-agonists will be 
assessed. 
 
 


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Depending on intensity, idiosyncratic reactions may also be treated with an antihistamine and steroids 
at low doses. Post-infusion reactions of the study drug will be assessed and treated in a similar way. 
Whenever a study drug infusion reaction occurs, the investigator should consult the medical monitor to 
determine the most suitable procedure for future infusions. 
 
TH-302 must be handled and stored safely and as specified on the label and in the Investigator’s 
Brochure. The label on the bottles will indicate the study protocol number, the medication or bottle 
number, the contents, instructions for use, storage instructions, the clinical trial declaration and the 
name of the sponsor. The patient number will be allocated to a bottle upon hand over. 
  
 6.2. Duration of Treatment 
Treatment with TH-302 in combination with sunitinib will continue until disease progression, 
unacceptable toxicity, non-compliance with the protocol, the patient’s withdrawal of informed consent 
or at the discretion of the investigator. In case of withdrawal of the study medication for toxicity, 
the patient will continue follow-up according to the scheduled study activities, and the 
investigator following the patient shall be responsible for initiating another systemic treatment 
option if deemed appropriate. 
  
 6.3. Titration of the Study Drug 
All dose modifications must be conducted according to the most severe preceding toxicity, as 
classified by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE, version 4.0).  
 
As far as possible, an attempt should be made to follow the dose and scheduled regimen. However, in 
case of an adverse event, administration of the study drug should be titrated as described below. 
 
The patient should notify the investigator of the date of onset of any adverse signs and symptoms. 
 
Dose modifications to both treatments may be required in 3 different situations: 
● During a cycle: treatment is discontinued until recovery and the dose is reduced, if 
necessary, during a particular treatment cycle. 
● Between different cycles: treatment administration is delayed in the next cycle due 
to persistence of residual toxicity at the beginning of a new cycle. 
● During the following cycle: the dose is reduced in the following cycle, taking into 
account the toxicity exhibited in the previous cycle. 
 
In the event of treatment delay, proceed as follows: 
● On day 1 of a cycle, if the administration of sunitinib must be postponed, the whole 
cycle must be delayed. 
 
 


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● On days 8 or 22, if the administration of both drugs must be postponed, that dose 
must be skipped. 
● On days 8 or 22, if the administration of just 1 drug must be postponed, that dose 
will be skipped and the cycle will not be delayed, but rather the other drug will be 
administered on its own. 
 
6.3.1. Discontinuation of Treatment 
The treatment will be temporarily discontinued until the resolution of ≤ grade 2 toxicity. Depending on 
the duration of treatment discontinuation, this will either lead to the loss of all subsequent scheduled 
doses within the same cycle, or even delay the start of the next cycle. If the patient recovers from the 
adverse event within the same cycle, therapy may be continued in that cycle. Any missed doses for 
toxicity will not be made up for within the same cycle. 
 
Dose reduction when reintroducing the treatment is determined below (section 6.3.3), unless, in the 
event of disagreement, the investigator prefers to discuss it with GETNE (investigacion@mfar.net). If 
a dose is reduced within a cycle, the patient should return to the site to receive the new treatment dose. 
 
If treatment discontinuation lasts > 4 weeks, for reasons other than study treatment toxicity (non-
cancer surgery, etc.), GETNE must be consulted before reintroducing the study drug 
(investigacion@mfar.net). 
 
Treatment will be discontinued permanently in the following situations: 
 
● The patient requires more than 2 dose-reduction steps.  
● The patient requires more than 4 weeks delay (one full cycle) to restart treatment 
due to study treatment toxicity. 
 
In patients for whom recovery from treatment toxicity involves treatment suspension lasting more than 
4 weeks, or delaying a treatment cycle, but there is a clear clinical benefit in the opinion of the 
investigator, reintroduction of the treatment may be discussed with GETNE (investigacion@mfar.net). 
 
Patients who discontinue treatment with TH-302 may continue receiving sunitinib as monotherapy 
within the trial. 
 
Under no circumstances may patients receive TH-302 as monotherapy. In the event that the 
administration of sunitinib must be discontinued, the administration of TH-302 will also be 
discontinued. 
 
Patients who permanently discontinue TH-302 and sunitinib will abandon active treatment and enter 
the follow-up phase. 
 
 6.3.2. Reintroduction of Treatment 
The study treatment will not be reintroduced until the following parameters with the adjusted dose are 
met, as described in section 6.3.4.: 
 
 
 


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● For TH-302, neutrophil count ≥ 1,500 mm³, with no evidence of fever (Temp. ≥ 
38 ºC) 
● For Sunitinib, neutrophil count ≥ 1,000 mm³. 
● Platelet count ≥75,000 mm3 (see section 6.3.3.) 
● Haemoglobin ≥ 9 g/dl on day 1 of the cycle and haemoglobin ≥ 8 g/dl in the weeks 
thereafter. If haemoglobin < 8 g/dl, the appropriate measures, in accordance with 
routine clinical practice, must be taken before continuing with the treatment. 
● Non-haematological toxicity recovery to grade ≤ 1 or baseline. Treatment 
reintroduction may be considered with ≤ grade 2 toxicity recovery at the discretion 
of the investigator, and if this decision does not compromise the safety of the 
patient. 
● QTc interval < 501 msec and after correcting potential reversible causes of the 
disorder, such as electrolyte disturbances or concomitant medications that prolong 
the QTc. If the QTc interval continues > 480 msec, an ECG must be performed 
more regularly at the discretion of the investigator, in accordance with routine 
clinical practice, until the QTc interval ≤ 480 msec. 
● ALT (and/or AST) value < 3 x ULN (< 5 in the event of liver metastases) and a 
total serum bilirubin value ≤ 1.5 x ULN. Patients who exhibit these parameters for 
more than 2 weeks must permanently discontinue the study treatment. 
 6.3.3. Dose Reduction 
Titration is not required in patients with grade 1 or 2 treatment-related toxicity. Despite this, 
investigators should always treat their patients according to their medical judgement and based on 
individual circumstances.  
 
2 dose-reduction steps are permitted depending on the type and severity of toxicity. If the investigator 
deems it to be necessary, the reduction of the two dose levels can be performed directly, without 
needing to wait for a time between both.  
 
Patients requiring more than 2 dose reductions will abandon the treatment phase and enter the follow-
up phase.  
 
All adjustments or dose modifications should be clearly documented in the patient’s medical record 
and in the CRF (Investigational product administration). 
 
Once a patient’s dose has been reduced, all subsequent cycles will be administered at that same dose, 
unless a further reduction is required. Dose reescalation will not be permitted as part of the study. 
Specific cases will be discussed with the study’s coordinating investigator (investigacion@mfar.net). 
 
 


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Table 1. Available dose levels with TH-302 and sunitinib 
 
DOSE LEVEL 
TH-302 DOSE 
SUNITINIB DOSE 
Starting 
340 mg/m2 D8, 22 
37.5 mg/24h D1-28 
-1 
280 mg/m2 D8, 22 
37.5 mg/24h D1-28 
-2 
280 mg/m2 D8, 22 
37.5 mg/24h D1-22, plus a rest week 
(3 weeks on / 1 week off) 
 
 
6.3.4. Dose Titration According to the Type and Severity of Toxicity 
 
Table 2. Titration according to haematological toxicity 
 
ABSOLUTE 
NEUTROPHIL 
COUNT 
(ANC) (/µl) 
AND
/OR 
PLATELET  
COUNT  
(/µl) 
DOSE LEVEL WHEN 
REINTRODUCING  
TH-302 
SUNITINIB 
Day 8 
Day 22 
≥ 1500 
AND 
≥ 100,000 
Starting 
Starting 
Starting 
1000-1499 
AND 
75,000-99,999 
Delay 
Delay 
Starting 
500-999 
OR 
50,000-74,999 
Delay and  
reduce one level 
in following 
cycles 
Delay and  
reduce one level in 
following cycles 
Reduce one level 
< 500 
OR 
< 50,000 
Delay and  
reduce one level 
in following 
cycles 
Delay and  
reduce one level in 
following cycles 
Reduce one level 
 
 
 
 
 
 


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Table 3. Titration according to non-haematological toxicity 
 
 
TH-302 
Toxicity 
grade 
Toxicity 
Discontinuation  
Dose after 
recovery 
Grade 2 
Except for asthenia, alopecia, nausea, vomiting 
and diarrhoea 
Until ≤ grade 1 
recovery 
Starting 
Unacceptable skin abnormality 
Until ≤ grade 1 
recovery 
Reduce one level  
(-1) 
Grade 3 
Except for nausea and vomiting 
Until ≤ grade 1 
recovery 
Reduce one level  
(-1) 
Grade 4 
Potentially fatal (drug-related) 
Permanent 
discontinuation 
N/A 
Others such as non-life threatening asthenia or 
pulmonary embolism 
Until ≤ grade 1 
recovery 
Reduce two levels 
(-2) 
 
 
Table 4. Titration according to non-haematological toxicity 
 
Sunitinib 
Toxicity grade 
Toxicity 
Discontinuation 
Dose after recovery 
Creatinine > x2  
upper limit  
of normal (ULN) 
Irrespective of the cause 
Until creatinine ≤ x2 upper 
limit of normal (ULN) 
Reduce one level (-1) 
Grade 2 
Except for asthenia, alopecia, 
nausea, vomiting and diarrhoea 
Until ≤ grade 1 recovery 
Starting 
Grade 3 
Except for nausea and vomiting 
Until ≤ grade 1 recovery 
Reduce one level (-1) 
Grade 4 
Potentially fatal (drug-related) 
Permanent discontinuation 
N/A 
Others such as non-life 
threatening asthenia or pulmonary 
embolism 
Until ≤ grade 1 recovery 
Reduce one level (-1) 
 
 
 
 


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Table 5. Titration according to ECG QTc interval prolongation 
 
 
 
Presence of a  
reversible cause 
Unidentified  
reversible cause 
G2 QTc interval  
prolongation 
- Treat the reversible cause. 
- ECG monitoring. * 
- If first event, continue TH-302 at 
the same dose if QTc < G2 (≤ 480 
msec) 
- If relapse, G2 or QTc > 480 msec 
more than two cycles after 
correction of the possible causes, 
and with no other identifiable 
cause, the dose will be titrated 
after consulting a cardiologist and 
GETNE, in accordance with the 
available TH-302 safety data and 
the investigator’s good medical 
practice.  
- ECG monitoring.* 
- If first event, continue TH-302 at the 
same dose. 
- If relapse or QTc > 480 msec more 
than two cycles after correction of the 
possible causes, and with no other 
identifiable cause, the dose will be 
titrated after consulting GETNE, in 
accordance with the available TH-302 
safety data and the investigator’s 
good medical practice. 
 
 
G3 QTc interval  
prolongation 
- Treat the reversible cause. 
- ECG monitoring. * 
- Discontinue treatment until  
QTc ≤ 500 msec. 
- Reintroduce TH-302 at the same 
dose  
- If G3 recurs, future dose titration 
will be performed after consulting 
a cardiologist and GETNE, in 
accordance with the available TH-
302 
safety 
data 
and 
the 
investigator’s 
good 
medical 
practice. 
- ECG monitoring. * 
- Discontinue treatment until  
QTc ≤ 500 msec. 
- Reintroduce treatment with one-
level dose reduction. 
- If G3 recurs, despite dose reduction, 
future dose titration will be performed 
after consulting a cardiologist and 
GETNE, in accordance with the 
available TH-302 safety data and the 
investigator’s good medical practice. 
G4 QTc interval 
 prolongation 
Permanent 
treatment 
discontinuation 
Permanent treatment discontinuation 
* In the event of a QTc interval prolongation and during treatment discontinuation,  
the frequency of performing control ECGs should be increased to once a week 
 (the same day each week), together with electrolytes analysis, until the QTc interval  
≤ 480 msec (≤ G1). 
  
 
6.3.5. Medication Errors or Overdose 
Medication errors may be due to a timing error or the drug dosage. These cases should be recorded as 
an adverse event (AE) or severe adverse event (SAE), as appropriate, in the CRF. 
 


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Should a medication error occur, GETNE must be notified immediately (investigacion@mfar.net).  
 
Examples of a medication error: 
 
● Medication 
errors 
that 
involve 
patient 
exposure 
to 
the 
drug 
(dispensation/administration of expired medication, dispensation of commercial 
sunitinib or TH-302 or not allocated for this trial, etc.) 
● Medication errors or practices not in accordance with the protocol and that may or 
may not involve the patient participating in the study (deviations from relevant 
temperatures, trial medication stock mismatches, etc.). 
 
An SAE will be reported where a patient voluntarily or accidentally ingests more than 60 sunitinib 
tablets in a single cycle (for example, more than 4 tablets in more than 2 days within a cycle or more 
than 4 tablets in one day). 
 
An AE will be reported in cases where a patient voluntarily or accidentally ingests 58 or 60 sunitinib 
tablets in a single cycle. The event will be recorded in the CRF. 
 
Any TH-302 dosage error which leads to > 20% of the expected dose should be considered a TH-302 
overdose. 
 
6.3.6. Concomitant treatment 
All concomitant medication, including any drug administered within 4 weeks (28 days) prior to the 
day 1 visit and 30 days after the last dose of the study drug, must be recorded in the case report form, 
together with the reason for administration.  
 
The patient should be informed about the importance of consulting the investigator prior to taking 
additional medications.  
 
Concomitant medication includes any vitamins, herbal remedies, over-the-counter drugs and 
prescribed medicines. 
 
Any additional treatment that becomes necessary during the study, and any change to concomitant 
drugs, must be recorded in the corresponding section of the case report form, including the name, dose, 
duration and indication of each drug. 
 
Should medication be administered intermittently, or in relation to an adverse event, this adverse event 
should be recorded on the adverse event form of the case report form. 
 
● Disallowed concomitant treatment: 
◦ 
Other oncology drugs (chemotherapy, immunotherapy, targeted therapy) during the 
treatment phase, whether approved healthcare drugs or under clinical trial. 
◦ 
Drugs that are known to cause QT interval prolongation, given the risk of 
developing polymorphic ventricular tachycardia. (Annex 4) 
◦ 
Strong or moderate CYP3A4 inhibitors 
 
 


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If, during the study, a patient requires treatment with one of these drugs for a limited period of time, 
TH-302 and sunitinib will not be administered simultaneously. Treatment will be reviewed together 
with the medical monitor, who will supply the dosage rules based on the half-life of the medicinal 
products, TH-302 and sunitinib, in addition to other clinical considerations. The medical monitor will 
advise the investigator, who will assess the search for alternative medicines. 
 
● Concomitant treatment not recommended: 
◦ 
Chronic immunosuppressant treatment, including systemic corticosteroids. Short 
courses of topical/inhaled or systemic corticosteroids are permitted 
◦ 
Herbal products 
 
For up-to-date information on drug interactions (substrates, inhibitors or inducers), visit the following 
website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLa
beling/ucm093664.htm#classSub 
 
● Permitted concomitant treatment 
◦ 
Treatment with somatostatin analogues (octreotide LAR or lanreotide Autogel) at 
doses established in the summary of product characteristics and with the aim of 
controlling the symptoms of the patient’s underlying disease 
◦ 
Any treatment for pre-existing comorbidities, complications or symptomatic 
control, taking into account the precautions mentioned above, and recorded in the 
patient’s medical record and in the CRF. 
◦ 
Stimulation of colony formation, following standard treatment and institutional 
guidelines. Its use is not allowed as primary prophylaxis, but is allowed as 
secondary treatment or prophylaxis, in the event that the alternatives of dose 
reduction or treatment delay are not deemed appropriate. 
◦ 
Transfusion of red blood cells/platelets or erythropoietin for supportive treatment of 
anaemia or for the prompt treatment of thrombopenia, following standard treatment 
and institutional guidelines.  
◦ 
Hormone replacement therapy within 2 months prior to study enrolment shall not 
constitute an exclusion criterion. The same dose must be maintained throughout the 
course of the study. 
◦ Palliative radiotherapy of non-target lesions is permitted, if necessary, while taking 
part in the study. The location, total dose received and treatment dates should be 
recorded in the case report form. 
  
  
 
 


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 7. PATIENT SELECTION 
 7.1. Inclusion Criteria 
1. Age ≥ 18 years capable of giving informed consent. 
2. ECOG performance status (Eastern Cooperative Oncology Group) 0 or 1 
3. Pancreatic neuroendocrine tumours (pNET) diagnosed histologically with a Ki67 ≤ 20% (well- or 
moderately-differentiated tumours). 
4. Evidence of unresectable or metastatic disease. Locally advanced disease must not be amendable to 
surgical resection or radiation therapy with curative intent.  
5. Prior systemic therapy is not permitted. Patients may be treated with somatostatin analogues prior to 
or during the trial. Concomitant or prior interferon (IFN) treatment is not permitted. 
6. Tumour progression documented by CT scan, MRI or octreoscan within 12 months prior to the 
baseline visit. 
7. Measurable disease by RECIST 1.1 criteria. Measurable lesions that have been previously radiated 
will not be considered target lesions unless increase in size has been observed following completion of 
radiation therapy. 
8. The patient must be able to consume the medication orally. 
9. Life expectancy more than 12 weeks. 
10. The required laboratory values corresponding to adequate organ function and bone marrow are as 
follows.  
● Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x 
upper limit of normal (ULN), or AST and ALT ≤ 5 x ULN if liver function 
abnormalities are secondary to underlying malignancy.  
● Total serum bilirubin ≤ 1.5 × ULN 
● Serum albumin ≥ 3.0 g/dl 
● Absolute neutrophil count ≥ 1500/µl. 
● Platelets ≥ 100,000/µl 
● Haemoglobin ≥ 5.6 mmol/l (9 g/dl)  
● Creatinine clearance > 40 ml/min (Cockroft and Gault Formula) 
11. Suitable cardiac function: 
● 12-lead ECG with no pathological findings (non-clinically significant abnormalities 
are permitted) 
● Normal echocardiogram/MUGA normal (LVEF ≥ 50%) 
12. Informed consent with date and signature indicating that the patient (or legal representative) has 
been informed of all study aspects prior to enrolment. 
 
 
13. The patient must be able to comply with the required study visits, treatment, laboratory tests and 
other study procedures. 


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 7.2. Exclusion Criteria 
Patients must NOT meet any of the following exclusion criteria: 
 
1. Previous treatments with chemotherapy, anti-VEGF monoclonal antibodies, tyrosine kinase 
inhibitors (TKI), mTOR inhibitors or interferon (IFN) administered for advanced disease. 
2. Prior treatment with another hypoxia-activated drug under clinical trial. 
3. Major surgery, radiotherapy or systemic therapy within 4 weeks prior to study enrolment, except 
palliative radiotherapy for non-target metastatic lesions. 
4. Prior high-dose chemotherapy requiring haematopoietic stem cell rescue. 
5. Immunosuppressive drugs such as cyclosporine, tacrolimus, azathioprine, or long-term 
corticosteroids taken concurrently or within 3 months prior to study enrolment. 
6. Treatment, within 7 days prior to study enrolment, with known strong CYP3A4 inhibitors or 
inducers, or drugs that prolong the QT interval. 
7. Prior radiation therapy to > 25% of the bone marrow. 
8. Treatment within another clinical trial. 
9. Uncontrolled brain metastatic disease, spinal cord compression, carcinomatous meningitis or 
leptomeningeal disease. Patients should have completed surgery or radiation therapy for existing brain 
lesions, should not have documented increase in size of said lesions over the three months prior to the 
first study treatment dose, and should be asymptomatic. 
10. Diagnosis of any second malignancy within the last 3 years, except for adequately treated basal 
cell or squamous cell skin cancer, or carcinoma in situ of the cervix. 
11. Clinically significant cardio/cerebrovascular disease within 12 months prior to treatment initiation, 
including:  
● Myocardial infarction 
● Severe/unstable angina 
● Coronary/peripheral artery bypass graft 
● Congestive heart failure NYHA (New York Heart Association) Class III or IV, or 
patients with a history of congestive heart failure NYHA class III or IV, unless an 
echocardiogram or MUGA scan within 3 months prior to screening shows a left 
ventricular ejection fraction ≥ 45%. 
● Significant cardiac valvular heart disease. 
● Cerebrovascular accident including transient ischaemic attack. 
● Pulmonary thromboembolism. 
12. Cardiac arrhythmias (NCI CTCAE version 4.0 grade ≥ 2), atrial fibrillation of any grade, or QTc 
interval > 450 msec for males or > 470 msec for females. 
13. Hypertension that cannot be controlled despite optimal medical therapy (> 150/100 mmHg) 
14. Chronic obstructive pulmonary disease (COPD) or any lung disease accompanied by hypoxaemia 
or oxygen saturation < 90% after a 2-minute walk. 
15. Current treatment with therapeutic doses of acenocoumarol (administration of low doses of 
acenocoumarol up to 2 mg/24 h for deep vein thrombosis prophylaxis is permitted). 
16. Known human immunodeficiency virus (HIV) infection. 
 
