Phase II Study of MIBG-I131 (Metaiodobenzylguanidine) in Patients With Well Differentiated Neuroendocrine Tumors and MIBG Positive Scan
Phase: PHASE2
Conditions: Neuroendocrine Tumors
Sponsor: AC Camargo Cancer Center

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Phase II Study of MIBG-I131 in Patients With Well-
Differentiated Neuroendocrine Tumors and MIBG 
Positive Scan (MIBNET) 
 
 
 
 
 
Rachel Riechelmann (Principal Investigator)1, Milton Barros1, Mauro Donadio1, Rodrigo 
Taboada1, Tiago Felismino1, Celso Abdon1, Virgílio Souza1, Marcos Camandaroba1, 
Victor Hugo de Jesus1, Rubens Chojniak2, Eduardo Nóbrega3  
Departments: 1-Clinical Oncology A.C.Camargo Cancer Center, 2-Image Department 
A.C.Camargo Cancer Center, 3-Nuclear Medicine A.C.Camargo Cancer Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A.C.Camargo Cancer Center – Brazil 
 
Registration Number on Institutional Research Ethics Committee: 3025/20 
 
 
 
 
March 2021  
 

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Abstract 
 
 
Neuroendocrine tumors (NET) are rare neoplasms, which frequently present 
metastatic and incurable at diagnosis. In this context, few effective therapies exist. 
When the disease becomes refractory to standard therapies, treatments with limited 
efficacy (eg, surgical debulking, cytotoxic chemotherapies, interferon alpha) that could 
lead to important adverse events are used. Therefore, clinical studies that test new 
therapeutic strategies in NET patients with refractory disease are needed. Treatment 
with radiopharmaceuticals have been studied in NET and showed to be promisor. As an 
example, is the treatment with Lutetium177 octreotate, disponible in Brazil for decades, 
and one of the most active therapeutic options to NET. 
The radiopharmaceutical MIBG-I131 (metaiodobenzylguanidine linked to 
Iodine131) is the first treatment choice for patients with paraganglioma/ 
pheochromocytoma (PggF), a rare type of neuroendocrine neoplasm originated from 
neural ganglia. Patients with this neoplasia are submitted to scintigraphy with MIBG-I131, 
a norepinephrine analog whose transporter protein is highly expressed in this tumor. If 
the uptake is positive, patients receive treatment with therapeutic doses of MIBG-I131. 
The disease control with this intervention could last two years. Old and small studies 
suggested that MIBG-I131 could also have an activity in other NET besides PggF. 
Gastrointestinal (GI) or lung NET could have a positive expression on MIBG-I131 scan in 
up to 50% of the cases. With this rationale, retrospective series reported that MIBG-I131 
could offer clinical benefit in patients with GI NET, with disease control in up to 80% of 
the cases. However, the literature regarding therapeutic MIBG-I131 to NET not PggF is 
scarce, heterogeneous regarding population, methods of response assessment, doses 
of the radiopharmaceutical, and short follow-up time. Therefore, due to the absence of 
effective therapeutic options for patients with metastatic well-differentiated NET 
refractory to standard treatments, the evidence that NET can have a positive expression 
on MIBG-I131 scan, and that small retrospective studies with a low level of evidence 
suggest a benefit for control disease and improvement of symptoms, the investigators 
proposed a phase II study of MIBG-I131 to well-differentiated GI or lung NET patients with 
positive MIBG-I131 scan. 