 


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17. Pregnant or breast-feeding. All female patients of childbearing age must have a negative pregnancy 
test (blood or urine) prior to study enrolment. 
18. Prior allergic reaction to ingredients structurally similar to TH-302 or sunitinib or to any of the 
drugs’ excipients.  
19. Non-healing wound, fistulae, active stomach ulcer or bone fractures. 
20. Any condition (medical or psychiatric) or reason that, in the opinion of the investigator, would 
interfere with the patient’s ability to participate in the clinical trial, by placing the patient at excessive 
risk or by complicating the interpretation of the safety data, therefore being unsuitable for enrolment in 
the study. 
 7.3 Criteria for treatment withdrawal 
The patient may withdraw the informed consent and stop treatment at any time during the study, for 
any reason. The investigators and medical monitors may discontinue treatment for reasons of safety 
and/or lack of compliance, as detailed below. These patients will attend the follow-up safety visit. 
Patients who discontinue treatment will be followed up to determine radiological progression, 
subsequent neuroendocrine tumour treatments and survival. 
 
Treatment withdrawal due to adverse events or safety reasons: 
 
● Any unacceptable adverse event that cannot be appropriately managed by medical 
intervention or which, in the opinion of the investigator or the clinical monitor, 
poses excessive risk for the patient if the current dose is continued. 
● Any unacceptable toxicity according to the protocol (see section 6.3. Safety 
assessment. Titration of the Study Drug.) 
● Disease progression based on protocol criteria. 
● Patients who, in the opinion of the investigator or clinical monitor, clearly fail to 
comply with the requirements of the protocol. 
● Patient’s absence from follow-up. 
● Administration of chemotherapy or immunotherapy not envisaged by the protocol 
but that, in the opinion of medical staff, is required by the patient. 
● Study ended by GETNE 
● Patients who experience a treatment delay greater than 4 weeks will discontinue 
treatment and enter the follow-up phase, unless there is an obvious clinical benefit 
in the opinion of the investigator and after discussing it with GETNE 
(investigacion@mfar.net). 
● Whenever possible, after permanent treatment discontinuation, the patient should 
continue with the follow-up assessments as scheduled after the last treatment dose 
received. Any permanent treatment discontinuation must be recorded in the eCRF. 
 
 
 
 


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8. METHODOLOGY 
 8.1. Translational Section. Determination of Biomarkers. 
Sample Collection 
Tumour block collection 
A paraffin-embedded tumour block will be requested and sent to the Pathology Department of the 
Hospital Universitario Ramón y Cajal for the hypoxia marker expression study. 
 
Collection of peripheral blood samples 
10 ml of peripheral blood will be taken from each patient during the baseline visit and placed in EDTA 
tubes, to be sent to the Spanish National Cancer Research Centre for polymorphism study.  
 
Handling and storage of samples 
Tumour block 
The paraffin blocks will be stored at room temperature under routine site conditions after the patient 
has signed the informed consent form, at which point they will be sent to the reference site. 
 
Peripheral blood samples 
The blood samples will be stored at -20 °C from the moment of extraction, and will be sent 
periodically to the reference site. 
 
Sample shipping 
Tumour block 
The paraffin blocks will be sent with the periodic deliveries at room temperature (< 25 ºC). 
Peripheral blood samples 
The blood samples will be sent all together and correctly identified in dry ice to the reference site. 
 
Centralised receipt of samples 
The paraffin-embedded tumour samples will be received by the Pathology Department of the Hospital 
Universitario Ramón y Cajal. 
Address: 
Ctra. Colmenar Viejo km 9100,  
Postcode: 28034 
Madrid.  
The samples will be received from Monday to Friday, from 08:00 to 15:00.  
 
Peripheral blood samples will be received by the Spanish National Cancer Research Centre (CNIO) for 
the attention of: 
Dr Cristina Rodríguez-Antona 
Grupo de Cáncer Endocrino Hereditario (Hereditary Endocrine Cancer Group) 
Programa de Genética del Cáncer Humano (Human Cancer Genetics Programme) 
Spanish National Cancer Research Centre (CNIO) 
Melchor Fernández Almagro, 3 
28029 Madrid 
The samples will be received from Monday to Friday, from 08:00 to 15:00. 
 
 


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Sample processing 
 
Tumour block 
The paraffin blocks will be analysed by specialised pathologists as they are received. The expression 
of hypoxia-related proteins such as CAIX, HIF2A/HIF-1alpha, VEGF, CYP2W1 and c-myc will be 
assessed centrally and retrospectively in immunohistochemistry. 
 
Peripheral blood:  
DNA will be isolated from the peripheral blood, following the instructions of the “FlexiGene DNA 
kit” (Qiagen), and the concentration of the DNA extracted will be quantitated by the “PicoGreen® 
dsDNA quantitation reagent” (Invitrogen). The DNA will be stored at -20 ºC until genotyping.  
Genotyping will be carried out by standard techniques (for example, “TaqMan Probes”, or “KASPar 
SNP Genotyping System”) using 15 ng of genomic DNA. Fluorescence detection and allele 
assignment will be performed using the “7900HT Detection System” by Applied Biosystems. The 
results obtained will be used to create a genetic database, which will collect the genotypes of each 
patient enrolled in the study.  
The list of polymorphisms to genotype includes variants in the following candidate genes:  
VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826), IL8 (rs1126647), CYP3A4 (rs35599367 
and rs67666821), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503 and rs2032582), POR 
(rs1057868 and c.1705_1706insG). If a polymorphism of particular relevance and related to the 
effectiveness of sunitinib or TH-302 appears in the literature as the study progresses, its inclusion in 
the study could be considered. 
The procedure for coding and shipping samples is detailed in a separate document. 
 
 
  
 
 


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 9. STATISTICAL ANALYSIS 
 9.1. Descriptive Analysis 
The descriptive analysis of patient characteristics will include demographic data, disease-specific data 
and prior treatments. Qualitative data will be described with absolute frequencies and corresponding 
percentages. Quantitative data will be studied using the mean ± standard deviation, median, minimum 
and maximum values. The response percentages will be estimated using confidence intervals of 95%. 
In the safety analysis, adverse events will be specified according to the maximum grade described at 
the discretion of the investigator and defined by NCI-CTCAE, version 4.0 (see section 10.2.3.), 
including adverse events described from treatment initiation until 28 days following its completion. 
 
The following safety analysis data will be presented: 
● Temporary and permanent treatment discontinuations due to an adverse event. 
● Deaths. 
● Adverse Events (AEs) and Serious Adverse Events (SAEs). 
● Hospitalisations. 
● Use of concomitant medication and growth factors. 
 9.2. Inferential Analysis 
The objective response rate corresponding to the percentage of patients in which there is confirmation 
of a complete response (CR) or a partial response (PR) according to RECIST criteria, in relation to the 
total analysis population, will include a confidence interval of 95%. The association between the 
marker expression profiles analysed in plasma and in tumour tissue for treatment response (yes/no) 
will be assessed using logistic regression models and univariate and multivariate Cox regression, 
establishing the corresponding hazard ratio and confidence interval at 95%. The predictive value (of 
genetic biomarkers, in plasma and tumour tissue) of each model will be estimated using an area under 
the ROC curve. 
 
The survival analyses will be performed using the Kaplan-Meier method presented with the 
corresponding graph, as well as by Cox regression analysis to obtain the hazard ratios and confidence 
intervals for the associations. For patients without documented progression or death at the time of 
analysis, the PFS will be censored at the last date of tumour assessment. For patients who have not 
died at the time of analysis, the OS will be censored. 
 
All statistical tests are bilateral, two-tailed tests, and all values with p < 0.05 will be considered 
significant. 
 
 
  
 
 


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 10. ASSESSMENT CRITERIA 
 10.1. Efficacy Assessment 
 
Objective response rate (ORR) 
 
This will be assessed according to RECIST version 1.1 criteria, to be performed every 8 weeks, 
regardless of treatment delays caused by treatment toxicity.  
The ORR is defined as the percentage of patients in which there is confirmation of a complete 
response (CR) or a partial response (PR) according to RECIST criteria, in relation to the total analysis 
population.  
A response is confirmed for patients in whom the response persists in an imaging test repeated ≥ 4 
weeks after initial documentation of response.  
 
Progression-free survival (PFS) 
 
This is defined as the time between the start of study treatment to the date of first objective evidence of 
radiological progression or patient death from any cause; whichever comes first. 
 
Time to progression (TTP) 
 
This is defined as the time between the start of study treatment to the date of first objective evidence of 
radiological progression. 
 
Response duration (RD) 
 
This is defined as the time between the first recorded objective response (CR or PR), which is 
subsequently confirmed, to the first objective evidence of radiological progression or death from any 
cause.   
RD will only be calculated in the subgroup of patients with objective response (CR + PR). 
 
Overall survival (OS) 
 
This is defined as the time between the start of study treatment to the date of death from any cause.  
If confirmation of death could not be obtained, survival will be censored with the date of the last visit 
at which time the patient was known to be alive. 
 
Safety 
 
See Safety Assessment section below. 
 
Biomarkers:  
 
They assess the correlation between radiological response and the patient’s clinical course and the 
following expression levels: 
 
 


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● ENO1 (enolase 1) in plasma (it will be performed locally at the same time as 
chromogranin at each participating site) 
● SNPs (single nucleotide polymorphisms) related to the activity and metabolism of 
sunitinib and TH-302 VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826), 
IL8 (rs1126647), CYP3A4 (rs35599367 and rs67666821), CYP3A5 (rs776746), 
ABCB1 
(rs1045642, 
rs1128503 
and 
rs2032582), 
POR 
(rs1057868 
and 
c.1705_1706insG). If a polymorphism of particular relevance and related to the 
effectiveness of sunitinib or TH-302 appears in the literature as the study 
progresses, its inclusion in the study could be considered. 
● Hypoxia markers related to paraffin-embedded tumour tissue (HIF1- α, CYP2W1 
and c-Myc). 
 
 10.2 Safety Assessment 
 
10.2.1. Safety Analysis 
The safety period runs from the date of the signature of the informed consent form until 28 days after 
the last dose of the study drug. Safety will be evaluated according to adverse event reports, the 
frequency of treatment discontinuations due to adverse events, and laboratory or ECG tests. 
Descriptive analysis will be used. 
 
10.2.2. Adverse Events 
 
An adverse event is defined as any unwanted or unintended symptom, sign, disease or experience 
(including a clinically significant laboratory result of any grade according to the common terminology 
criteria for adverse events [CTCAE] of the National Cancer Institute, version 4.0) that emerges or 
worsens during the course of the study, whether related or not to the study drug. 
The assessment of adverse events will include type (symptoms from the medical history, physical 
examination findings or laboratory/ECG/radiological/other diagnostic procedure abnormalities), 
prevalence, severity/seriousness, time and their link. 
 
Examples of adverse events are the following: 
● Deterioration (excluding mild fluctuations) of the nature, intensity, frequency, or 
duration of a pre-existing condition. 
● Development of an intercurrent illness during the study. 
● Development of symptoms that may or may not be associated with the use of a 
concomitant medication or the study drug. 
● Injury or accidents: if a medical condition is known to have caused the injury or 
accident, both the medical condition as well as the accident should be recorded as 
two independent medical events (e.g., in the event of a fall caused by dizziness, 
both the “fall” and the “dizziness” must be recorded separately). 
 
The following situations will not be classified as adverse events: 
 
 


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● Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion). However, the disease precipitating the procedure is an adverse event. 
● Pre-existing conditions or diseases present or detected prior to the first 
administration of the study drug that do not deteriorate. 
● Circumstances in which no unwanted medical events manifest (e.g., hospitalisation 
for elective surgery, hospitalisations for social circumstances and/or convenience). 
 
The relationship between the adverse event and the study drug:  
 
The reasonable possibility of a link between the adverse event and the study drug will be determined. 
In cases where the study site investigator is unable to make an objective judgement, the opinion of the 
clinical monitor should be sought. The following definitions will be used: 
 
● Not related: There is no possible relationship to the study drug. The temporal 
relationship between drug exposure and the start/evolution of the adverse event is 
unreasonable or incompatible, or a causal relationship to the study drug is 
implausible. 
 
● Unlikely: If the study drug is deemed not to be reasonably related to the adverse 
event, but a causal relationship cannot be ruled out. Although the temporal 
relationship between exposure to the study drug and the start/evolution of the 
adverse event does not exclude causality, there is a clear alternative cause that is 
more likely to have caused the adverse event than the study drug. 
 
● Possible: The causal relationship to the study drug is not clear. The temporal 
relationship between drug exposure and the start/evolution of the adverse event is 
reasonable or unknown, information regarding the discontinuation of exposure or 
re-exposure is unknown or ambiguous, and although there are no other potential 
causes, a causal relationship with the study drug does not seem likely. 
 
● Likely: There is a high degree of certainty for the causal relationship between the 
study drug and the adverse event. The temporal relationship between drug exposure 
and the start/evolution of the adverse event is reasonable, the response is clinically 
compatible with discontinuation of exposure, other causes have been ruled out and 
the event must be conclusive from a pharmacological or phenomenological point of 
view, adopting a re-exposure procedure if necessary. 
 
● Definite: The causal relationship is clear. The temporal relationship between drug 
exposure and the start/evolution of the adverse event is reasonable, the response is 
clinically compatible with discontinuation of exposure, other causes have been ruled 
out and the event must be pharmacologically or phenomenologically conclusive, 
adopting a re-exposure procedure if necessary. 
 
 


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For the purposes of expedited reporting, the categories “definite”, “probable” and “possible” will be 
considered related to the study medication, and the categories “improbable” and “not related” shall be 
considered unrelated to the study medication. 
The site’s principal investigator, or the person delegated by said investigator, is responsible for 
determining the relationship of the adverse event to the study medication. 
 
Recording and reporting of adverse events: 
 
All adverse events experienced by patients, regardless of their relationship to the study drug, must be 
reported in full on the adverse event page of the case report form and in the patient’s medical record, 
adopting the appropriate medical terminology. The severity, the result and relationship to the study 
drug will be determined and documented in the case report form.  
Should a patient discontinue the study drug due to an adverse event, this must be recorded in the case 
report form. In the event of patient death caused by disease progression, the data will be included in 
the efficacy analysis, unless the investigator feels that the event is related to the study medication. 
Adverse events will be monitored until they have been resolved, or until they have stabilised and/or 
reached a new baseline level. If an adverse event has not been resolved before the end of the study, the 
investigator and the medical monitor will perform a clinical assessment to determine whether its 
follow-up is justified. 
 
The site investigator must record all directly observed adverse events and all adverse events that were 
spontaneously reported.  
It should be noted that the intermittent or on-demand use of any medicine (and specifically any newly-
prescribed medication) throughout the study could precipitate the onset of an adverse event that would 
have to be recorded on the case report form, both on the adverse event form as well as the concomitant 
medication form. 
 
Adverse events will be recorded on the case report form from patient enrolment after the informed 
consent form has been signed, during the study treatment and 28 days following the end of treatment. 
During the long-term follow-up, following the 28-day period after the end of treatment, adverse events 
(AEs) related to the study treatment or procedures will be recorded, even after study completion, until 
stabilisation or until the outcome is known, unless the subject is documented as “lost to follow-up”. In 
addition, should the patient sign the informed consent form but not receive treatment, adverse events 
will be recorded that the investigator considers to be related to the study procedures. 
 10.2.3. Intensity Grading of Adverse Events 
Adverse events and their severity will be assessed based on National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.0). These criteria can be consulted 
at the following address:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
 


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10.2.4. Serious Adverse Events (SAEs): 
A serious adverse event (SAE) or reaction is any harmful medical event that, regardless of the dose: 
 
● Results in the death of the patient. 
● Is life-threatening to the patient or potentially fatal (i.e., the patient is at immediate 
risk of death at the time of the event).  
● Requires patient hospitalisation or the prolongation of existing hospitalisation. 
● Results in permanent or significant disability or incapacity. 
● Causes a defect, congenital malformation or results in cancer. 
 
In addition, medical and scientific judgement should be used to decide whether other situations should 
be considered as a serious adverse event, although they do not meet the above criteria, such as those 
that endanger the patient’s life or require intervention to prevent any of the above outcomes.  
It must not be confused with the term “severe”, which indicates the intensity of the adverse event. 
 Recording and Reporting of Serious Adverse Events (SAEs): 
Information on SAEs, whether related to the treatment or not, will be collected and recorded on the 
SAE form of the corresponding case report form. SAEs, as defined above, must be recorded from the 
date the informed consent form was signed, and the pharmacovigilance contact person must be notified 
immediately, within 24 hours of awareness by the study site, by fax to  
 
Marketing Farmacéutico & Investigación Clínica 
FAX: +34 93 253 11 68 
email: investigacion@mfar.net 
 
The initial report must state the site name and number, the name of the investigator, the patient ID 
number and initials, patient demographics, study drug administration data and everything known about 
the serious adverse event, including date of onset, intensity, treatment and relationship to the study 
drug. If the patient dies, the report should include the cause of death and its potential relationship to 
the study drug, in addition to the autopsy findings (if available). 
 
This includes the determination of one or more SAE criteria, a detailed description of the event, 
relevant clinical reports (without names or other patient identifiers), the date of death and an autopsy 
report (where applicable, and if available), the updated investigator assessment regarding the 
relationship of the study drug to the SAE, and actions taken. 
The Sponsor will send the safety reports to the health authorities in an appropriate manner, in 
accordance with the applicable laws and regulations. 
SAEs must also be reported by the investigator to the responsible Independent Ethics Committee 
(IEC), in accordance with regulatory requirements. 
The assessment of the expected SAEs considered to be reportable to the health authorities and Ethics 
Committees, which were specified above, will be carried out by the Sponsor in accordance with the 
“Guide for the investigator” section of the most up-to-date version of the Investigator’s Brochure for 
TH-302. The updated version of the Investigator’s Brochure will be provided by Threshold. 
 
 


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The notification of a suspected SAE must not be delayed in order to obtain further information. The 
follow-up report will be completed with the collection of any additional data after the initial report. 
This report will also be issued should the event be resolved, in the absence of significant changes, or 
should the situation stabilise. This report will be issued in the following 24 hours. 
 
Through the study’s principal investigator, the sponsor (GETNE) will assess the SAEs, taking into 
account the product safety reference documents, and will report, through the CRO, those SAEs that 
meet the expedited reporting criteria (serious, unexpected and related to the study medication) with the 
help of the monitor. The sponsor is responsible for notifying the competent authorities (Spanish 
Agency of Medicines and Medical Devices - AEMPS, central IEC, hospital IEC, competent bodies of 
the Autonomous Communities) and the principal investigators/institutions involved in the study, and 
this will be carried out within the time scales determined by current Spanish legislation. The maximum 
period for notification shall be 15 calendar days from the time the sponsor learns of the suspected 
adverse reaction. However, if the unexpected serious adverse reaction leads to the patient’s death, or 
endangers the patient’s life, the sponsor shall inform the AEMPS within 7 calendar days from the time 
it became aware of the situation. Said information shall be completed, as far as possible, within the 
following 8 calendar days. 
All SAEs will undergo a follow-up until the following situations are reached: 
 
● Event resolution 
● Event stabilisation. 
● Restoration of the baseline situation and, if available, a baseline value. 
● The event can be attributed to products other than the study treatment or factors not 
related to the study. 
● It is not possible to obtain further information. 
 
All unresolved SAEs at the conclusion of the study must be followed up, to determine the end result.  
 
SAEs will be recorded from the time the patient signs the informed consent form until the follow-up 
safety visit, 28 days after the last dose of the study drug, or until the start of administration of an 
investigational or medical drug, whichever comes first. 
 
Fatal events (regardless of their relationship to the study drug) will be recorded as serious adverse 
events up to the follow-up safety visit (28 days after discontinuation of the study drug) or until the start 
of further treatment, whichever comes first. Fatal events that occur after the follow-up safety visit (28 
days after discontinuation of the study drug) or upon initiation of an investigational or medical drug, 
whichever comes first, will not be recorded as serious adverse events but will be recorded on the 
corresponding case report form.  
In the event of death, the main cause of death (the event that led to death) should be recorded and 
reported as an SAE. The result of this event will be recorded as “Fatal”; the death will not be recorded 
as a separate event. It may only be notified as an event if there is no cause of death (for example: 
sudden death, unexplained death). In this case, the death in itself could be reported as an SAE. 
 
 


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This event will not be reported expeditiously as an SAE within 24 hours, but will be recorded in the 
case report form and analysed as a study objective. The death of a patient is not an adverse event in 
itself, but an outcome of an adverse event. All patient-death reports must include an adverse event as a 
cause of death (if known). 
 
The sponsor will inform the investigators as soon as possible of any safety information that might 
affect patients. 
 Reporting pregnancy 
Women of childbearing potential who are sexually active must use an effective contraception method 
during the course of the study, so as to minimise the risk of failure. Before enrolment in the study, 
women of childbearing potential will be informed of the importance of avoiding pregnancy during 
their participation in the study, and the potential risk factors of an unwanted pregnancy.  
 
All women of childbearing potential MUST have a negative pregnancy test within 7 days prior to 
enrolment.  
In addition, all women of childbearing age will be asked to immediately contact the investigator if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time during their 
participation in the study. 
 
If, after initiating administration of the investigational medicinal product, it is discovered that a study 
patient is pregnant or may have been pregnant at the time of exposure to the product, the 
investigational medicinal product will be permanently discontinued as appropriate (e.g., dose reduction 
if required for the safety of the patient). The investigator must immediately inform the sponsor of this 
event in accordance with the SAE reporting procedures, and the pregnancy must be recorded on a 
pregnancy form (Annex 7).  
 
Initial information on a pregnancy must be reported immediately to the sponsor and information about 
its outcome must be provided once it is known. Completed pregnancy follow-up forms must be sent to 
the sponsor, in accordance with the SAE reporting procedures. 
 
The sponsor must be informed of any pregnancy that occurs in a female partner of a male study 
participant. Information on this pregnancy will be collected on the pregnancy form (Annex 7). 
 
Pregnancies must be reported to: 
 
 
Marketing Farmacéutico & Investigación Clínica 
FAX: +34 93 253 11 68 
email: investigacion@mfar.net 
 
The treatment discontinuation and follow-up procedures laid down in the protocol must be applied to 
the patient, unless contraindicated for pregnancy (e.g., x-rays). If indicated, other appropriate 
pregnancy follow-up procedures will be considered. 
 
 


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In addition, the investigator must inform the sponsor of any pregnancy, and follow-up on information 
regarding the course of the pregnancy, including a perinatal and neonatal outcome. Infants should be 
monitored for a minimum of 8 weeks 
 
 
 
 


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11. STUDY PROCEDURES 
 11.1. Schedule of Assessments 
See Annex I. 
 11.2. Baseline Visit (Days -28 to -1) 
At this visit the patient should be informed about all aspects of the study, including visits and tests to 
be performed. The patient will be asked to sign and date the informed consent form prior to 
performing any study procedure.  
The informed consent form must be signed within 4 weeks before the start of the study medication. 
The original signed and dated informed consent form must be stored by the investigator in the patient’s 
medical record and the patient must be provided with a copy. 
The investigator will assess and confirm the eligibility of each patient, and all inclusion criteria must 
be met, but none of the exclusion criteria. 
All the results of the tests undertaken during screening must be available before deciding whether a 
patient is eligible. 
 
The specific baseline visit procedures envisaged by the protocol are as follows and must be performed 
within 28 days of initiating study treatment, or, failing that, screening must be repeated. 
● Medical history. 
● 12-lead ECG. 
● Vital signs (blood pressure, heart rate, temperature, height and weight). 
● A full physical examination. 
● Complete blood test (See schedule of assessments, Annex I). 
● NET markers (chromogranin A, enolase 1 and others depending on the tumour 
type). 
● Urinalysis. 
● Performance Status (ECOG Performance Status) (Annex 3). 
● Concomitant medication. 
● Echocardiogram/MUGA. 
● Thoracic, abdominal, and pelvic CT scan (bone scan). 
● Extraction of peripheral blood sample (biomarker analysis in blood). 
● Tumour block for diagnosis of well- or moderately differentiated neuroendocrine 
tumour for biomarker analysis. 
 
Patients should start the study treatment within two working days following the baseline visit. 
 
11.3 Day 1 visit (may occur on the same day as the baseline visit if all baseline visit test results are 
available). 
● Confirm that all the screening period and baseline visit procedures have been 
carried out. 
● Confirm that the patient meets the inclusion criteria and none of the exclusion 
criteria. 
● Instruct the patient regarding the administration of the study medication and provide 
the study medication for a complete cycle, i.e., 28 days. 
 
 


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11.4 Treatment Visit 
● Days 1, 8, 15 and 22 of each cycle: 
◦ 
Physical examination. 
◦ 
Signs and symptoms. 
◦ 
ECOG performance status. 
◦ 
Vital signs (blood pressure, heart rate, temperature, height and weight). Recalculate 
body surface area if the variation has been shown to be greater than 10%. 
◦ 
Complete blood test (See schedule of assessments, Annex I).  
◦ 
Recording of adverse events. 
◦ 
Recording of concomitant medication. 
◦ 
Accounting for medication. 
◦ 
Administration of the study intravenous medication (TH-302 is not administered on 
D1 or on D15) and dispensation of oral medication. 
 
● Visit every 8 weeks (from D1 C1 onwards): 
◦ 
NET markers (chromogranin A, enolase 1 and others depending on the tumour 
type) (+/- 1 week). 
◦ 
Thoracic, abdominal, and pelvic CT scan reassessment (+/- 1 week). 
◦ 
If reassessing via bone scan, perform every 24 weeks. 
 
These procedures will not be postponed in the event of cycle delays and must be performed every 8 
weeks until disease progression, regardless of whether the patient has completed the treatment. 
 
 11.5 End-of-Study Treatment Visit 
This visit will take place once disease progression has been identified, in the event of unacceptable 
toxicity or if the patient decides to withdraw their consent to continue in the study. The end of 
treatment visit must take place 4 weeks after concluding treatment, irrespective of the cause of 
treatment discontinuation. 
 
The following procedures will be performed: 
● Physical examination. 
● Signs and symptoms. 
● ECOG performance status. 
● Complete blood test (See schedule of assessments, Annex I). 
● NET markers (chromogranin A, enolase 1 and others depending on the tumour 
type). 
● Urinalysis. 
● Echocardiogram/MUGA. 
● Recording of adverse events. 
● Recording of concomitant medication. 
● 12-lead ECG (only if clinically indicated). 
● Thoracic, abdominal, and pelvic CT scan (if applicable). 
● Bone scan, if clinically indicated. 
● Drug accountability. 
 
 


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 11.6 Follow-up 
The following procedures will be performed during follow-up until disease progression: 
 
● ECOG performance status. 
● Thoracic, abdominal, and pelvic CT scan and/or bone scan (if applicable). 
● Cancer treatment received. 
 
Tumour assessment must be performed every 8 +/- 1 weeks until disease progression, irrespective of 
whether the patient has completed the treatment. 
 
After disease progression, the overall survival secondary endpoint will be performed following the 
site’s usual practices (in terms of scheduling visits), and must be continued until death or end of the 
trial, whichever occurs first. 
 
  
 
 


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 12. ETHICAL ASPECTS 
 12.1. Legal Considerations 
This clinical study will be conducted in accordance with the protocol, the principles established in the 
latest revised version of the Declaration of Helsinki (Annex 5) and in accordance with applicable 
regulatory legislation, in particular, the ICH harmonised tripartite guideline on good clinical practice 
1996 and Royal Decree 223/2004 on Clinical Trials, regulating clinical trials with medicinal products 
in Spain, which incorporates the whole of European Directive 2001/20/EC on the approximation of 
provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials 
on medicinal products for human use. 
 12.2. Patient’s Informed Consent 
Before the screening assessment, the patient will be informed about the nature of the study drug and 
will receive the relevant information concerning the purpose of the study, the potential benefits and 
potential adverse events. The patient will be informed of the procedures to be undertaken and the 
potential risks to which he/she could potentially be exposed.  
 
Then, the patient (or, in the case of disabled patients, his/her legal representative) must read (or be 
informed orally before witnesses) and sign two copies of the informed consent form that will have 
previously been approved. The patient will receive a signed copy of the informed consent form. The 
patient may withdraw from the study at any time without it affecting his/her ongoing medical care. 
Verification that the patient has given written informed consent will be recorded in the patient’s CRF. 
 12.3. Respect for Confidentiality 
The investigator will be responsible for storing the appropriate information about each patient (for 
example, name, address, telephone number, social security number and study ID number) so that the 
health authorities may have access to said information if necessary. These records shall be kept 
confidential for as long as required by local legislation. 
 
The highest levels of professional conduct and confidentiality will be maintained at all times, ensuring 
compliance with national data protection legislation.  
 
The patient’s identity in the study documents will be coded, and authorised personnel, the sponsor, the 
study monitor, and the investigator’s staff at each site will have access to personal details that could 
identify the patient if required for the data verification processes. The patient study codes will be 
assigned by the study sponsor through the monitor, and will be created by assigning a unique identity 
number to each patient enrolled in the study. These codes will be safeguarded by the study sponsor and 
monitor. Personal details that could identify the patient will be kept confidential. 
 12.4. Liability Insurance 
The sponsor has taken out an insurance policy to cover the liability of the investigator and other parties 
participating in the study: 
 
 


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Insurance Company: HDI HANNOVER INTERNATIONAL ESPAÑA Seguros y Reaseguros S.A., 
with registered address at C/Luchana 23 
 
Policy Number: 130/001/009638 
 
  
 
 


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 13. STUDY DOCUMENTATION  
 13.1 Files 
The investigator must maintain adequate and accurate records to ensure that the study is fully 
documented and to allow the study data to be subsequently checked. These documents are:  
 
● Copies of completed CRFs, informed consent forms and the source documents. 
● Investigator’s file containing the protocol and any amendments, investigational 
medicinal product information as well as copies of essential documents. 
● Records related to the investigational medicinal product(s).  
 
In addition, all original source documents supporting CRF entries must be readily available. 
 
The patients’ original medical documentation would include the patients’ hospital/medical records, 
doctors’/nurses’ notes, the appointment book, original laboratory reports, ECG, EEG, X-ray, 
pathology and special assessment reports, signed informed consent forms, letters from specialists and 
patients’ screening and enrolment forms.  
 13.2 Case Report Form 
The principal investigator or a study team authorised representative must complete and sign an 
electronic CRF for each patient enrolled in the study. This also applies to patients who do not complete 
the study (even during the screening period prior to enrolment, if completion of a CRF has been 
started). If a patient withdraws from the study, the reason must be indicated in the CRF. If a patient 
withdraws due to a treatment-limiting adverse event, every effort should be made to clearly document 
the result. 
 
The database will be managed to allow the eCRF to generate further information requests that the 
investigator will be obliged to answer by confirming or modifying the data asked about. The requests, 
with their responses, will be managed through the eCRF. The eCRF must be kept up-to-date in order 
to allow the monitor to review the patients’ status during the course of the study. Procedures and 
controls will be employed to ensure the confidentiality of electronic records. 
 13.3 Monitoring 
The study will be monitored by the company MFAR. The accuracy of data collected in the CRFs shall 
be guaranteed by the monitor by verifying the data recorded in the CRF against data recorded in the 
medical record or in other documents such as laboratory reports, images, drug dispensation records, or 
any other source document containing information regarding the progression and follow-up of patients 
during their participation in the study. 
 
 


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Data to be verified shall be set out in the data verification plan, drawn up by the monitor and approved 
by the sponsor. The planned frequency of monitoring for each site will also be established. 
 
To ensure data accuracy, precision and completeness, GETNE: 
● Will provide the material with the necessary information to properly coordinate the 
study procedures. 
● Will provide a training session for the investigator’s team that will include a review 
of the protocol, the completion of the eCRF and study procedures. 
● Will conduct regular site visits to review study progress, investigator and patient 
compliance with procedures and to address any urgent problems. 
● Will remain in contact with the site for any query via e-mail, phone and/or fax. 
● Will review and evaluate the CRF entries to detect any possible errors. 
● Will ensure the quality of the data. 
 
To ensure data accuracy for the safety of the patient, the investigator must include the original 
laboratory reports, imaging tests, medical reports and medical notes taken at each visit.  
 13.4.- Publication of results 
The sponsor undertakes to promptly disseminate the results through the usual scientific means 
(conferences and publications), under the responsibility of the scientific coordinator and translational 
study coordinator. The study coordinator reserves the right to select his/her position in the different 
publications and reports that the study may envisage. The translational study coordinator will hold an 
assured position amongst the study authors. The remaining positions will be assigned to the 
participating investigators according to a rigorous order of recruitment. 
  
  
 
 


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advanced neuroendocrine tumours. J Clin Oncol 2011 ASCO Annual Meeting; 29 (15s): abstr 4079 
 
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Ortega, L., et al. Correlation of VEGFR2 expression in tumor tissue with longer progression-
free survival in patients with neuroendocrine tumours (NETs) treated with pazopanib. J Clin Oncol 
2014 Asco Annual Meeting; abstr 131956 
 
36. 
García-Donas J., et al. Single nucleotide polymorphism associations with response and toxic 
effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, 
observational, prospective study. Lancet Oncol 2011; 12: 1143-50 
 
37. 
Zhang, J., et al. Current Understanding of the Molecular Biology of Pancreatic 
Neuroendocrine Tumors. J Natl Cancer Inst 2013;105:1005–1017. 
 
38. 
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of 
antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumours. Cancer Cell. 2005 
Oct;8(4):299-309 
 
39. 
Tijeras-Raballand A, Neuzillet C, Couvelard A, et al. Resistance to targeted therapies in 
pancreatic neuroendocrine tumours (PNETs): molecular basis, preclinical data, and counteracting 
strategies. Target Oncol 2012;7(3):173-81 
 
40. 
Duan JX, Jiao H, Kaizerman J, Stanton T, Evans JW, Lan L, et al. Potent and highly selective 
hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. J Med Chem 2008;51:2412–
20 
 


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ANNEXES 
 
ANNEX 1. SCHEDULE OF ASSESSMENTS 
 
Screening 
(28 days) 
Cycles  
End of 
treatment  
(at 4 weeks 
+/- 1)  
after the 
end of 
treatment 
Follow-up 
 until 
progression 
(every 8 weeks  
until progression) 
Post-  
progression 
follow-up 
Day 1  
(D1) 
Week 2 
(D8) 
Week 3 
(D15) 
Week 4 
(D22) 
Informed consent 1 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical record and demographic data2 
X 
 
 
 
 
 
 
Physical examination (weight, height and vital si
X 
X 
X 
X 
X 
X 
X 
Signs/symptoms  
 
X 
X 
X 
X 
X 
X 
ECOG performance status (Annex 3) 
X 
X 
X 
X 
X 
X 
X 
Haematology and haemostasis4 
X 
X 
X 
X 
X 
X 
X 
Full clinical chemistry5 
X 
X 
X 
X 
X 
X 
X 
NET markers6 
X 
Every 8 weeks from D1C1 until progression 
and end of treatment visit. 
Pregnancy test7 
X  
≤ 7 days) 
 
 
 
 
 
 
12-lead ECG8 
X 
 
X8 
 
X8 
 
 
Urinalysis 
X 
 
 
 
 
X 
 
Echocardiogram/MUGA9 
X 
 
 
 
 
X 
 
Recording of adverse events  
X 
X 
X 
X 
X 
X 
X 
Recording of concomitant medication  
X 
X 
X 
X 
X 
X 
X 
Sunitinib dispensation record 
 
X 
 
 
 
 
 
Dose record/sunitinib compliance 
 
X 
X 
X 
X 
 
 
TH-302 administration 
 
 
X 
 
X 
 
 
CT image tumour measurements10 
X 
Every 8 weeks from D1C1 until progression and end of treatment visit. 
 
Collection and freezing of blood sample 
for marker tests11 
X 
 
 
 
 
 
 
Shipment of tumour sample for marker tests12 
X 
 
 
 
 
 
 
Post-study survival13 
 
 
 
 
 
 
 
X 
 
 
 


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1. Patients will be required to sign two copies of the informed consent form. The patient must indicate his/her 
degree of consent with respect to the use of biological samples. 
2. Medical record and demographic data: Includes but is not limited to: specific cancer history, date of 
diagnosis, type of primary tumour with histological diagnosis, previous surgical procedures and dates, and any 
other relevant medical history within the last 6 months. 
3. Physical examination: weight, height, body surface area and vital signs: heart rate, blood pressure, body 
temperature. 
4. Haematology and haemostasis: haematocrit, haemoglobin, platelet count, white blood cell count, red blood 
cell count, neutrophil count and lymphocyte count. Coagulation will include prothrombin time (PT), the 
international normalised ratio (INR) and activated partial thromboplastin time (APTT). This will be conducted 
at the baseline visit (≤ 7 days) and at each pre-treatment visit (+/- 3 days prior to day 8 and +/- 1 day prior to 
day 22 of each cycle). It will also be conducted +/- 1 day prior to day 15 to ensure a weekly follow-up of the 
patients. 
5. Clinical chemistry: AST, ALT, GGT, alkaline phosphatase, direct and total bilirubin, urea, calcium, chloride, 
creatinine, glucose, LDH, phosphorus, magnesium, potassium, sodium, albumin at the baseline visit (≤ 7 days) 
and at each pre-treatment visit (+/- 3 days prior to day 8 and +/- 1 day prior to day 22 of each cycle). It will also 
be conducted +/- 1 day prior to day 15 to ensure a weekly follow-up of the patients. 
6. Enolase 1, chromogranin A (or peptide secreted functionally) tumour markers at baseline visit, every 8 weeks 
(+/- 1 week) and at the end-of-study visit. 
7. Urine and blood pregnancy test in female patients of childbearing age. This will be conducted within 7 days 
prior to the day 1 visit and whenever pregnancy is suspected. 
8. 12-lead electrocardiogram: before every test, the subject must be at rest for approximately 10 minutes. The 
subject should be in a semi-lying or supine position; the same position must be adopted for all subsequent ECG 
tests. 
In the first cycle, an ECG will be performed at day 8 and at day 22 immediately after completion of the TH-
302 infusion. Thereafter, an ECG will be performed at the discretion of the investigator 
9. Baseline and end-of-study visit echocardiogram, and if clinically indicated. 
10. Thoracic, abdominal, and pelvic CT scan within 28 days prior to study enrolment and subsequently every 8 
+/- 1 weeks and at the end-of-study visit. For tumour reassessments, the same exploratory technique used in the 
baseline examination must be adopted. A baseline bone scan may be performed within 28 days prior to day 1 of 
the first cycle, if there is a clinical suspicion of bone metastases. In the event of bone metastases, a reassessment 
bone scan will be performed every 12 weeks until week 24 and thereafter every 24 weeks until the end of 
treatment. Margin of +/- 14 days with reference to the scheduled visit. 
An MRI may only be performed in exceptional circumstances and only in cases when a CT scan is not possible. 
11. Blood sample for the analysis of genetic markers that will be sent to the CNIO. Only the tubes from the 
baseline visit will be sent. 
 
 


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12. Paraffin-embedded tumour sample for marker analysis that will be sent to the Pathology Department of the 
Hospital Ramón y Cajal. 
13. Determination of overall survival of patient (living/death/lost to follow-up). According to the site’s usual 
practices, until the end of the trial. 
 