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Adult patients, ECOG 0-2, with good organic functions, with progressing 
metastatic or locally advanced NET of GI or lung origin, with refractory disease or 
intolerant to available standard therapies, and with positive MIBG-I131 scintigraphy in 
metastatic lesions are eligible for receive up to 4 doses of 7,400Mbq (200 mCi) each, 
with an interval of at least 60 days. The primary outcome will be the disease control rate 
(DCR) at 6 months after the end of treatment, per RECIST 1.1; secondary outcomes will 
be DCR at 3 months post treatment, progression-free survival, radiological and 
biochemical response (functional NET), toxicities and quality of life measured by the 
EORTC QLQ-C30 and GINET21 questionnaires. Laboratory tests and clinical evaluation 
will be performed every 2 weeks during the study; Imaging exams will be performed 
every 3 months until progression. The study sample will be 22 patients. For this 
calculation, we consider the H0 of DCR in 6 months of 40% (placebo arm of phase III 
studies in TNE), H1 as 67%. Two-tailed type I error margin of 10%, power of 80% and loss 
of follow-up/non-adherence of 10% were considered. We estimated a 50% screening 
failure (50% positivity on MIBG-I131). 
If the study is positive, it can be cost-effective, as we estimate that 67% of 
patients will obtain disease control lasting at least 12 months, which will provide time 
free of toxic therapies with a low level of evidence and costly to patients and paying 
sources. In addition, the study has the potential to change the treatment guidelines for 
NET, facilitating the incorporation of MIBG-I131 as a therapeutic strategy in the treatment 
protocols for NET at A.C.Camargo Cancer Center. The study, therefore, may allow the 
institution in the future to offer treatment with MIBG-I131 to patients with 
supplementary health, recovering the costs invested in the MIBNET study. 
 
Introduction 
 
Neuroendocrine tumors (NET) are rare neoplasms, but with increasing incidence 
and prevalence in the last decades. In more than half of the cases, they present 
metastatic and incurable at diagnosis. Few effective therapies are approved for these 
tumors (somatostatin analogues, everolimus, and sunitinib), none have demonstrated 
gains in overall survival, and none is approved in the Brazilian public health system (SUS).  

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Well-differentiated NET express, in more than 80% of the cases, somatostatin 
receptors. Somatostatin analogues, lanreotide or octreotide, have anti-proliferative and 
anti-secretory activity, and, frequently, are considered the first-line treatment in the 
metastatic setting.1 Somatostatin receptors expression, through scintigraphy scan 
marked with radionuclide and octreotate (Octreoscan©) or positron emission 
tomography labelled with Ga68 (Ga68-PET-CT), is mandatory to effectively indicate the 
treatment with Lutetium177 radionuclide. The NETTER-1 study demonstrated the efficacy 
of Lutetium177, a type of peptide receptor radionuclide therapy (PRRT), in combination 
with long-acting releasing (LAR) octreotide 30 mg in second-line, with progression-free 
survival of approximately 40 months versus 8.5 months for the group treated only with 
LAR octreotide monthly in patients with midgut NET metastatic (HR: 0.20; p < 0.0001).2  
The NETTER-1 study established one more therapeutic strategy to NET, the PRRT. 
However, invariably, metastatic NET patients develop disease progression to 
standard treatment. Different chemotherapeutic regimens (FOLFOX, cisplatin/ 
etoposide, 
cisplatin/irinotecan, 
capecitabine/oxaliplatin, 
and 
capecitabine/ 
temozolomide), hepatic debulking surgery, and interferon alpha are used based on small 
phase 2 trials and/or retrospectives studies. In the Brazilian consensus of NET, these 
treatment modalities, even with low evidence level, are recommended when there are 
no other effective treatments available. Although some patients could benefit from 
these therapeutic options, the results relating to tumor response and quality of life tend 
to be modest and the toxicity significant (Table 1). Therefore, new treatment should be 
investigated in this context.   
The role of other PRRT therapies for NET has been the focus of research with 
new radiopharmaceuticals. Scintigraphy exam with I123 or I131-metaiodobenzylguanidine 
(MIBG) is the standard for the staging and therapeutic planning of patients with 
paraganglioma/pheochromocytoma (PggF), a rare type of NET. Metaiodo-
benzylguanidine is molecularly analogous to norepinephrine and, therefore, is used in 
exams and treatment in these tumors of origin in sympathetic and parasympathetic 
neural ganglia. Patients whose tumors show positive uptake on the MIBG-I131 exam are 
treated with therapeutic doses of MIBG-I131. The radiolabelled norepinephrine/ 
norepinephrine analogue is injected intravenously, reaching target cells and emitting 
Beta radiation within them. In patients with metastatic PggF, therapy with MIBG-I131 