 


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 ANNEX 2. WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION OF 
GASTROENTEROPANCREATIC NEUROENDOCRINE TUMOURS (GEP-NETs) 
 
 
WHO 
 
Tumour 
Grade 
Mitosis (10 HPF) 
Ki67 index (%) 
WHO 1 
NET 
G1 
< 2 
≤ 2 
WHO 2 
NET 
G2 
2-20 
3-20 
WHO 3 
NEC 
G3 
> 20 
> 20 
 
MANEC 
Tumour-like lesions 
 
 
 
 
WHO: World Health Organization; NET: Neuroendocrine tumour; NEC: Neuroendocrine carcinoma; 
HPF: High-power Fields. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 ANNEX 3. PATIENT PERFORMANCE STATUS SCALE: ECOG SCALE.  
 
GRADE 
0 
Fully active, able to perform all pre-disease activities without restrictions. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a sedentary nature. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Out of bed > 50%. 
3 
Capable of only limited self-care and personal hygiene. Bedbound > 50%. 
4 
Completely disabled. Incapable of self-care. Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 ANNEX 4. NON-PERMITTED CONCOMITANT MEDICATION 
 
I.  Drugs that cause QT interval prolongation, with the risk of developing polymorphic 
ventricular tachycardia 
Amiodarone 
Arsenic trioxide 
Astemizole 
Azithromycin 
Chloroquine 
Chlorpromazine 
Cisapride 
Citalopram 
Clarithromycin 
Disopyramide 
Dofetilide 
Domperidone 
Droperidol 
Erythromycin 
Flecainide  
Halofantrine 
Haloperidol 
Ibutilide 
Levomethadyl 
Mesoridazine 
Methadone 
Moxifloxacin 
Pentamidine 
Pimozide 
Probucol  
Procainamide  
Quinidine 
Sotalol  
Sparfloxacin 
Terfenadine 
Thioridazine 
Vandetanib 
 
II.  Strong or moderate CYP3A4 inducers 
 
CYP3A4 enzyme-inducing drugs 
Bosentan 
Carbamazepine* 
Dexamethasone 
Efavirenz 
Felbamate* 
Phenobarbital* 
Phenytoin* 
Glutethimide 
St John’s Wort* 
Modafinil 
Nafcillin 
Nevirapine* 
Omeprazole 
Primidone* 
Rifabutin* 
Rifampicin* 
Rifapentine* 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Troleandomycin 
 
 
*Strong CYP3A4 enzyme inducers 
 
 
 
 


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CYP3A4 enzyme-inhibiting drugs 
Amprenavir* 
Atazanavir* 
Boceprevir* 
Clarithromycin* 
Clotrimazole 
Conivaptan* 
Delavirdine* 
Diltiazem 
Erythromycin* 
Ethinylestradiol 
Fluoxetine 
 
Fosamprenavir* 
Gestodene 
Indinavir* 
Itraconazole* 
Ketoconazole* 
Lopinavir*  
Mibefradil* (withdrawn USA) 
Miconazole* 
Nefazodone*  
Nelfinavir* 
Nicardipine 
 
Grapefruit 
or 
any 
product 
containing grapefruit* 
Posaconazole* 
Ritonavir* 
Saquinavir* 
Telaprevir* 
Telithromycin* 
Troleandomycin 
Verapamil* 
Voriconazole* 
Grape or any product containing 
grape* 
 
*  Strong CYP3A4 enzyme inhibitors. 
 
 
 


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 ANNEX 5. WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI.  
 
Ethical Principles for Medical Research Involving Human Subjects. 
 
Adopted by the 
18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
Note of Clarification, added by the WMA General Assembly, Washington 2002 
Note of Clarification, added by the WMA General Assembly, Tokyo 2004 
59th WMA General Assembly, Seoul, Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
 The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles. 
 General principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that: “A 
physician shall act in the patient’s best interest when providing medical care”. 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician’s knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
 
 


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6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 
or other health care professionals and never with the research subjects, even though they have given 
consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other 
health care professional. 
13. Groups that are under-represented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
 
 


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 Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
 Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
 Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate how 
the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. 
 
 


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In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
 Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. No 
amendment to the protocol may be made without consideration and approval by the committee. After 
the end of the study, the researchers must submit a final report to the committee containing a summary 
of the study’s findings and conclusions. 
 Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information. 
 Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, 
no individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods used to deliver the 
information. 
 
 


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After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general outcome 
and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorised representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to 
give assent to decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorised representative. The potential subject’s dissent should be 
respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group. In such circumstances the 
physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must be obtained as soon 
as possible from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 


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impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
  
 Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or where for 
compelling and scientifically sound methodological reasons the use of any intervention less effective 
than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy 
or safety of an intervention. 
Patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
 Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process. 
 Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration should not be 
accepted for publication. 
 Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering.  
 
 


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This intervention should subsequently be made the object of research, designed to evaluate its safety 
and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEX 6. Serious Adverse Event Report Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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 ANNEX 7. Pregnancy Report Form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ANNEX 8. Sample shipment form  
 
I. Tumour 
block. 
Hospital 
Universitario Ramón y Cajal, Madrid. 
 
 
"A phase II trial to assess the activity and safety of TH-
302 in combination with sunitinib in patients with well- 
and moderately-differentiated advanced pancreatic 
neuroendocrine tumours (pNET) previously untreated.  
Prognostic and predictive biomarker research”. 
 
 
 
Determination of biomarkers:  
José Palacios Calvo, Hospital Universitario Ramón y 
Cajal 
 
 
TUMOUR BLOCK 
 
 
 
Site of origin: 
 
 
Investigator of the site of origin: 
 
 
 
 
PATIENT CODE 
 DATE OF SAMPLE COLLECTION 
LOCATION OF TUMOUR BLOCK  
ANATOMOPATHOLOGICAL 
DIAGNOSIS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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II. Plasma sample for the Spanish National Cancer Research Centre (CNIO) 
 
 
"A phase II trial to assess the activity and safety of TH-
302 in combination with sunitinib in patients with well- 
and moderately-differentiated advanced pancreatic 
neuroendocrine tumours (pNET) previously untreated.  
Prognostic and predictive biomarker research”. 
 
 
 
Determination of biomarkers:  
Cristina Rodríguez-Antona, Spanish National Cancer 
Research Centre (CNIO) 
 
 
BLOOD SAMPLE 
 
 
 
Site of origin: 
 
 
Investigator of the site of origin: 
 
 
 
 
PATIENT CODE 
 
 
 
 
 
 
 
DATE OF SAMPLE COLLECTION 
 
 
 
 
 
 
 
LOCATION OF TUMOUR BLOCK  
 
 
ANATOMOPATHOLOGICAL 
DIAGNOSIS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 ANNEX 9. Informed Consent 
 
PATIENT INFORMATION SHEET/ 
INFORMED CONSENT FORM 
 
Study title: A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in 
patients with well- and moderately-differentiated advanced pancreatic neuroendocrine tumours 
(pNET) previously untreated.  
Prognostic and predictive biomarker research. 
 
Study code: GETNE-1408 
 
Sponsor: GETNE 
 
Investigator Details: _____________________________ 
 
Hospital: _________________________________________ 
 
Contact telephone, in case of any doubts: ________________ 
 
Dear patient, 
 
We are inviting you to participate in this clinical trial because you have been diagnosed with a 
pancreatic neuroendocrine tumour. Below we explain, in a summarised form, information about the 
study which you are being invited to participate in, the purpose of which is to understand the activity 
and safety of sunitinib and TH-302 treatment in combination, in patients with your disease. The 
activity and safety of the treatment proposed here will be studied by analysing specific markers in 
your tumour and blood samples, as it is possible that they indicate the progression of your disease 
and the treatment response (targeted molecular analysis).  
 
TH-302 is an investigational drug which has not yet been approved for marketing by the Spanish 
Medicines Agency. It will be provided by Threshold, which supports this project. 
 
A total of 43 patients will participate in the study. Your participation in the study is entirely voluntary, 
and the relationship with the medical team looking after you will in no way be affected should you 
decide not to participate. You are free to withdraw consent for participation in the study at any time, 
without having to provide justification and without it affecting your ongoing medical care. Should you 
not wish to receive the proposed study treatment, your doctor will inform you of alternative treatment 
options available for your particular case. You are hereby reminded that you may speak with third 
parties before signing this form. Please do not hesitate to speak with your doctor should you have any 
questions. 
 
This study has been issued a favourable opinion by the corresponding Independent Ethics Committee 
(IEC) and has been approved by the Spanish Agency of Medicines and Medical Devices (AEMPS), 
pursuant to current legislation, Royal Decree 223/2004, of 6 February, which regulates clinical trials 
with medicinal products. It will be conducted in compliance with the principles stated in the 
Declaration of Helsinki and Good Clinical Practice guidelines. The sponsor undertakes to ensure 
compliance with the principles established by Law 14/2007 regarding Biomedical Research, and 
Royal Decree 1720/2007, which approves the regulation implementing Organic Law 15/1999.  
 
 
 


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Your participation in the clinical trial will not involve any expense for you over and above what you 
would incur if you did not participate in it. Sunitinib and TH-302 will be provided to you free of charge 
by the Sponsor. Visits to the site, examinations and other procedures related to the study will not cost 
you anything. If you experience any problem which requires medical attention, your doctor will 
examine you and will provide you with medical care. 
 
The sponsor may cancel the study due to various reasons. In this case, you will be informed of this 
circumstance. 
 
INTRODUCTION 
 
Pancreatic neuroendocrine tumours represent a heterogeneous group of tumours. The proportion of 
the population presenting this type of tumour has increased in recent years. Treatment goals of 
current treatments in the management of this type of tumour are symptom control and limiting tumour 
growth. If you agree to participate in this study, specific biological markers from tumour tissue and 
blood samples taken at the baseline visit will be analysed, which could help predict the course of 
pancreatic neuroendocrine tumours and the response to the treatment that you will be administered 
(targeted molecular analysis). It is unlikely that the study results will benefit you directly. However, the 
results derived from this study could benefit other patients who suffer from this disease by allowing 
those patients who are going to benefit from this treatment to be selected. 
 
Pancreatic neuroendocrine tumours are characterised by the formation of blood vessels 
(angiogenesis) that allow the tumour cells to continue to grow. For this reason, research has focussed 
in recent years on the development of drugs which inhibit the formation of new blood vessels, such as 
sunitinib, which has already been approved in the USA and Europe for the treatment of pancreatic 
neuroendocrine tumours because of its proven activity and survival benefit. However, certain tumour 
cells can survive this low-oxygenation setting caused by the destructive action of sunitinib on the 
blood vessels. Based on this hypothesis, the potential role of TH-302, a prodrug active in conditions 
of severe hypoxia (low oxygen levels) that causes cell death, has been investigated. The results have 
shown anti-tumour activity of this drug in combination with other chemotherapeutic agents and other 
drugs, such as sunitinib. 
 
METHODOLOGY  
 
Your doctor will ask you questions about your medical records, in particular about your personal 
history and concomitant medication. You will undergo a comprehensive study prior to entry into the 
trial, which will include the following procedures: complete physical examination (height, weight and 
vital signs), measurement of the functional status index, an electrocardiogram, echocardiogram, a 
complete laboratory tests, including urinalysis, pregnancy test and radiological tests to understand the 
circumstances of your disease. 
 
If you agree to participate in the study, a tumour tissue sample that has already been extracted for 
your diagnosis will be sent to the Pathology Department of the Hospital Universitario Ramón y Cajal 
in Madrid, and it will be necessary to take one blood sample (10 ml) at the start of the study that will 
be sent to the Spanish National Cancer Research Centre. There, a molecular analysis will be 
conducted to investigate its relationship to treatment response. By signing this consent form, you 
agree to this collection, processing and transfer. 
 
 
 


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During the treatment period, you must visit the hospital every week to evaluate tolerability and 
treatment response. Every 8 weeks, a full reassessment of tumour progression will be conducted. 
The investigators may discontinue the treatment for safety reasons and/or lack of compliance, 
unacceptable toxicity, growth of the disease, or if your doctor considers that it is in your best interest 
to receive another treatment for your disease, which is different from the study treatment. 
 
Once treatment has ended, irrespective of the reason, you must attend an end-of-study visit. This visit 
will comprise another comprehensive study incorporating vital signs, medical history (collection of 
relevant clinical data by your doctor, including personal and family history regarding the disease), a 
physical examination, and comprehensive laboratory and radiological tests. Thereafter, you will be 
examined approximately every 8-12 weeks to check on your health and disease status. 
It is important to attend all the scheduled study visits and to tell your doctor should you experience 
any incident or side effects. 
 
At the end of your participation in the clinical trial, you will receive the best and most suitable 
treatment available for your disease, in the opinion of your doctor. In this situation, it is possible that 
you may not continue to be administered the study medication. 
 
STUDY TREATMENT 
 
This study proposes just one treatment regimen. Once you have agreed to participate in the trial, you 
will be registered, using the enrolment list, and you will be assigned an enrolment number which will 
identify you throughout the clinical trial. You will receive the treatment regimen proposed for this trial 
(TH-302 + Sunitinib) in the form detailed below: 
 
TH-302: 
Prior to the administration of TH-302, the doctor will perform laboratory tests and the appropriate 
assessment procedures to check that it is safe for you to receive the treatment. TH-302 is 
administered intravenously on days +8 and +22 of each 28-day cycle (it will not be administered on 
day +1 or on day +15 of the cycle) at the Day Hospital over 30-60 minutes. During infusion of the 
drug, you must check for any signs or symptoms (itching, stinging, redness, pain) that might be 
suggestive of extravasation of the drug (leakage of the fluid from the blood vessel that contains it), in 
order to proceed with proceeding to interrupt treatment early and initiate the appropriate therapeutic 
measures.  
 
Sunitinib: 
Prior to the administration of Sunitinib, the doctor will perform laboratory tests and the appropriate 
assessment procedures to check that it is safe for you to receive the treatment. Sunitinib is 
administered daily at a dose of 37.5 mg per day for 28 consecutive days, which constitutes a 
treatment cycle. Sunitinib will be dispensed by the hospital pharmacy, at a frequency to be 
determined by your doctor.  
 
 
 
 
 


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ALTERNATIVE TREATMENTS AVAILABLE  
 
The standard treatment for your disease may include one or several of the agents listed below: 
Streptozotocin, Doxorubicin, Temozolomide, Capecitabine, Sunitinib and Everolimus, either as single 
agents or in combination. 
 
Regimens with Streptozotocin and 5-Fluorouracil or Adriamycin are particularly used in the 
chemotherapy of well-differentiated tumours.  
 
In high-grade, poorly-differentiated tumours, the standard treatment regimen comprises the 
combination of Cisplatin/Carboplatin and Etoposide.  
 
In recent years, the results from studies with Sunitinib and Everolimus in pNET patients has 
broadened the therapeutic horizon. The benefit demonstrated has led to the approval of both drugs by 
the European and American Medicine Agencies. 
 
In this case, your doctor will inform you of the advantages and disadvantages of these medicines, and 
together you will decide on the best alternative. Your doctor will also inform you of the consequences 
of not administering any treatment at all. 
 
RISKS AND BENEFITS 
 
Direct benefits due to your participation in this clinical trial cannot be guaranteed. 
A reduction, stabilisation or, in very exceptional circumstances, the disappearance of your tumour 
could be obtained with any of the standard treatments which are currently available. However, in the 
treatment of pancreatic neuroendocrine tumours, such as the one you present, the main objective is 
the duration of disease control. We therefore hope to be able to improve the control of this disease 
with the treatment proposed in this study. 
The results of this study may help investigators to gain a better understanding of the advantages and 
disadvantages of using this treatment in patients suffering from your condition, which may benefit 
patients with the same disease in the future. 
Besides having desirable effects, medicines may also have undesirable effects (side effects). The 
medications given may have no side effects, or one or more side effects. As a general rule, we 
recommend you contact your doctor if you experience any symptoms as he/she will be better able to 
assess their importance and what is best for you. 
 
In the case of TH-302, the most commonly-reported side effects are: fatigue, nausea, vomiting, 
mucositis, skin abnormality, immunosuppression, anaemia and reduced platelet count. 
 
The most frequently detected side effects with Sunitinib are: fatigue, increased blood pressure, 
thrombosis or bleeding, oral aphthous ulcers, immunosuppression, anaemia, changes in bowel 
movements or a reduced platelet count. 
 
Regarding pregnancy and lactation: 
 
 


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 Women 
 
It is not known whether the medicine under study, TH-302, affects breast milk or the foetus. For this 
reason, both women who are breastfeeding and pregnant women cannot take part in this study. 
Given that the drugs in this study may affect the foetus, you must not fall pregnant or breastfeed a 
child while you are participating in the study.  
If you are fertile, you must have a negative pregnancy test before being enrolled in the study. 
 
Unless you are sterile due to surgical or other reasons, you should use two effective birth control 
methods, accepting this condition when you sign the consent form. This control must be maintained 
throughout the treatment period and for at least 6 months after you have received the last dose of the 
drug. You must use these methods of birth control unless you maintain complete sexual abstinence.  
 Male patients 
 
It is not known whether TH-302 affects sperm. For this reason, and given the risks, you must avoid 
fathering a child during your participation in this study. Even if you have been surgically sterilised (e.g. 
vasectomy), you must agree that if you maintain sexual relations you will do so using a barrier 
contraception method (latex condom with spermicide) from the moment you sign the consent form, 
throughout the study treatment period and for up to 6 months after having received the last dose of 
the drug. 
 All participants (Males or Females) 
 
If you think you have fallen pregnant, or that you have made your partner pregnant during the study, 
you must inform the study doctor immediately. He/she will explain the possible risks for the foetus and 
the various options for continuing with the pregnancy or not. If you fall pregnant during this study, the 
treatment with the drug that you are receiving will be discontinued and it is possible that you will be 
withdrawn from some study procedures, but not from the follow-up carried out by the study doctor. 
The study doctor will request permission to stay in contact with you throughout the duration of your 
pregnancy. 
 
Any new information discovered during your participation with regard to the trial drugs that may affect 
your decision to continue participating in the trial will be communicated to you as soon as possible by 
your doctor and, if necessary, a new consent form will be signed. 
 
INSURANCE 
 
The Sponsor of the clinical trial (Grupo Español de Tumores Neuroendocrinos - Spanish Task Force 
Group for Neuroendocrine Tumours) has taken out a civil liability insurance policy that complies with 
the provisions of current legislation (RD 223/2004) with the company HDI Hannover International, with 
policy no. 130/001/009658, which will provide compensation and indemnity in case your health is 
impaired or lesions occur. 
 
CONFIDENTIALITY 
 
Your medical documentation may need to be made available to others working on behalf of the 
sponsor, to members of the Independent Ethics Committee and to Regulatory Health Authorities.  
 
 


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By signing this consent form, you grant this access for this study. However, the Sponsor will take 
steps to protect your personal information and will not include your name on any form, report, 
publication or future disclosure by the Sponsor. You will be identified by a code within the study. If you 
withdraw from the study, we will not collect any further personal information about you, but it may be 
necessary to continue using the information already collected. By taking part in this study, you agree 
not to restrict the use of the data or results derived from this research. 
 
The Sponsor undertakes to ensure compliance with the principles established by Organic Law No. 
15/1999 on the protection of personal data and to facilitate the practice of the rights of access, 
rectification, cancellation and opposition. To exercise these rights, you must contact the Site where 
the trial was conducted. If study data is transferred to third parties (other countries), at least the same 
level of data confidentiality as that exercised in Spain will be maintained. 
 
SUB-STUDY WITH BIOLOGICAL SAMPLES 
 
Introduction: 
 
Human body cells contain a wide variety of substances, including genetic material. The genetic 
material is like an “instruction book” which serves to duplicate cells, among other things. It also 
contains the biological information which directs the development of an individual. This genetic 
material is found inside cells, arranged in structures called chromosomes. Each small part of the 
genetic material that forms the chromosomes is called a gene. Genes tell the cell how to make 
proteins and other substances that organise the biological work of each cell. Genes also determine 
some characteristics of individuals and are sometimes responsible for some people developing 
certain diseases and responding to specific treatments with medicines. When genetic material is used 
to investigate the causes of diseases or to understand how people respond to medicines, this 
research is called genomic research. It is used to help develop new treatments and diagnostic tools. 
 
We are contacting you to request your consent for the extraction and use of your samples in order to 
perform genetic analyses to identify genes or genetic markers (simple tests used on blood or tumour 
samples which provide crucial information for the diagnosis and for a better treatment selection), of 
which you are a carrier and which may determine your response to the treatment regimen proposed 
in the previously-described clinical trial. 
 
It is our intention that you receive correct and sufficient information so that you can evaluate and 
judge whether or not to participate in this sub-study. To this end, please read this information sheet 
carefully and we will clarify any doubts you may have following this explanation. You may also 
discuss it with whomever you wish.  
 
Objective of the sub-study: 
 
The objective of this sub-study with biological samples is to study specific biomarkers (simple tests 
used on blood or tumour samples), which will allow patients who will benefit the most from the 
different treatment options for pNET to be selected. 
 
 
 


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Sample collection: 
 
A sample of your tumour will be coded and sent to the Pathology Department of the Hospital Ramón y 
Cajal, Ctra Colmenar Viejo Km 9,100 - Postcode: 28034 - Madrid, where the determinations of this 
sub-study will be carried out. 
 
Once you have been enrolled in the trial and before starting treatment, approximately 10 ml of blood 
will be taken from you. This will be frozen, coded and sent to the Spanish National Cancer Research 
Centre (CNIO), Melchor Fernández Almagro, 3 - 28029 - Madrid, for the sub-study determinations to 
be carried out.  
 
Use and destination of samples at the end of the research: 
 
Samples will only be used by the Sponsor and/or investigators working for the Sponsor, and only for 
the research described above. Samples will be stored in the same laboratories where the 
determinations are carried out. 6 years after the date the blood sample is drawn, genetic information 
derived from the study will be made public and may be consulted, but your identity will be kept 
confidential so that your genetic data cannot be linked to you. After this period, the genomic material, 
i.e. the samples, will be destroyed or kept for subsequent use in this line of research or any further 
research, provided that you sign your express authorisation for storage of this material in a biobank 
(you will be informed by your doctor of the details of the receiving biobank as soon as the specific 
information is available). Under no circumstances and at no time will samples be used for direct profit, 
either by the sale of the material itself or the sale of the rights to perform studies on said samples. 
 
Expected benefits 
 
Direct benefits due to your participation in this sub-study with samples cannot be guaranteed. 
The blood and tumour samples of patients participating in clinical trials, such as GETNE 1408, are 
extremely important, as they are linked to accurate clinical information of these patients. This 
information, including whether the cancer responds to treatment or if it reappears in the future, can be 
used together with the information discovered in the laboratory in order to help answer questions 
about this type of cancer and its treatment 
 
Drawbacks and risks of participating in the sub-study  
 
Obtaining the tumour tissue does not pose any additional risk to you as a sample that will be 
obtained/was obtained at the time of surgery for your disease will be used. 
 
The blood sample will be taken following the same procedure as that used to take other blood tests. 
There may be stinging and swelling on your skin at the puncture site and a bruise may form at the 
puncture site. The risks of this practice are the same as those that you would be exposed to if you 
were not participating in the study. 
 
If necessary, you may be contacted after the study in order to gather new data and obtain further 
samples. 
 
 
 
 
 


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Confidentiality 
The processing, reporting and transfer of personal data from all the research participants will be in 
compliance with the provisions of Organic Law 15/1999, of 13 December, on personal data 
protection, and its implementing regulation. In line with this legislation, you are entitled to access, 
modify, object to and cancel said data, for which you should contact your study doctor.  
Your data and samples collected for the study will be identified by a code, and, throughout the course 
of the study, this code will be the only way in which your data will be linked to the study information. 
Only your clinical trial doctor/collaborators will be able to link this data with you and your medical 
records. Therefore, your identity will not be revealed to anyone, except in the case of a medical 
emergency or a legal requirement.  
Access to your personal information will be restricted to the study doctor/collaborators, health 
authorities, the Independent Ethics Committee, and personnel authorised by the sponsor, when they 
need to check the data and study procedures. However, they will always maintain the confidentiality 
of such information in accordance with current legislation. This check will be performed, as far as 
possible, in the presence of the principal investigator or collaborators responsible for guaranteeing the 
confidentiality of medical record data pertaining to subjects participating in the clinical trial. 
Only the data collected for the clinical trial that contains no information that directly identifies you (e.g. 
name and surnames, initials, address, social security number, etc.) will be disclosed to third parties or 
other countries. If this disclosure occurs, it will be for the study purposes described and the degree of 
confidentiality and requirements set forth in current legislation in Spain as a minimum will be 
guaranteed. 
If you decide to participate in the study with biological samples, the information will be collected and 
entered into the study database. The scientific personnel and doctors of GETNE and individuals who 
work with the people carrying out the study may need to examine your medical record to ensure that 
the study is being conducted correctly. However, your data will be kept confidential in accordance 
with Spanish legislation. 
More information 
This sub-study complies with Law 14/2007, of 3 July, on Biomedical Research and Royal Decree 
1716/2011, of 18 November, which establishes the basic requirements of authorisation and 
functioning of biobanks used for biomedical research and the handling of biological samples of human 
origin and they regulate the functioning and organisation of the National Register of Biobanks for 
biomedical research.  
 
In accordance with this regulation, you can request access to the genetic information obtained from 
your samples in this study through your study doctor. It is important to know that this research data is 
exploratory and/or preliminary. It may have no impact on your wellbeing and should not be used to 
guide your diagnosis, prognosis or medical care. This type of preliminary or exploratory data will not 
be able to be individually interpreted by your doctor or any specialist, so no individual advice 
associated with it will be given. If you decide to request your genetic data, ask your doctor about the 
implications that this information may have for you and your family. 
 
 


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It is possible that results which may have an impact on both you and members of your family will be 
obtained from conducting this study. You may refuse to be notified of these results. In addition, if you 
decide not to be informed of these results, your study doctor may contact members of your family in 
the event that the results might affect them. If you decide to be notified of results of the study that may 
affect members of your family, you will be advised to inform them. 
If you would like to know the results, your doctor will provide you (or will tell you where you can be 
provided) with genetic counselling for both you and your family members. 
Both this document, and the research sub-study, have been reviewed and issued a favourable 
opinion by your Hospital’s Ethics Committee.  
 
You will be given a copy of this document as part of the files of this research project, separate from 
the findings of the research project. Thank you for having read this document and for considering 
participating in the study. Please do not hesitate to contact your doctor should you have any queries. 
 
If you agree to participate, please sign this sheet, which will be kept in your medical record. 
 
 
 


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WRITTEN INFORMED CONSENT FORM 
 
Study title: A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in 
patients with well- and moderately-differentiated advanced pancreatic neuroendocrine tumours 
(pNET) previously untreated.  
Prognostic or predictive biomarker research. 
 
I, ……………………………………………………. (full name) 
 
● Have been informed of this study. 
● Have read and understood the information sheet given to me. 
● Have been able to ask questions about the study and have received satisfactory 
replies to my questions. 
● Accept that Sponsor employees or people acting on the Sponsor’s behalf and the 
competent authorities can review my medical record for data verification purposes. 
● Consent to the collection and processing of my personal data according to the 
conditions specified in the Information Sheet. 
● Have received a copy of this document. 
 
I have spoken to: …………...................................................... Contact telephone no.: .................... 
(full name of the investigator) 
 
● Understand that my participation is voluntary. 
● Understand that I may withdraw from the study: 
o 
Whenever I want. 
o 
Without having to give explanations. 
o 
Without this having any effect on my medical care. 
 
I freely grant my consent to participate in the study. 
 
I wish to donate tumour tissue samples for the corresponding analysis. 
 
I wish to donate a blood sample for the corresponding analysis. 
 
I consent to my sample being used for research purposes in this and other lines of 
research. 
 
Participant 
 
 
(full name)                       (signature)                                            (date) 
 
Investigator (the person obtaining the consent must sign and date the form at the same time as the 
participant) 
 
 
(full name)                       (signature)                                            (date) 
You will be given a signed and dated copy of this consent form. First copy or original 
for the investigator. 
 


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LEGAL REPRESENTATIVE’S ORAL INFORMED CONSENT 
 
Where applicable, for example in subjects with severe dementia, state the name and signature of the 
subject’s legal representative. 
 
Study title: A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in 
patients with well- and moderately-differentiated advanced pancreatic neuroendocrine tumours 
(pNET) previously untreated.  
Prognostic or predictive biomarker research. 
 
I, 
……………………………………………………. 
(full 
name) 
as 
…………………………………(relationship to the participant) of ……………………………...... (name of 
participant) 
● Have been informed of this study. 
● Have read and understood the information sheet given to me. 
● Have been able to ask questions about the study and have received satisfactory 
replies to my questions. 
● Accept that Sponsor employees or people acting on the Sponsor’s behalf and the 
competent authorities can review my medical record for data verification purposes. 
● Consent to the collection and processing of my personal data according to the 
conditions specified in the Information Sheet. 
● Have received a copy of this document. 
 
I have spoken to: …………..................................................... Contact telephone no.: ........................ 
(full name of the investigator) 
● Understand that my participation is voluntary. 
● Understand that I may withdraw from the study: 
◦ 
Whenever I want. 
◦ 
Without having to give explanations. 
◦ 
Without this having any effect on my medical care. 
 
I freely give my consent to take part in the study. 
 
I wish to donate tumour tissue samples for the corresponding analysis. 
 
I wish to donate a blood sample for the corresponding analysis. 
 
I consent to my sample being used for research purposes in this and other lines of 
research. 
 
Representative 
 
 
(full name)                       (signature)                                            (date) 
 
Investigator (the person obtaining the consent must sign and date the form at the same time as the 
participant) 
 
(full name)                       (signature)                                            (date) 
 
You will be given a signed and dated copy of this consent form. First copy or original for the 
investigator. 
 


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ORAL INFORMED CONSENT BEFORE WITNESSES 
 
If the subject or the subject’s legal representative cannot read, the signature of an impartial witness is 
required, and in this event the following form must be signed. 
 
Study title: A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in 
patients with well- and moderately-differentiated advanced pancreatic neuroendocrine tumours 
(pNET) previously untreated.  
Prognostic or predictive biomarker research. 
 
I, ……………………………………………………. (full name) hereby declare under my responsibility 
that ……………………………...... (full name of participant) 
● Has been informed of this study. 
● Has been able to ask questions about the study and I have received satisfactory 
answers to my questions. 
● Accepts that Sponsor employees or people acting on the Sponsor’s behalf and the 
competent authorities can review my medical record for purposes of data 
verification. 
● Consents to the collection and processing of my personal data according to the 
conditions specified in the Information Sheet. 
● Has received a copy of this document. 
● Has been informed of this study. 
● Has read and understood the information sheet given to me. 
● Has been able to ask questions about the study and I have received satisfactory 
answers to my questions. 
● Accepts that Sponsor employees or people acting on the Sponsor’s behalf and the 
competent authorities can review my medical record for purposes of data 
verification. 
● Consents to the collection and processing of my personal data according to the 
conditions specified in the Information Sheet. 
● Has received a copy of this document. 
 
Has spoken to: …………..................................................... Contact telephone no.: ....................... 
(full name of the investigator) 
 
▪ 
Understands that his/her participation is voluntary. 
▪ 
Understands that he/she can withdraw from the study: 
o 
Whenever he/she wants. 
o 
Without having to give explanations. 
o 
Without this having any effect on his/her medical care. 
 
I freely grant my consent to participate in the study. 
 
I wish to donate tumour tissue samples for the corresponding analysis. 
 
I wish to donate a blood sample for the corresponding analysis. 
 
I consent to my sample being used for research purposes in this and other lines of research. 
 
 
 
 
 


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Witness 
 
 
 
(full name)                       (signature)                                            (date) 
 
Investigator (the person obtaining the consent must sign and date the form at the same time as the 
participant) 
 
 
 
(full name)                       (signature)                                            (date) 
 
 
You will be given a signed and dated copy of this consent form. First copy or original for the 
investigator. 
 
 
 
 

SAP_001.pdf: 
 
 
 
 
GETNE-1408 (SUNINET) 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
12th of November 2018 (version 1.1) 
 
Written by: Jordi Curto 
 
A phase II trial to assess the activity and safety of TH-302 in 
combination with sunitinib in patients with well- and moderately-
differentiated metastatic pancreatic neuroendocrine tumours 
(pNET) previously untreated 


Study GETNE 1408                                                                                                        STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos (GETNE) 
 
 
 
 
Date: 12/11/18 (version 1.1) 
                         CONFIDENTIAL 
Page 2 of 47 
 
GENERAL INFORMATION 
 
 TITLE 
A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in 
patients with well- and moderately-differentiated Metastatic Pancreatic Neuroendocrine 
Tumours (pNET) previously untreated. 
STUDY DESIGN 
A phase II, open-label, non-controlled, multicenter prospective clinical trial.  
  TREATMENT 
Single arm of TH-302 administered at 340 mg/m2 by intravenous infusion on days 8 and 22 in 
combination with sunitinib given orally at doses of 37.5 mg per day continuously in 28-day 
cycles. 
Pharmaceutical form:  
• Sunitinib: hard gelatin capsules of 25 and 12.5 mg. Oral administration. 
• TH-302: the dose will be adjusted according to body surface area and will be 
administered by intravenous infusion over 30 to 60 minutes. In the event of weight 
variation > 10%, the body surface area will be recalculated and the dose readjusted.   
The physical and chemical properties of sunitinib and TH-302, as well as the list of excipients, 
are included in the Investigator’s Brochure. 
  SPONSOR 
Spanish Task Force Group For Neuroendocrine Tumours (Grupo Español de Tumores 
Neuroendocrinos - GETNE) 
SECRETARIA TECNICA GETNE - MFAR 
c/Secretari Coloma, 64-68 esc. B entresuelo 5ª. 08024 Barcelona 
Teléfono 93 434 44 12 
  STUDY CHIEF INVESTIGATOR 
Dr. Enrique Grande. Medical Oncology Department, MD Anderson Cancer Center.  
 MONITORING ORGANISATION (CRO) 
MFAR Clinical Research 
c/Secretari Coloma, 64-68 esc. B entresuelo 5ª. 08024 Barcelona.  
Teléfono 93 434 44 12 
e-mail: investigacion@mfar.net. Web: www.mfar.es 
 
 


Study GETNE 1408                                                                                                        STATISTICAL ANALYSIS PLAN 
Sponsor: Grupo Español de Tumores Neuroendocrinos (GETNE) 
 
 
 
 
Date: 12/11/18 (version 1.1) 
                         CONFIDENTIAL 
Page 3 of 47 
 
INDEX OF CONTENTS DE CONTENIDOS 
ABREVIATURAS Y DEFINICIONES ………………………………………………………………….. 6 
1. MATERIAL AND METHODS ............................................................................... 9 
1.1. INTRODUCTION ................................................................................................................. 9 
1.1.1. 
BACKGROUND ......................................................................................................... 9 
1.2. STUDY OBJECTIVES ........................................................................................................... 13 
1.2.1. 
PRIMARY OBJECTIVE .............................................................................................. 13 
1.2.2. 
SECONDARY OBJECTIVES ........................................................................................ 13 
1.2.3. 
SAFETY OBJECTIVE ................................................................................................. 13 
1.3. STUDY FLOWCHART ......................................................................................................... 14 
1.4. STUDY POPULATION ........................................................................................................ 14 
1.4.1. Selection criteria ............................................................................................... 14 
1.4.1.1 
Inclusion criteria ........................................................................................ 14 
1.4.1.2 
Exclusion criteria ........................................................................................ 15 
1.5. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .............................................. 17 
1.5.1. 
DESCRIPTION OF ANALYSIS SETS ............................................................................. 17 
1.5.1.1 
Total analysis population ............................................................................ 17 
1.5.2. 
EFFICACY ASSESSMENT .......................................................................................... 17 
1.5.3. 
SAFETY ASSESSMENT ............................................................................................. 18 
1.5.4. 
DETERMINATION OF SAMPLE SIZE .......................................................................... 18 
1.5.5. 
METHODS OF STATISTICAL ANALYSES ..................................................................... 19 
1.5.5.1 
Descriptive analysis .................................................................................... 19 
1.5.5.2 
Primary Efficacy analysis ............................................................................. 19 
1.5.5.3 
Secondary Efficacy analysis ......................................................................... 20 
1.5.5.4 
Safety analysis ........................................................................................... 20 
1.5.6. 
INTERIM ANALYSES ................................................................................................ 20 
1.5.7. 
RECORDING OF DATA ............................................................................................. 20 
2. RESULTS ........................................................................................................ 21 
2.1. STUDY POPULATION ........................................................................................................ 21 
2.1.1. Recruited patients (centres/investigators) ........................................................... 21 
2.1.2. Evaluable patients ............................................................................................. 21 
2.2. BASELINE PATIENT CHARACTERISTICS ............................................................................... 23 
2.3. TUMOR DATA AND PRIOR TREATMENTS ........................................................................... 25 
2.4. CONCOMITANT MEDICATION ........................................................................................... 26 


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2.5. TREATMENT EXPOSURE .................................................................................................... 26 
2.5.1. Withdrawal of patients from therapy or assessment ............................................ 28 
2.6. ANALYSIS SETS ................................................................................................................. 30 
2.7. EFFICACY ANALYSIS .......................................................................................................... 31 
2.7.1. Primary efficacy analysis .................................................................................... 31 
2.7.2. Secondary efficacy analysis ................................................................................ 32 
2.7.2.1 
Progression Free Survival ............................................................................ 32 
2.7.2.2 
Time to tumour progression ........................................................................ 33 
2.7.2.3 
Response duration ..................................................................................... 33 
2.7.2.4 
Overall survival .......................................................................................... 34 
2.7.2.5 
Biomarkers ................................................................................................ 35 
2.7.2.6 
Association between ORR and Biomarkers ................................................... 36 
2.7.2.7 
Association between PFS and Biomarkers .................................................... 38 
2.7.2.8 
Association between OS and Biomarkers ...................................................... 40 
2.7.2.9 
ROC curves: Area Under Curve, ORR vs. Biomarkers ...................................... 42 
2.8. SAFETY ANALYSIS ............................................................................................................. 43 
3. CONCLUSIONS ............................................................................................... 44 
4. ANEXES ......................................................................................................... 45 
4.1. ANEX I: DATABASE MANAGEMENT ................................................................................... 45 
5. REFERENCES .................................................................................................. 46 
 


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INDEX OF TABLES 
Table 1. Recruited patients by site ...................................................................................................... 21 
Table 2. Non evaluable patients .......................................................................................................... 22 
Table 3. Patients evaluable by Site ...................................................................................................... 22 
Table 4. Evaluable patients ................................................................................................................. 22 
Table 5. Baseline patient characteristics ............................................................................................. 23 
Table 6. Baseline analytics .................................................................................................................. 24 
Table 7. Tumour characteristics .......................................................................................................... 25 
Table 8. Concomitant medication ....................................................................................................... 26 
Table 9. TH-302 compliance ................................................................................................................ 26 
Table 10. List of patients that did not receive TH-302 ......................................................................... 27 
Table 11. Sunitinib compliance ........................................................................................................... 27 
Table 12. List of patients that did not receive Sunitinib ....................................................................... 28 
Table 13. Study treatment premature interruption ............................................................................. 28 
Table 14. List of patients that did not receive Sunitinib/TH-302 .......................................................... 29 
Table 15. Reason for end of treatment ............................................................................................... 29 
Table 16. Study treatment length ....................................................................................................... 29 
Table 17. Analysis sets ........................................................................................................................ 30 
Table 18. List of patients that are excluded total analysis population ................................................. 30 
Table 19. Response ............................................................................................................................. 31 
Table 20. Time to response ................................................................................................................. 32 
Table 21. Progression free survival ..................................................................................................... 32 
Table 22. Progression free survival events .......................................................................................... 33 
Table 23. Time to tumour progression ................................................................................................ 33 
Table 24. Response duration time ...................................................................................................... 34 
Table 25. Overall survival .................................................................................................................... 34 
Table 26. Overall survival events ........................................................................................................ 34 
Table 27. Biomarkers .......................................................................................................................... 35 
Table 28. Univariate logistic regression ............................................................................................... 36 
Table 29. Multivariate logistic regression ............................................................................................ 37 
Table 30. Univariate Cox regression PFS .............................................................................................. 38 
Table 31. Multivariate logistic regression PFS ..................................................................................... 39 
Table 32. Univariate Cox regression OS ............................................................................................... 40 
Table 33. Multivariate logistic regression OS ...................................................................................... 41 
Table 34. Adverse events .................................................................................................................... 43 
 