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demonstrates objective tumor response rates of 30% and 50% of biochemical response 
in PggF.4  In 2018, at the American Society of Clinical Oncology (ASCO) congress, the first 
clinical study with PRRT with a noradrenaline analogue in patients with PggF, AZEDRA® 
(iobenguane I131), was presented. In this study, 88 patients with metastatic PggF 
received a maximum dose of 18.5 GBq (500 mCi every 3 months twice).5,6 The primary 
outcome was the proportion of participants who reduced at least 50% of 
antihypertensive medications for at least 6 months; secondary outcomes were response 
rate and survival. The study was positive (25% decreased the use of antihypertensive 
medications), the median overall survival was 17.5 and 48.7 months in the participants 
who received one or two doses of treatment, respectively.7 Adverse events were 
considered manageable, the most common of which were haematological (mainly 
thrombocytopenia), fatigue and nausea.  
Retrospective studies demonstrated that 50% to 60% of patients with 
gastroenteropancreatic (GEP) NET may have tumors with positive expression of MIBG-
I123,8,9 especially those with well-differentiated G1 and functioning tumors (producers of 
amines that cause clinical symptoms , such as carcinoid syndrome). Based on this 
information, it is intuitive to investigate the treatment with MIBG-I131 in other types of 
NET than PggF. In the largest series of cases, 211 patients with GEP or pulmonary NET 
treated with MIBG-I131 from 1994 to 2014, at the maximum dose of 18,500 MBq, had a 
median survival of 29 months since the start of treatment, 71% of clinical improvement 
with a median duration of 12 months and 20% with radiological response (80% disease 
control).10 Retrospective study with 38 patients with progressive NET GEP treated with 
a single dose of 7,400 MBq demonstrated 75% of radiological control of disease (3% of 
objective response), 63% with improvement of symptoms and median overall survival 
of 4 years.11 Toxicity was manageable, with 10% of transient neutropenia or 
thrombocytopenia and without complications. In another retrospective study of 38 
patients with NET (most GEP NET [25 midgut]; one patient with lung NET and 4 with 
PggF), MIBG-I131 was administered at a dose of 5.5 GBq in three cycles at intervals of 10 
to 12 weeks.12 The median progression-free survival was 13 months, the median overall 
survival was 48 months and the disease control rate was 65% (3 objective responses and 
22 with stable disease).12 In terms of tolerability, only 2 patients (5%) had grade 3 
myelotoxicity, which prevented the third application of MIBG-I131.12 Another 

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retrospective study with 25 metastatic (17 NET) patients treated with MIBG-I131 with a 
cumulative dose of 27.7 GBq (751mCi) showed improvement in symptoms in 80% of 
cases and 48% of radiological response by WHO criteria. The median overall survival was 
17 months since the last dose of MIBG-I131, with a 5-year survival rate of 59%.13 Other 
studies have assessed the role of MIBG-I131 in controlling symptoms of refractory 
carcinoid syndrome. A retrospective study from the 1990s reported improvement in 
carcinoid symptoms in 14 out of 30 patients, with a median duration of 8 months.9  
Despite the encouraging data, the few existing studies have important 
methodological limitations, such as, heterogeneous population (patients with GEP NET 
and PggF in the same study), varied criteria for evaluating efficacy (WHO and RECIST) 
and eligibility (presence or absence of disease progression in the baseline; distinct types 
of tumors with different prognosis), varying doses of MIBG-I131 and do not report data 
on quality of life or symptom control prospectively. 
Therefore, based on the premises that: (1) there is a need for research on rare 
neoplasms; (2) no effective systemic treatment for patients with well differentiated 
metastatic NET refractory to standard therapy; (3) GEP and lung NET may show positive 
expression in the MIBG-I123/131 scintigraphy exam, (4) data from retrospective studies 
suggest disease control and symptom improvement, but without data on quality of life 
and outcomes evaluated prospectively, (5) treatment of MIBG-I131 is available in the 
Brazilian public health system for the treatment of PggF, so there is no need for 
structural investment in the services that have this therapy, we propose a phase II study 
of MIBG-I131 for patients with GEP or pulmonary well differentiated NET with positive 
expression on MIBG-I131 scintigraphy. 
 