INDEX OF FIGURES 
FIGURE 1 PFS RESULTS OF THE PHASE III STUDY OF SUNITINIB VS. PLACEBO IN PNET PATIENTS. .. 11 
FIGURE 2 TH-302 ACTIVATION PATHWAY DIAGRAM .................................................................. 12 
FIGURE 3 TRIAL SCHEMA .......................................................................................................... 14 
FIGURE 4 WATERFALL PLOT: MAXIMUM % CHANGE FROM BASELINE IN TARGET TUMOR 
MEASUREMENT FOR EACH ....................................................................................................... 31 
PATIENT 
31 
FIGURE 5 KAPLAN MEIER CURVE: PFS ........................................................................................ 33 
FIGURE 6 KAPLAN MEIER CURVE: OS ......................................................................................... 34 


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FIGURE 7 ROC CURVE: ORR VS. BIOMARKER MODEL 1 ............................................................... 42 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation Explanation 
AE  
Adverse events 
ALP  
Alkaline phosphatase 
ALT 
Alanine transaminase 
AML   
Acute myeloid leukaemia 
ANC 
Absolute neutrophil count 
AOC  
Advanced ovarian cancer 
aPTT 
Activated partial thromboplastin time 
AST  
Aspartate transaminase 
AUC 
Area under the curve 
bd  
twice a day 
CHO   
Chinese hamster ovary 
CI 
Confidence interval  
CIOMS 
Council for International Organizations of Medical Sciences 
CRA  
Clinical research associate (monitor) 
CTCAE 
Common terminology criteria for adverse events 
DSBs  
Double strand breaks 
E-code  
Enrolment code 
ECOG  
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
EDC  
Electronic data capture 
EOC 
Epithelial ovarian cancer 
EU  
European Union 
G-CSF  
Granulocyte colony-stimulating factor 
GMI 
Growth modulation index 
HDPE  
High-density polyethylene  
HIV  
Human immunodeficiency virus 
HRD  
HR deficiencies  


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HRR  
Homologous recombination repair 
IB  
Investigator’s brochure 
ICH-GCPs 
International Committee Harmonization – Good Clinical Practice 
INR  
International normalized ratio 
MDS  
Myelodysplastic syndrome  
MedDRA  
Medical dictionary for regulatory activities 
mg 
milligrams 
MTD  
Maximum tolerated dose 
NCI  
National Cancer Institute from United States of America 
OC  
Ovarian cancer 
OS  
Overall survival 
PFS 
Progression-free survival 
PFS6m  
Progression-free survival rate at 6 months 
PFS 
Progression-free survival rate 
Pgx 
Pharmacogenetics 
PLD   
PEGylated liposomal doxorubicin 
PPE   
Palmar-plantar erythrodysesthesia 
PRO  
Patient reported outcome 
QoL  
Quality of life 
RECIST 
Response Evaluation Criteria In Solid Tumours 
RR 
Response rate 
SAEs  
Serious adverse events 
SEER 
NCI Surveillance, Epidemiology and End Result Program  
SmPC  
Summary of product characteristic 
SOC  
System organ class 
SOPs 
Standard operational procedures 
SSBs  
Single strand breaks 
t-AML 
therapy-related acute myeloid leukaemia 
TDT 
Time from randomization to study of Discontinuation of Treatment or 
death 
TEAE  
Treatment-emergent adverse events 


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TFST  
Time from randomization to first subsequent therapy or death 
TSST  
Time from randomization to second subsequent therapy or death 
ULN  
Upper limit of normal 
WBC  
White blood cells 
 
 


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1. MATERIAL AND METHODS 
1.1. INTRODUCTION 
1.1.1. 
BACKGROUND 
Epidemiology 
pNETs represent a heterogeneous tumour group classified according to their functional 
capacity and histological differentiation (1) (Annex 2). The prevalence of neuroendocrine 
tumours (NET) has increased in recent years at an estimated rate of 35/100,000/year, of which 
approximately 30% are pNET. In particular, the incidence of pNET is 0.32/100,000/year (2). 
Most are non-functioning tumours. Those that are functioning are identified according to the 
hormone secreted, and some are found outside the pancreas.  
The 5-year survival rate is 80%; 60-100% for localised disease, 40% for locally advanced disease 
and 25% for metastatic disease (which can reach 60% in reference sites). 
 
Therapeutic options for managing metastatic pancreatic neuroendocrine tumours (pNET) 
Treatment goals in the management of pNETs are symptom control and limiting tumour 
growth in order to positively affect patient survival. 
In the context of cytotoxic drugs, it appears that pNETs are more sensitive to chemotherapy 
than other NETs, including carcinoid tumours. For decades, cytotoxic therapy was the only 
available treatment option, with streptozotocin as the first drug to demonstrate NET activity, 
being approved in 1976 by the FDA (Food and Drug Administration). Its combination with 
fluoropyrimidines, particularly doxorubicin, further increased its activity, and it became the 
standard treatment for well- and moderately-differentiated tumours. These combinations 
achieved a pNET response rate of between 35-69%, with median overall survival of up to 26 
months (3), (4). However, this goal was not always measured according to radiological 
assessments, but also clinical ones, so its interpretation was limited and no definite correlation 
was found between these data and those obtained in reviews of routine clinical practice (5). A 
second cytostatic agent that is key in the treatment of pNETs is temozolomide, an alkylating 
agent, the benefit of which appears to be correlated with MGMT enzyme deficiency. The 
combination of temozolomide and capecitabine studied in retrospective reviews, such as the 
one published in 2011 with 30 treatment-naïve patients with pNET (6), showed an objective 
response rate of 70%, a median progression-free survival (PFS) of 18 months and an overall 2-
year survival rate of 92%.  
In high-grade, poorly-differentiated tumours, the standard treatment regimen comprises the 
combination of platinum and etoposide, which, in retrospective reviews and prospective 
studies, achieves a high response rate of between 56-67%, but they are unfortunately not as 
durable as expected (7).  
The pNET population was represented in the CLARINET phase III study, which randomised 204 
patients with G1/G2 non-functioning GEP-NETs, to receive lanreotide Autogel 120 mg (N = 
101) versus placebo (N = 103) (8). The first endpoint - PFS - was achieved by showing a 53% 
reduction in the risk of progression in favour of somatostatin analogues (HR 0.47; 95% CI 0.30-


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0.73, p = 0.0002). Subgroup analysis according to the location of the primary demonstrated a 
PFS for pNET patients (N = 91) that had not been achieved in the arm with lanreotide Autogel 
and 12.1 months in the placebo arm (HR 0.58; 95% CI 0.32-1.04, p = 0.0637).  
In recent years, data from two phase III studies with targeted therapy against vascular 
endothelial growth factor receptor (VEGFR), sunitinib, and the mammalian target of rapamycin 
(mTOR), everolimus, in pNET patients, has broadened the therapeutic horizon for these 
patients. The improved PFS demonstrated led to the approval of both drugs by the EMA and 
the FDA. 
The PI3K/AKT/mTOR pathway is also key in tumour development, as it regulates the 
metabolism, growth, cell proliferation and angiogenesis, integrating multiple signalling 
pathways.  Its activation can be responsive to VEGFR, PDGFR and insulin-like growth factor 
receptor (IGFR) stimulation, and it is regulated through two tumour suppressor genes (TSG) - 
TSC2 and PTEN. As everolimus deregulates this molecular pathway in pNET, use of the drug 
should be developed against these tumours. Thus, based on the phase II results published in 
2008 with two cohorts of 60 patients treated with octreotide and everolimus at doses of 5 and 
10 mg daily, a response rate of 27% was observed in pNET patients with a median PFS of 63 
weeks (9). Based on these results, a second phase II study was developed, called RADIANT-1, 
targeting pNET patients who had progressed during or after chemotherapy and who received 
everolimus 10 mg/day, being stratified according to prior treatment with octreotide (115 
patients in monotherapy and 45 patients in combination) (10). The results for both strata 
showed a response rate of 9.6% and 4.4%, respectively, and PFS was 9.7 vs. 16.7 months, 
respectively, for both arms. In a third phase III study, RADIANT-3, 410 pNET patients were 
randomised to receive everolimus 10 mg/day vs. placebo (11). The results of the study 
demonstrated significantly improved PFS with everolimus of 11.4 months versus 5.4 months 
(HR 0.34; p<0.0001). 
Unfortunately, patients ultimately progress and the development of new active drugs, as well 
as the development of predictive biomarkers of progression, is vital. The first study to analyse 
the sequence of therapeutic targets was the PAZONET study, the results of which were 
presented at ESMO 2012 (12). A total of 44 patients were enrolled who had previously 
received treatment with a tyrosine-kinase inhibitor (TKI) and/or mTOR inhibitor, and who were 
treated with pazopanib 800 mg/day allowing concomitance with somatostatin analogues. The 
results showed that pazopanib was active in this patient arm with a clinical benefit of 83% for 
those previously treated with TKI, 89% with an mTOR inhibitor and 60% with both drugs. The 
PFS in these three subgroups was 12.1 months, 6.8 months and 4.1 months, respectively. For 
the overall population it was 9.5 months.  
 
Sunitinib in Pancreatic Neuroendocrine Tumours 
In pNET, there is a high expression of VEGF and VEGFR2-3, PDGFR alpha and beta, cKIT and 
EGFR, and hypoxia are a key event in the regulation of tumour angiogenesis. This constitutes a 
strong rationale when it comes to developing anti-angiogenic drugs for these tumours. In 
clinical studies, the activity of sunitinib on NET was first demonstrated in a phase I study where 
the 3 enrolled NET patients, all of whom had been previously treated, showed reduced tumour 
lesions to varying degrees, being exceptional in one patient with a higher partial response (21 
weeks) and two long-lasting minor responses (13). Thereafter, a multicenter, phase II study 
was conducted in patients with carcinoid tumours and pNET (14). Results from the 66 pNET 


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patients showed an objective response rate of 16.7% and a stable disease rate of 68%. The 
time to progression and overall survival at one year was 7.7 months and 81.1%, respectively. 
To definitively confirm this benefit, a phase III study versus placebo was developed, in which 
171 patients of the 340 initially estimated were finally randomised against independent data 
monitoring (15). The benefit in terms of PFS was 11.4 months for the sunitinib arm at a dose of 
37.5 mg/day versus 5.5 months for the placebo arm (HR 0.42; p<0.001). Efficacy data on 
patients in routine clinical practice treated with sunitinib were consistent with those obtained 
on selected populations in clinical trials (16).  
Figure 1 PFS results of the phase III study of sunitinib vs. placebo in pNET patients. 
 
 
TH-302 (Preclinical and Clinical Development in Solid Tumours) 
• Introduction 
(1-methyl-2-nitro-1H-imidazole-5-yl) methyl N, N’-bis (2-bromoethyl) diamidophosphate (also 
known as TH-302) is a nitroimidazole-triggered prodrug of a brominated version of 
isophosphoramide mustard (Br-IPM) (17). TH-302 is able to diffuse into hypoxic tissues without 
activation by NADP (H) quinone oxidoreductase (DT-diaphorase). It is preferentially activated 
under severe hypoxic conditions that are unlikely to be present in healthy tissue but in solid 
tumours (18). 
The molecule TH-302 is activated by a process that involves a one electron reduction at the 2-
nitroimidazole site of the prodrug, mediated by ubiquitous cellular reductases such as the 
NADPH-cytochrome P450, to generate a radical anion prodrug (RP). In the presence of oxygen 
(normoxia) the radical anion prodrug reacts rapidly with oxygen to generate the original 
prodrug and superoxide (SO). In these situations, TH-302 is relatively inert, remaining intact as 
a prodrug. However, under hypoxic conditions, (<0.5% O2), the radical anion prodrug can 
either fragment directly or undergo further reduction at the nitroimidazole site of the prodrug, 
causing Br-IPM to be released (Figure 2). Br-IPM can then act as a DNA alkylating agent and 


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form DNA crosslinks, causing damage through the presence of γH2AX. Br-IPM can diffuse 
through normoxic tissues and act as a cytotoxic agent in these regions. Previously, other 
alkylating mustards such as ifosfamide or cyclophosphamide had already demonstrated 
activity in many tumours. 
Tumours often contain highly hypoxic regions that are known to be resistant to chemotherapy 
and radiotherapy. These regions develop due to the creation of irregular and aberrant blood 
vessels that prevent adequate oxygenation and penetration of the majority of chemotherapy 
treatments, which act on highly proliferating cells adjacent to the blood vessels, but not on the 
relatively quiescent cells found in the hypoxic regions. For this reason, they are resistant to 
these regimens of cytostatic drugs (19). In contrast, the prodrug TH-302 is activated in 
conditions of severe hypoxia, and not in the majority of normal tissues with a similar structure 
(20). Recent preclinical findings support the hypothesis of the induction of hypoxia within the 
tumour developed by anti-angiogenic drugs, which could constitute a synergistic effect with 
TH-302. 
The molecular formula of TH-302 is C9H16Br2N5O4P and the molecular mass is 449 g/mol.  
Figure 2 TH-302 activation pathway diagram 
 
 
Figure obtained from Meng, F., et al. Molecular and cellular pharmacology of the hypoxia-activated 
prodrug TH-302. Mol Cancer Ther. 2012;11:740–51 
• Preclinical Data  
In preclinical investigations, TH-302 as monotherapy or in combination with numerous 
cytotoxic drugs has shown broad activity in murine models (21). In particular, TH-302 has 
shown consistent activity in cell lines from neural crest derived tumours such as melanoma 
and glioblastoma/astrocytoma (TH-302 Investigator’s Brochure). 
TH-302 is very active in vitro, as demonstrated in proliferation studies of H460 lung carcinoma 
cells (22), where TH-302 activity is related to dose-exposure and oxygen dependence, which 
practically achieves linearity (23). This activity is also observed in H69 small-cell lung cancer 
cells (SCLC), B16-F10 melanoma, SKMEL-5 melanoma, HT-29 colon cancer, HCT116 colon 
cancer, MES-SA uterine cancer, DX5 uterine cancer, ACHN renal cancer and PC-3 prostate 
cancer in anoxic conditions (CI50 from 0.1 to 10 μM) and weakly cytotoxic in the presence of 
air (CI50 > 80 μM). Consistent results are obtained in clonogenic models. 
In vivo studies demonstrate activity both as monotherapy and in combination with other 
cytostatic drugs (cisplatin, paclitaxel or 5-fluorouracil) (22). 
The effect of TH-302 has been studied in many murine xenograft models (H82 small-cell lung 
cancer, H460 and Calu-6 non-small cell lung cancer, A375 and Stew2 melanoma, 786-0 renal 


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cell and PLC/PRF/5, Hs766t and BxPC-3 pancreatic cancer). The cytotoxic activity of TH-302 
increases in vivo in hypoxic conditions, as shown by excision methods and tumour growth 
models. Acute (single dose) or chronic (for 2 weeks) treatment with TH-302 demonstrates 
selective reduction in tumour volume of the hypoxic regions in xenograft models, with their 
corresponding increase in necrotic compartments (20). TH-302 achieves a significantly greater 
benefit in combination with chemotherapy, and even the complete eradication of some 
tumours, including metastatic ones (24). 
With regard to the combination with anti-angiogenic drugs, the rationale starts from the 
knowledge of hypoxia induced by these agents that, in tumour progression, provide a more 
aggressive phenotype. The study of murine xenograft models in human 786-O renal cell 
carcinoma, melanoma A375, H460 non-small cell lung cancer and hepatocellular carcinoma 
PLC/PRF/5, investigated the synergistic activity of TH-302 in combination with sunitinib or 
sorafenib (25). Both anti-angiogenic drugs increased hypoxia detected in the tumour tissue, 
and were time and dose-dependent. In the 786-O renal cell model, the activity of sunitinib (40 
mg/kg) increased when combined with TH-302 (50 mg/kg) in terms of tumour growth control, 
from 38% to 75%. In addition, no significant weight loss was identified when combining anti-
angiogenic drugs with TH-302, which is an indicator of toxicity. In conclusion, the synergism 
reached in terms of the anti-tumour efficacy of the combination of sunitinib or sorafenib with 
TH-302 by selective action on hypoxic tissue induced by anti-angiogenic drugs, forms the basis 
for the future clinical development of this combination.  
 
1.2. STUDY OBJECTIVES 
 
1.2.1. 
PRIMARY OBJECTIVE 
Objective response rate (ORR). 
1.2.2. 
SECONDARY OBJECTIVES 
Secondary endpoints are: 
• Progression-free survival (PFS) 
• Time to progression (TTP) 
• Response duration (RD) 
• Overall survival (OS) 
• Safety 
• Serological and tumour tissue biomarkers  
1.2.3. 
SAFETY OBJECTIVE 
To determine the safety of TH-302 in combination with sunitinib.  


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1.3. STUDY FLOWCHART 
Figure 3 Trial Schema 
 
 
 
 
 
 
 
 
 
 
 
 
1.4. STUDY POPULATION 
1.4.1. 
Selection criteria 
Patients with a well- or moderately-differentiated metastatic pancreatic neuroendocrine 
tumour (pNET) (grade 1-2 of histological differentiation and Ki67 ≤ 20%) who are naïve to 
systemic treatment, with the exception of somatostatin analogues, will be eligible for the trial 
if they meet all the inclusion criteria and none of the exclusion criteria, as described below. 
1.4.1.1 Inclusion criteria 
For inclusion in the study subjects should fulfil the following criteria: 
1. Age ≥ 18 years capable of giving informed consent. 
2. ECOG performance status (Eastern Cooperative Oncology Group) 0 or 1 
3. Pancreatic neuroendocrine tumours (pNET) diagnosed histologically with a Ki67 ≤ 20% 
(well- or moderately-differentiated tumours). 
4. Evidence of unresectable or metastatic disease. Locally advanced disease must not be 
amendable to surgical resection or radiation therapy with curative intent.  
5. Prior systemic therapy is not permitted. Patients may be treated with somatostatin 
analogues prior to or during the trial. Concomitant or prior interferon (IFN) treatment 
is not permitted. 
6. Tumour progression documented by CT scan, MRI or octreoscan within 12 months prior 
to the baseline visit. 
- Pancreatic NET 
- Unresectable/Metastatic 
- Well/moderately differentiated 
- Naïve to systemic treatment 
(except somatostatin analogues) 
TH-302  
+  
Sunitinib 
Biomarkers 
- Serological 
- Tumour tissue 
Radiological Progression 
(RECIST 1.1) 
Unacceptable toxicity 
Withdrawal of Consent 


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7. Measurable disease by RECIST 1.1 criteria. Measurable lesions that have been previously 
radiated will not be considered target lesions unless increase in size has been observed 
following completion of radiation therapy. 
8. The patient must be able to consume the medication orally. 
9. Life expectancy more than 12 weeks. 
10. The required laboratory values corresponding to adequate organ function and bone 
marrow are as follows.  
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x 
upper limit of normal (ULN), or AST and ALT ≤ 5 x ULN if liver function 
abnormalities are secondary to underlying malignancy.  
• Total serum bilirubin ≤ 1.5 × ULN 
• Serum albumin ≥ 3.0 g/dl 
• Absolute neutrophil count ≥ 1500/µl. 
• Platelets ≥ 100,000/µl 
• Haemoglobin ≥ 5.6 mmol/l (9 g/dl)  
• Creatinine clearance > 40 ml/min (Cockroft and Gault Formula) 
11. Suitable cardiac function: 
• 12-lead 
ECG 
with 
no 
pathological 
findings 
(non-clinically 
significant 
abnormalities are permitted) 
• Normal echocardiogram/MUGA normal (LVEF ≥ 50%) 
12. Informed consent with date and signature indicating that the patient (or legal 
representative) has been informed of all study aspects prior to enrolment. 
13. The patient must be able to comply with the required study visits, treatment, 
laboratory tests and other study procedures. 
1.4.1.2 Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
Patients must NOT meet any of the following exclusion criteria: 
1. Previous treatments with chemotherapy, anti-VEGF monoclonal antibodies, tyrosine 
kinase inhibitors (TKI), mTOR inhibitors or interferon (IFN) administered for advanced 
disease. 
2. Prior treatment with another hypoxia-activated drug under clinical trial. 
3. Major surgery, radiotherapy or systemic therapy within 4 weeks prior to study 
enrolment, except palliative radiotherapy for non-target metastatic lesions. 
4. Prior high-dose chemotherapy requiring haematopoietic stem cell rescue. 
5. Immunosuppressive drugs such as cyclosporine, tacrolimus, azathioprine, or long-term 
corticosteroids taken concurrently or within 3 months prior to study enrolment. 


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6. Treatment, within 7 days prior to study enrolment, with known strong CYP3A4 inhibitors 
or inducers, or drugs that prolong the QT interval. 
7. Prior radiation therapy to > 25% of the bone marrow. 
8. Treatment within another clinical trial. 
9. Uncontrolled brain metastatic disease, spinal cord compression, carcinomatous 
meningitis or leptomeningeal disease. Patients should have completed surgery or 
radiation therapy for existing brain lesions, should not have documented increase in 
size of said lesions over the three months prior to the first study treatment dose, and 
should be asymptomatic. 
10. Diagnosis of any second malignancy within the last 3 years, except for adequately 
treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. 
11. Clinically significant cardio/cerebrovascular disease within 12 months prior to 
treatment initiation, including:  
• Myocardial infarction 
• Severe/unstable angina 
• Coronary/peripheral artery bypass graft 
• Congestive heart failure NYHA (New York Heart Association) Class III or IV, or 
patients with a history of congestive heart failure NYHA class III or IV, unless an 
echocardiogram or MUGA scan within 3 months prior to screening shows a left 
ventricular ejection fraction ≥ 45%. 
• Significant cardiac valvular heart disease. 
• Cerebrovascular accident including transient ischaemic attack. 
• Pulmonary thromboembolism. 
12. Cardiac arrhythmias (NCI CTCAE version 4.0 grade ≥ 2), atrial fibrillation of any grade, 
or QTc interval > 450 msec for males or > 470 msec for females. 
13. Hypertension that cannot be controlled despite optimal medical therapy (> 150/100 
mmHg) 
14. Chronic obstructive pulmonary disease (COPD) or any lung disease accompanied by 
hypoxaemia or oxygen saturation < 90% after a 2-minute walk. 
15. Current treatment with therapeutic doses of acenocoumarol (administration of low 
doses of acenocoumarol up to 2 mg/24 h for deep vein thrombosis prophylaxis is 
permitted). 
16. Known human immunodeficiency virus (HIV) infection. 


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17. Pregnant or breast-feeding. All female patients of childbearing age must have a 
negative pregnancy test (blood or urine) prior to study enrolment. 
18. Prior allergic reaction to ingredients structurally similar to TH-302 or sunitinib or to any 
of the drugs’ excipients.  
19. Non-healing wound, fistulae, active stomach ulcer or bone fractures. 
20. Any condition (medical or psychiatric) or reason that, in the opinion of the investigator, 
would interfere with the patient’s ability to participate in the clinical trial, by placing 
the patient at excessive risk or by complicating the interpretation of the safety data, 
therefore being unsuitable for enrolment in the study. 
 
1.5. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
 
1.5.1. 
DESCRIPTION OF ANALYSIS SETS 
1.5.1.1 Total analysis population 
All safety and efficacy analyses will be based in the total analysis population. Any patient 
fulfilling all the inclusion criteria and none of the exclusion criteria will be included the total 
analysis population. 
1.5.2. 
EFFICACY ASSESSMENT 
Objective response rate (ORR) 
This will be assessed according to RECIST version 1.1 criteria, to be performed every 8 weeks, 
regardless of treatment delays caused by treatment toxicity.  
The ORR is defined as the percentage of patients in which there is confirmation of a complete 
response (CR) or a partial response (PR) according to RECIST criteria, in relation to the total 
analysis population.  
A response is confirmed for patients in whom the response persists in an imaging test 
repeated ≥ 4 weeks after initial documentation of response.  
Progression-free survival (PFS) 
This is defined as the time between the start of study treatment to the date of first objective 
evidence of radiological progression or patient death from any cause; whichever comes first. 
Time to progression (TTP) 
This is defined as the time between the start of study treatment to the date of first objective 
evidence of radiological progression. 
Response duration (RD) 
This is defined as the time between the first recorded objective response (CR or PR), which is 
subsequently confirmed, to the first objective evidence of radiological progression or death 
from any cause.   


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RD will only be calculated in the subgroup of patients with objective response (CR + PR). 
Overall survival (OS) 
This is defined as the time between the start of study treatment to the date of death from any 
cause.  
If confirmation of death could not be obtained, survival will be censored with the date of the 
last visit at which time the patient was known to be alive. 
Safety 
See Safety Assessment section below. 
Biomarkers:  
They assess the correlation between radiological response and the patient’s clinical course and 
the following expression levels: 
• ENO1 (enolase 1) in plasma (it will be performed locally at the same time as 
chromogranin at each participating site) 
• SNPs (single nucleotide polymorphisms) related to the activity and metabolism of 
sunitinib and TH-302 VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826), IL8 
(rs1126647), CYP3A4 (rs35599367 and rs67666821), CYP3A5 (rs776746), ABCB1 
(rs1045642, rs1128503 and rs2032582), POR (rs1057868 and c.1705_1706insG). If a 
polymorphism of particular relevance and related to the effectiveness of sunitinib or 
TH-302 appears in the literature as the study progresses, its inclusion in the study 
could be considered. 
• Hypoxia markers related to paraffin-embedded tumour tissue (HIF1- α, CYP2W1 and c-
Myc). 
1.5.3. 
SAFETY ASSESSMENT 
The safety period runs from the date of the signature of the informed consent form until 28 
days after the last dose of the study drug. Safety will be evaluated according to adverse event 
reports, the frequency of treatment discontinuations due to adverse events, and laboratory or 
ECG tests. Descriptive analysis will be used. 
Adverse Events 
An adverse event is defined as any unwanted or unintended symptom, sign, disease or 
experience (including a clinically significant laboratory result of any grade according to the 
common terminology criteria for adverse events [CTCAE] of the National Cancer Institute, 
version 4.0) that emerges or worsens during the course of the study, whether related or not to 
the study drug. 
1.5.4. 
DETERMINATION OF SAMPLE SIZE 
It is estimated that a total of 43 eligible patients will be enrolled in the study (having received 
at least one dose of treatment). The design will follow Simon’s two-stage design for phase II 
studies, with a baseline number of 18 patients. The combination of TH-302 with sunitinib will 
be considered as inactive in terms of the response rate if less than 5% of patients are 


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responders, with a response rate threshold of 20%. These figures are based on the results 
shown with other drugs for the treatment of pNET.  
Should a response be identified in at least 3 out of every 18 patients treated, recruitment will 
continue up to 43 patients in order to be able to better estimate the response rate. If the study 
shows a response in at least 8 patients, the treatment is likely to continue its research 
development. 
The likelihood of terminating the study after the first part with 18 patients enrolled is 0.42 if 
the response rate is 10%, and 0.06 if the response rate is 25%. 
The likelihood of not accepting the null hypothesis and considering the combination of TH-302 
with sunitinib active with a response rate less than 5% is 5% (Type I or alpha error).  
The likelihood of not rejecting the null hypothesis and considering the combination of TH-302 
with sunitinib inactive with a response rate greater than 5% is 20% (Type II or beta error). The 
statistical power of the study will be 0.80. 
1.5.5. 
METHODS OF STATISTICAL ANALYSES 
1.5.5.1 Descriptive analysis 
The descriptive analysis of patient characteristics will include demographic data, disease-
specific data and prior treatments. Qualitative data will be described with absolute frequencies 
and corresponding percentages. Quantitative data will be studied using the mean ± standard 
deviation, median, minimum and maximum values. The response percentages will be 
estimated using confidence intervals of 95%. 
In the safety analysis, adverse events will be specified according to the maximum grade 
described at the discretion of the investigator and defined by NCI-CTCAE, version 4.0, including 
adverse events described from treatment initiation until 28 days following its completion. 
The following safety analysis data will be presented: 
• Temporary and permanent treatment discontinuations due to an adverse event. 
• Deaths. 
• Adverse Events (AEs) and Serious Adverse Events (SAEs). 
• Hospitalisations. 
• Use of concomitant medication and growth factors. 
1.5.5.2 Primary Efficacy analysis 
Objective response rate (ORR). 
The objective response rate corresponding to the percentage of patients in which there is 
confirmation of a complete response (CR) or a partial response (PR) according to RECIST 
criteria, in relation to the total analysis population, will include a confidence interval of 95%.  


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1.5.5.3 Secondary Efficacy analysis 
The secondary efficacy objectives of the study are:  
• Progression-free survival 
• Time to tumour progression 
• Duration of response 
• Overall survival 
• Prognostic/predictive value of biomarkers analysed in peripheral blood and in paraffin-
embedded tumour tissue. 
The survival analyses will be performed using the Kaplan-Meier method presented with the 
corresponding graph, as well as by Cox regression analysis to obtain the hazard ratios and 
confidence intervals for the associations. For patients without documented progression or 
death at the time of analysis, the PFS will be censored at the last date of tumour assessment. 
For patients who have not died at the time of analysis, the OS will be censored. 
The association between the marker expression profiles analysed in plasma and treatment 
response (yes/no) will be assessed using logistic regression models and univariate and 
multivariate Cox regression, establishing the corresponding hazard ratio and confidence 
interval at 95%. The predictive value (of genetic biomarkers, in plasma and tumour tissue) of 
each model will be estimated using an area under the ROC curve. 
All statistical tests are bilateral, two-tailed tests, and all values with p<0.05 will be considered 
significant. 
1.5.5.4 Safety analysis 
Safety of TH-302 treatment in combination with sunitinib 
Adverse events and serious adverse events, laboratory test results, physical examination 
findings and vital signs, and their changes from baseline will be summarized using descriptive 
statistics. Abnormal values will be flagged.  
1.5.6. 
INTERIM ANALYSES 
There are no efficacy interim analyses planned on the primary endpoint because all secondary 
variables and safety at the end of the treatment period and during the follow-up period will be 
evaluated. 
1.5.7. 
RECORDING OF DATA 
An Electronic Data Capture (EDC) System will be used for data collection and query handling. 
The investigator will ensure that data are recorded on the eCRF as specified in the study 
protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the GCPs. 
 


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2. RESULTS 
2.1. STUDY POPULATION 
2.1.1. 
Recruited patients (centres/investigators) 
Initially XXX patients were recruited in XXX Spanish sites. The recruited period lasted from 
xxxxxx 20xx until xxxxxx 20xx. The distribution of patients by centres will be shown in the 
following table: 
Table 1. Recruited patients by site 
Centre 
Investigator 
Patients 
 
 
N (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
 
xx (100.0) 
 
Moreover XXX patients were screened without being finally recruited for the study. 
2.1.2. 
Evaluable patients  
Following protocol indications it was analysed which patients could be included in the analysis:  
General inclusion criteria: 
• 
Patients over 18 years with performance status ECOG 0 or 1. 
• 
Obtaining informed consent in writing and signed. 
• 
Pancreatic neuroendocrine tumours (pNET) diagnosed histologically with a Ki67 ≤ 20% 
(well- or moderately-differentiated tumours). 
• 
Evidence of unresectable or metastatic disease. Locally advanced disease must not be 
amendable to surgical resection or radiation therapy with curative intent.  
• 
Prior systemic therapy is not permitted. Patients may be treated with somatostatin 
analogues prior to or during the trial. Concomitant or prior interferon (IFN) treatment 
is not permitted. 
• 
Adequate hematologic, hepatic, renal and cardiac function 


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In the following table the number of non evaluable patients along with the reason why, will be 
reported. 
Table 2. Non evaluable patients  
No. 
ID patient 
Hospital 
Reason 
 
 
 
 
 
 
 
 
 
 
 
 
 
 The population by sites will be described in Table 3: 
Table 3. Patients evaluable by Site 
 
 
 
Total 
 
N (%) 
Hospital 1 
 
Hospital 2 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 
xx (100.0) 
 
In this report, data from xxx patients from xx Spanish sites will be analysed.  A database cut-
off was made in xxxxxx 2017 for this 1st preliminary analysis.  
 
Table 4. Evaluable patients 
 
n 
%1 
Total number of recruited patients 
 
100,0 
Recruited 
 
 
- 
Patients over 18 years with performance status ECOG 0 or 1. 
- 
Obtaining informed consent in writing and signed. 
- 
Pancreatic 
neuroendocrine 
tumours 
(pNET) 
diagnosed 
histologically with a Ki67 ≤ 20% (well- or moderately-differentiated 
tumours). 
- 
Evidence of unresectable or metastatic disease. Locally advanced 
disease must not be amendable to surgical resection or radiation 
 
 


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therapy with curative intent.  
- 
Prior systemic therapy is not permitted. Patients may be treated 
with somatostatin analogues prior to or during the trial. 
Concomitant or prior interferon (IFN) treatment is not permitted. 
- 
Adequate hematologic, hepatic, renal and cardiac function 
 
Total number of non recruited patients 
 
 
- 
Exclusion criteria 
 
 
1 Calculated percentage from the total of patients with available data 
2.2. BASELINE PATIENT CHARACTERISTICS 
For the descriptive analysis of the patients, the evaluable population will be used (see section 
2.1).  
The mean age of the women included in the study was XXXX years. 
Table 5. Baseline patient characteristics 
Sociodemographic 
N 
Mean (SD) 
Median (Min-Max) 
Age 
 
 
 
 
 
N (%) 
Gender 
Male 
 
Female 
 
Race 
White 
 
Black 
 
Hispanic 
 
Asian 
 
Other 
 
Vital signs 
 
N (%) 
Performance status 
0 
 
1 
 
 
N 
Mean (SD) 
Median (Min-Max) 
Body weight 
 
 
 
Height 
 
 
 
BMI 
 
 
 
Body area 
 
 
 
Systolic Blood pressure 
 
 
 
Diastolic Blood pressure 
 
 
 
Basal comorbidity 
N (%) 
Charlson 
0 
 
1 
 
2 
 
≥3 
 
Cerebral vascular disease 
Normal 
 
Abnormal 
 
Peripheral arterial disease 
Normal 
 
Abnormal 
 
Diabetes 
Normal 
 
Abnormal 
 


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Heart failure/ ischemic heart 
disease 
Normal 
 
Abnormal 
 
Dementia 
Normal 
 
Abnormal 
 
Chronic renal failure 
Normal 
 
Abnormal 
 
Cancer 
Normal 
 
Abnormal 
 
Chronic obstructive pulmonary 
disease 
Normal 
 
Abnormal 
 
Electrocardiogram (ECG) 
N (%) 
QT interval corrected 
<450 mseg 
 
450-480 mseg 
 
481-500 mseg 
 
>501 mseg 
 
Others 
 
Echocardiogram /MUGA 
N (%) 
LVEF 
<50% 
 
≥50% 
 
 
Table 6. Baseline analytics 
Haematology 
N 
Mean (SD) 
Median (Min-Max) 
Haemoglobin (g/dL) 
 
 
 
White blood cells (x109/L) 
 
 
 
Absolute neutrophil count (x109/L) 
 
 
 
Absolute Lymphocytes count (x109/L) 
 
 
 
Platelet count (x109/L) 
 
 
 
Biochemical 
N 
Mean (SD) 
Median (Min-Max) 
Sodium (mmol/L) 
 
 
 
Potassium (mmol/L) 
 
 
 
Calcium(mmol/L) 
 
 
 
Magnesium (mmol/L) 
 
 
 
Glucose (mmol/L) 
 
 
 
Creatinine (mg/dL) 
 
 
 
Aspartate AST (SGOT) 
 
 
 
Alanine transaminase ALT (SGPT) 
 
 
 
AST (SGOT)/ ALT (SGPT) 
 
 
 
Total bilirubin (mg/dL) 
 
 
 
Gamma-glutamyltransferase (GGT) 
 
 
 
Alkaline phosphatase (AP) 
 
 
 
Albumin (mg/dL) 
 
 
 
Lactate dehydrogenase [LDH] 
 
 
 
Blood clotting 
N 
Mean (SD) 
Median (Min-Max) 
Prothrombin time (PT) 
 
 
 
Activated Partial Thromboplastin Time (aPTT) 
 
 
 
Thyroid function 
N 
Mean (SD) 
Median (Min-Max) 
Thyroid-Stimulating Hormone (TSH) 
 
 
 
T4 
 
 
 
Tumour markers 
N 
Mean (SD) 
Median (Min-Max) 


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Cg A 
 
 
 
Enolase 1 
 
 
 
 
 
2.3. TUMOR DATA AND PRIOR TREATMENTS 
Baseline tumour characteristics will be reported in this section. 
Table 7. Tumour characteristics 
 
 
N (%) 
Histological grade 
G1 – Well differentiated 
 
G2 – Moderately differentiated 
 
Unknown 
 
Ki-67 Index 
≤2% 
 
>2-5% 
 
>5-10% 
 
>10% 
 
Mitosis 10 CGA 
<2 
 
2-20 
 
Type of tumour 
Functioning 
 
Not functioning 
 
Histological subtype 
Gastrinoma 
 
Glucagonoma 
 
Insulinoma 
 
VIPoma 
 
Somatostatinoma 
 
Others, multisecretor or unknown 
 
Surgery 
Yes 
 
No 
 
Stage at diagnosis 
I 
 
II 
 
III 
 
IV 
 
CT relapse 
Yes 
 
No 
 
Relapse location 
Hepatic 
 
Extra-hepatic 
 
 
N 
Mean (SD) 
Median (Min-Max) 
Time between diagnosis (anatomical 
pathology) and treatment initiation 
 
 
 
Time between diagnosis (anatomical 
pathology) and surgery 
 
 
 
Time between diagnosis (anatomical 
pathology) and CT relapse 
 
 
 
Somatostanine analoguesprior the trial 
Yes 
 
No 
 
 


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2.4. CONCOMITANT MEDICATION 
In this section concomitant medications will be shown.  
Table 8. Concomitant medication 
 
 
N (%) 
Concomitant medication 
No 
 
Yes 
 
Concomitant medications 
Concomitant medication 1 
 
Concomitant medication 2 
 
Concomitant medication 3 
 
… 
 
 
2.5. TREATMENT EXPOSURE 
The TH-302 dose administered will be 340 mg/m2 by intravenous infusion over 30-60 minutes, 
on days 8 and 22 of each cycle. The dose should be adjusted according to body surface area. In 
the event of patient weight variation > 10%, the body surface area will be recalculated and the 
TH-302 dose readjusted. 
Details of TH-302 compliance will be shown in the following table: 
Table 9. TH-302 compliance 
 
N 
Mean (SD) 
Median (Min-Max) 
Number of TH-302 cycles 
 
 
 
Length of TH-302 treatment 
(weeks) 
 
 
 
 
 
N (%) 
Total number of cycles with 
TH-302 
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
5 cycles 
 
6 cycles 
 
… 
 
Total number of TH-302 
reductions 
1 reduction 
 
2 reductions 
 
3 reductions 
 
4 reductions 
 
… 
 
Reason for TH-302 reductions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Total number of TH-302 delays 
1 delay 
 
2 delays 
 
3 delays 
 
4 delays 
 
… 
 
Reason for TH-302 delays 
Reason 1 
 
Reason 2 
 


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Reason 3 
 
… 
 
Total number of TH-302 
omissions 
1 omission 
 
2 omissions 
 
3 omissions 
 
4 omissions 
 
… 
 
Reason for TH-302 omissions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
 
N 
Mean (SD) 
Median (Min-Max) 
Length of TH-302 temporary 
interruption (weeks) 
 
 
 
 
If any patient did not receive TH-302 it will be listed below along with her details. 
Table 10. List of patients that did not receive TH-302 
Patient ID 
code 
Total number of 
TH-302 cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle 6 
 
0 
 
 
 
 
 
 
 
Sunitinib will be administered at a dose of 37.5 mg per day (1 capsule of 25 mg and 1 capsule 
of 12.5 mg) orally for 28 days on an ongoing basis. It must always be taken at the same time 
every day (or as close as possible) and capsules must be swallowed whole.  
Details of Sunitinib compliance will be shown in the following table:  
Table 11. Sunitinib compliance 
 
N 
Mean (SD) 
Median (Min-Max) 
Number of Sunitinib cycles 
 
 
 
 
 
N (%) 
Total number of cycles with 
Sunitinib 
1 cycle 
 
2 cycles 
 
3 cycles 
 
4 cycles 
 
5 cycles 
 
6 cycles 
 
Total number of Sunitinib 
reductions 
1 reduction 
 
2 reductions 
 
3 reductions 
 
4 reductions 
 
5 reductions 
 
6 reductions 
 
Reason for Sunitinib reductions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Total number of Sunitinib 
delays 
1 delay 
 
2 delays 
 


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3 delays 
 
4 delays 
 
5 delays 
 
6 delays 
 
Reason for Sunitinib delays 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
Total number of Sunitinib 
omissions 
1 omission 
 
2 omissions 
 
3 omissions 
 
4 omissions 
 
5 omissions 
 
6 omissions 
 
Reason for Sunitinib omissions 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 
 
N 
Mean (SD) 
Median (Min-Max) 
Length of Sunitinib temporary 
interruption (weeks) 
 
 
 
 
If any patient did not receive Sunitinib it will be listed below along with her details. 
Table 12. List of patients that did not receive Sunitinib 
Patient ID 
code 
Total number of 
Sunitinib cycles 
Date of 
cycle 1 
Date of 
cycle 2 
Date of 
cycle 3 
Date of 
cycle 4 
Date of 
cycle 5 
Date of 
cycle 6 
 
0 
 
 
 
 
 
 
 
2.5.1. 
Withdrawal of patients from therapy or assessment 
Treatment with TH-302 in combination with sunitinib will continue until disease progression, 
unacceptable toxicity, non-compliance with the protocol, the patient’s withdrawal of informed 
consent or at the discretion of the investigator. In case of withdrawal of the study medication 
for toxicity, the patient will continue follow-up according to the scheduled study activities, and 
the investigator following the patient shall be responsible for initiating another systemic 
treatment option if deemed appropriate. 
If any patient stopped the study treatment prematurely, it will be listed below along with her 
details. 
Table 13. Study treatment premature interruption 
 
 
N (%) 
Study treatment premature 
interruption 
Yes 
 
No 
 
Reasons for study treatment 
premature interruption 
Reason 1 
 
Reason 2 
 
Reason 3 
 
… 
 


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If any patient did not receive Sunitinib/TH-302 during any cycle, it will be listed below along 
with her details. 
Table 14. List of patients that did not receive Sunitinib/TH-302 
Patient ID code 
Reason for premature interruption 
 
 
 
Details of the end of treatment reasons will be shown in the following table. 
Table 15. Reason for end of treatment 
 
 
N (%) 
Reasons for 
end of 
treatment 
Progression 
 
Unaccepted toxicity 
 
Details of toxicities 
Toxicity 1 
 
Toxicity 2 
 
…. 
 
Investigator decision 
 
Details of investigator decisions 
Investigator decision 1 
 
Investigator decision 1 
 
… 
 
Other reasons 
 
Details of other reasons 
Other reasons 1 
 
Other reasons 2 
 
… 
 
 
The median of the study treatment was XXX weeks: 
Table 16. Study treatment length 
 
N 
Mean (SD) 
Median (Min-Max) 
Length of study treatment 
(weeks) 
 
 
 
 


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2.6. ANALYSIS SETS 
All safety and efficacy analyses will be based in the total analysis population. Any patient 
fulfilling all the inclusion criteria and none of the exclusion criteria will be included the total 
analysis population. 
Table 17. Analysis sets 
 
 
N (%) 
Total analysis population 
Yes 
 
No 
 
Reason excluded 
Reason 1 
 
Reason 2 
 
…. 
 
 
 
 
If any patient is excluded from the total analysis population, it will be listed below along with 
the reasons why: 
Table 18. List of patients that are excluded total analysis population 
Patient ID 
code 
Total analysis 
population 
Reason excluded from total analysis 
population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.7. EFFICACY ANALYSIS 
The total analysis population will be used to present the efficacy analysis. 
2.7.1. 
Primary efficacy analysis 
Objective response rate (ORR) 
The objective response rate (ORR) will be reported with absolute and relative frequencies and 
using the binomial test procedure their 95% confidence interval (CI95%) will be provided. 
According to the protocol the ORR is defined as the percentage of patients in which there is 
confirmation of a complete response (CR) or a partial response (PR) according to RECIST 
criteria, in relation to the total analysis population. 
In the total analysis population (n=XX), the objective response rate, disease control rate and 
CA 125 rate will be detailed below: 
Table 19. Response 
 
 
N (%; IC 95%) 
Response rate according to 
RECIST 
Complete response (CR) 
 
Partial response (PR) 
 
Stable disease (SD) 
 
Progression disease (PD) 
 
Total 
 
Objective response rate:  
CR or PR according to RECIST 
Yes 
 
No 
 
Total 
 
Disease–control rate: 
CR or PR o SD according to 
RECIST 
Yes 
 
No 
 
Total 
 
 
Figure 4 Waterfall plot: Maximum % change from baseline in target tumor measurement for each 
patient  
 


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In those patients that responded (CR or PR according to RECIST) the “time to response” will be 
calculated. This is defined as the time between date of treatment initiation and the first 
recorded objective response (CR or PR), which is subsequently confirmed.  
The median of the time to response was XXX weeks: 
Table 20. Time to response 
 
N 
Mean (SD) 
Median (Min-Max) 
Time to response (weeks) 
 
 
 
 
2.7.2. 
Secondary efficacy analysis 
The progression free survival will be estimated and plotted using the Kaplan-Meier product-
limit method, along with their corresponding log-log transformed 95% confidence intervals 
Time to tumour progression, duration of response and overall survival will also be described 
using these same Kaplan-Meier methods. 
Cox regression analysis will be used to obtain hazard ratios and their confidence intervals for 
the associations. For patients without documented progression or death at the time of 
analysis, the PFS will be censored at the last date of tumour assessment. For patients who 
have not died at the time of analysis, the OS will be censored. 
The association between the marker expression profiles analysed in plasma and treatment 
response (yes/no) will be assessed using logistic regression models and univariate and 
multivariate Cox regression, establishing the corresponding hazard ratio and confidence 
interval at 95%. The predictive value (of genetic biomarkers, in plasma and tumour tissue) of 
each model will be estimated using an area under the ROC curve. 
 
2.7.2.1 Progression Free Survival 
The progression-free survival rate will be estimated and plotted using the Kaplan-Meier 
product-limit method, along with their corresponding log-log transformed 95% confidence 
intervals. 
In the total analysis population (n=XX), at 3 months the proportion of patients that survived 
without PD or exitus was XXXX with a 95% CI XXXX-XXXX. The overall median of PFS was XXX 
months (95% CI XXX-XXX). 
Table 21. Progression free survival 
PFS 
N events 
Patients at risk  %  estimated cumulative 
survival ratio1 
95% CI 
% with PD 
at 3 months 
 
 
 
 
 
at 6 months 
 
 
 
 
 
at 12 months 
 
 
 
 
 
 
N 
N (%) events 
Median 
(months) 
Standard  
error 
95% CI 
Estimated PFS1 
 
 
 
 
 
1: Estimated using Kaplan-Meier product-limit method 


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Table 22. Progression free survival events 
 
 
 
N (%; IC 95%) 
PFS event 
Without PD/Exitus 
 
PD 
 
Exitus (without previous PD) 
 
Total 
 
Figure 5 Kaplan Meier curve: PFS 
 
 
 
2.7.2.2 Time to tumour progression 
The time to tumour progression will be calculated in those patients with objective evidence of 
radiological progression. This is defined as the time between the start of study treatment to 
the date of first objective evidence of radiological progression. 
The median of the time to tumour progression was XXX weeks: 
Table 23. Time to tumour progression 
 
N 
Mean (SD) 
Median (Min-Max) 
Time to tumour progression 
(weeks) 
 
 
 
 
2.7.2.3 Response duration 
The response duration (RD) will be calculated in those patients with objective response (CR + 
PR). This is defined as the time between the first recorded objective response (CR or PR), which 
is subsequently confirmed, to the first objective evidence of radiological progression or death 
from any cause.   


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The median of the RD was XXX weeks: 
Table 24. Response duration time 
 
N 
Mean (SD) 
Median (Min-Max) 
Response duration time (weeks) 
 
 
 
 
2.7.2.4 Overall survival 
The overall survival rate will be estimated and plotted using the Kaplan-Meier product-limit 
method, along with their corresponding log-log transformed 95% confidence intervals. 
In the total analysis population (n=XX), at 3 months the proportion of patients that survived 
was XXXX with a 95% CI XXXX-XXXX. The overall median of OS was XXX months (95% CI XXX-
XXX). 
Table 25. Overall survival 
OS 
N events 
Patients at risk  %  estimated cumulative 
survival ratio1 
95% CI 
% exitus 
at 3 months 
 
 
 
 
 
at 6 months 
 
 
 
 
 
at 12 months 
 
 
 
 
 
 
N 
N (%) events 
Median (months) 
Standard error 
95% CI 
Estimated OS1 
 
 
 
 
 
1: Estimated using Kaplan-Meier product-limit method 
 
 
Table 26. Overall survival events 
 
 
 
N (%; IC 95%) 
OS event 
No exitus at end of follow-up 
 
Exitus 
 
Total 
 
Figure 6 Kaplan Meier curve: OS 
 


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2.7.2.5 Biomarkers 
In the total analysis population (n=XX), the proportion of patients with the following 
expression levels: 
• ENO1 (enolase 1) in plasma (it will be performed locally at the same time as 
chromogranin at each participating site) 
• SNPs (single nucleotide polymorphisms) related to the activity and metabolism of 
sunitinib and TH-302 VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826), IL8 
(rs1126647), CYP3A4 (rs35599367 and rs67666821), CYP3A5 (rs776746), ABCB1 
(rs1045642, rs1128503 and rs2032582), POR (rs1057868 and c.1705_1706insG). If a 
polymorphism of particular relevance and related to the effectiveness of sunitinib or 
TH-302 appears in the literature as the study progresses, its inclusion in the study 
could be considered. 
• Hypoxia markers related to paraffin-embedded tumour tissue (HIF1- α, CYP2W1 and c-
Myc). 
 
 
Table 27. Biomarkers 
 
 
 
N (%; IC 95%) 
ENO1 
Yes 
 
No 
 
Total 
 
VEGFR2 
Yes 
 
No 
 
Total 
 
VEGFR3 
Yes 
 
No 
 
Total 
 
IL8 
Yes 
 
No 
 
Total 
 
CYP3A4 
Yes 
 
No 
 
Total 
 
ABCB1 
Yes 
 
No 
 
Total 
 
POR 
Yes 
 
No 
 
Total 
 
HIF1- α 
Yes 
 
No 
 
Total 
 
CYP2W1 
Yes 
 
No 
 
Total 
 
c-Myc 
Yes 
 
No 
 
Total 
 


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2.7.2.6 Association between ORR and Biomarkers  
In the total analysis population, the association between the marker expression profiles 
analysed in plasma and treatment response (yes/no) will be assessed using logistic regression 
models (univariate and multivariate). 
Table 28. Univariate logistic regression 
 
 
 
 
95% CI EXP(B) 
 
Variables 
Categories 
Exp(B) 
p-value 
Inferior 
Superior 
N 
ENO1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR2 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR3 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
IL8 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP3A4 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
ABCB1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
POR 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
HIF1- α 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP2W1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
c-Myc 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 


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In the total analysis population, in the multivariate model, those variables that were found 
statistically significant (p<0,1), will be entered as factors in the multivariate model for 
treatment response (yes/no). 
Table 29. Multivariate logistic regression 
 
 
 
 
95% CI EXP(B) 
 
Variables 
Categories 
Exp(B) 
p-value 
Inferior 
Superior 
N 
ENO1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR2 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR3 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
IL8 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP3A4 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
ABCB1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
POR 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
HIF1- α 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP2W1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
c-Myc 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
  


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2.7.2.7 Association between PFS and Biomarkers  
In the total analysis population, the association between the marker expression profiles 
analysed in plasma and PFS will be assessed using the Cox regression models (univariate and 
multivariate). 
Table 30. Univariate Cox regression PFS 
 
 
 
 
95% CI HR 
 
Variables 
Categories 
HR 
p-value 
Inferior 
Superior 
N 
ENO1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR2 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR3 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
IL8 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP3A4 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
ABCB1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
POR 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
HIF1- α 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP2W1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
c-Myc 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 


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In the total analysis population, in the multivariate model, those variables that were found 
statistically significant (p<0,1), will be entered as factors in the multivariate model for PFS. 
Table 31. Multivariate logistic regression PFS 
 
 
 
 
95% CI HR 
 
Variables 
Categories 
HR 
p-value 
Inferior 
Superior 
N 
ENO1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR2 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR3 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
IL8 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP3A4 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
ABCB1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
POR 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
HIF1- α 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP2W1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
c-Myc 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.7.2.8 Association between OS and Biomarkers  
In the total analysis population, the association between the marker expression profiles 
analysed in plasma and OS will be assessed using the Cox regression models (univariate and 
multivariate). 
Table 32. Univariate Cox regression OS 
 
 
 
 
95% CI HR 
 
Variables 
Categories 
HR 
p-value 
Inferior 
Superior 
N 
ENO1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR2 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR3 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
IL8 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP3A4 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
ABCB1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
POR 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
HIF1- α 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP2W1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
c-Myc 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 


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In the total analysis population, in the multivariate model, those variables that were found 
statistically significant (p<0,1), will be entered as factors in the multivariate model for OS. 
Table 33. Multivariate logistic regression OS 
 
 
 
 
95% CI HR 
 
Variables 
Categories 
HR 
p-value 
Inferior 
Superior 
N 
ENO1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR2 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
VEGFR3 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
IL8 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP3A4 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
ABCB1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
POR 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
HIF1- α 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
CYP2W1 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
c-Myc 
Yes 
 
 
 
 
 
No 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.7.2.9 ROC curves: Area Under Curve, ORR vs. Biomarkers  
The predictive value (of genetic biomarkers, in plasma and tumour tissue) of each model 
previously obtained assessing the factors (marker expression profiles analysed in plasma) of 
treatment response (yes/no). The accuracy will be measured by the area under the ROC curve. 
An area of 1 represents a perfect test and an area of 0,5 represent a worthless test. A rough 
guide for classifying the accuracy of a diagnostic test is the traditional academic point system:  
• 0,90-1 = excellent (A)  
• 0,80-0,90 = good (B)  
• 0,70-0,80 = fair (C)  
• 0,60-0,70 = poor (D)  
• 0,50-0,60 = fail (F) 
Figure 7 ROC curve: ORR vs. Biomarker model 1 
 


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2.8. SAFETY ANALYSIS 
Adverse events and serious adverse events, laboratory test results, physical examination 
findings and vital signs, and their changes from baseline will be summarized using descriptive 
statistics. Abnormal values will be flagged.  
The total analysis population will be used for the safety analysis. 
Table 34. Adverse events 
Adverse Events 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Total 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Hematologic 
 
 
 
 
 
Neutropenia 
 
 
 
 
 
Anaemia 
 
 
 
 
 
Thrombocytopenia 
 
 
 
 
 
Metabolic/Laboratory 
 
 
 
 
 
GGT (γ-Glutamyl transpeptidase)  
 
 
 
 
 
Alkaline phosphatase 
 
 
 
 
 
Lipase 
 
 
 
 
 
AST, SGOT (serum glutamic oxaloacetic transaminase)  
 
 
 
 
 
ALT, SGPT (serum glutamic pyruvic transaminase)  
 
 
 
 
 
Gastrointestinal 
 
 
 
 
 
Nausea 
 
 
 
 
 
Diarrhoea 
 
 
 
 
 
Abdominal pain 
 
 
 
 
 
Constipation 
 
 
 
 
 
Vomiting 
 
 
 
 
 
Heartburn/dyspepsia  
 
 
 
 
 
Mucositis 
 
 
 
 
 
Others 
 
 
 
 
 
Hypertension 
 
 
 
 
 
Fatigue (asthenia) 
 
 
 
 
 
Dry mouth/salivary gland (xerostomia)  
 
 
 
 
 
Headache 
 
 
 
 
 
Anorexia 
 
 
 
 
 
Vaginal bleeding 
 
 
 
 
 
Fistula 
 
 
 
 
 
Hypothyroidism 
 
 
 
 
 
Subclinical Hypotiroidism 
 
 
 
 
 
Neuropathy 
 
 
 
 
 
Hepatic toxicity 
 
 
 
 
 
GGT: Gamma glutamil transpeptidase; AST: Aspartate aminotransferase; ALT: Alanine transaminase. 
 
 


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3. CONCLUSIONS 
 


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4. ANEXES 
4.1. ANEX I: DATABASE MANAGEMENT 
In this section, the process of data base management and data cleaning will be described. 
 
 
 


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5. REFERENCES 
1.       O’Toole, D., et al. Rare functioning pancreatic endocrine tumours. Neuroendocrinology 
2006; 84: 189-195. 
2.       Öberg, K., et al. Neuroendocrine gastro-entero-pancreatic tumours: ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (suppl): vii124-
vii130 
3.       Moertel, GC., et al. Streptozocin-Doxorubicin, Streptozocin-Fluorouracil, or Chlorozotocin 
in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992; 326: 519-523 
4.        Kouvaraki, M.A., et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of 
patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 
2004; 22: 4762-4771 
5.         Cheng, P.N. and Saltz, B. Failure to confirm major objective antitumor activity for 
streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. 
Cancer 1999; 86 (6): 944-948 
6.         Strosberg, J.R., et al. First-Line chemotherapy with capecitabine and temozolomide in 
patients with metastatic pancreatic endocrine carcinomas. Cancer 2011; 117: 268-275 
7.         Fjällskog, M.H., et al. Treatment with cisplatin and etoposide in patients with 
neuroendocrine tumours. Cancer 2001; 92: 1101-1107 
8.         Caplin ME, Ruszniewski P, Pavel M, Cwkla J, Phan A, Raderer M, et al. A randomized 
double blind placebo-controlled study of lanreotide antiproliferative response in patients with 
gastroenteropancreatic Neuroendocrine NET (CLARINET). ESMO European Cancer Congress. 
2013 Sep 28;abstr:3 
9.         Yao, JC., et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low to 
intermediate grade neuroendocrine tumours: Results of a phase II study. J Clin Oncol 2008; 26 
(26): 4311-4318 
10.       Yao, JC., et al. Daily oral everolimus activity in patients with metastatic pancreatic 
neuroendocrine tumours after failure of cytotoxic chemotherapy; A phase II trial. J Clin Oncol 
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11.       Yao, JC., et al. Everolimus for advanced pancreatic neuroendocrine tumours. N Engl J 
Med 2011; 364 (6): 514-523 
12.       Grande E, et al. Oral presentation at ECCO ESMO 2012; Vienna, Austria: Abstract 11570 
13.       Faivre, S., et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel 
oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006; 24 (1): 25-
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14.         Kulke, M.H., et al. Activity of Sunitinib in patients with advanced neuroendocrine 
tumours. J Clin Oncol 2008; 26 (20): 3403-3410 
15.       Raymond, E., et al. Sunitinib Malate for the treatment of pancreatic neuroendocrine 
tumours. N Engl J Med, 2011; 364 (6): 501-513 


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16.       Castellano, D., Grande, E., Barriuso, J. Advances in pancreatic neuroendocrine tumor 
treatment. N Engl J Med 2011;364: 1872-1873 
17.       Weiss GJ, Infante JR, Chiorean EG, et al. Phase 1 study of the safety, tolerability, and 
pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid 
malignancies. Clin Cancer Res 2011;17(9):2997-3004. 
18.       Hart CP., et al. Bench to bedside experience with TH-302: a tumor-selective hypoxia-
activated prodrug as a promising treatment for prostate cancer. Proceedings of the AACR 
Annual Meeting; 2009. Abstract B185. 
19.         Williams, KJ., et al. Hypoxia in tumours: molecular targets for anti-cancer therapeutics. 
Adv Enzyme Regul 2004; 44: 93-108.