Hypotheses 
 
Well-differentiated NETs, with positive expression in the MIBG-I131 scintigraphy 
exam, will obtain significant radiological, symptomatic and biochemical control, and 
improved quality of life with therapeutic MIBG-I131, which may be a treatment option 
instead of expensive, toxic and ineffective treatments, such as chemotherapy regimens, 
interferon alpha and/or liver debulking surgery. 

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Objectives 
 
Primary:  
1 - Control of radiological disease at 6 months after the end of treatment. 
2- Control of clinical/biochemical (functional NET) at 6 months after the end of 
treatment. 
 
Secondary: 
1- Control of radiological disease at 3 months after the end of treatment. 
2- Control of clinical/biochemical (functional NET) at 3 months after the end of 
treatment. 
3- Progression-free survival. 
4- Radiological response and duration of response. 
5- Biochemical response in patients with functional NET. 
6- Evaluate tolerability and quality of life. 
 
Outcomes 
 
Primary:  
Disease control rate (DCR). Defined by absence of radiological progression in 
conventional imaging examinations by RECIST 1.1 at 6 months after the end of 
treatment. For patients with functioning syndrome, beside radiological DCR, patients 
should have improved in at least 10% of the baseline score of quality-of-life (EORTC QLQ-
GINET21) and stability or decrease in tumor markers. 
 
Secondary: 
1- Disease control rate (DCR). Defined by absence of radiological progression in 
conventional imaging examinations by RECIST 1.1 at 3 months after the end of 
treatment. For patients with functioning syndrome, beside radiological DCR, patients 
should have improved in at least 10% of the baseline score of quality-of-life (EORTC QLQ-
GINET21) and stability or decrease in tumor markers. 

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2- Progression-free survival. Defined by time from day 1 cycle 1 to death from any cause 
or radiological progression by RECIST 1.1, whichever occurs first. Patients alive and 
without progression at the time of study analysis will be censored for time-to-event 
analysis. 
3- Radiological response rate. Assessed by RECIST 1.1 criteria. 
4- Rate of Biochemical response. Defined by at least 30 percent drop in the tumor 
marker (24-hour urine 5-hydroxyindoleacetic acid (5-HIAA) and/or specific hormone), if 
functioning syndrome, at any time of treatment in relation to pre-treatment value. 
5- Quality of life. Assessed by the EORTC QLQ-C30 and QLQ-GINET21; both available in 
Brazilian Portuguese. Improvement of at least 10% in the baseline score at 3 and 6 
months after the end of the treatment will be considered clinically meaningful. 
Improvement by 10% of the baseline score at 3 and 6 months will be considered clinically 
meaningful. 
6- Incidence of Treatment-related Adverse Events. Frequency of adverse events of 
grades 2 or more by Common Adverse Event Toxicity Criteria (CTCAE) version 5.0. 
 
Methodology 
 
Study design 
 
This is a single-arm, unicentric, single-stage, phase 2 clinical study of therapeutic 
metaiodobenzylguanidine (MIBG) for patients with metastatic well-differentiated 
neuroendocrine tumors and radiological progression or intolerance after standard lines 
of treatment and with MIBG-I131 positive scan. 
Eligible patients will receive MIBGI-131 in up to 4 doses of 7,400Mbq (200 mCi) 
each, with an interval of at least 60 days. The administration of the cycles will depend 
on the results of the haematological exams, therefore, each patient will be able to 
receive from 1 to 4 cycles; In the experience of A.C.Camargo Cancer Center, most 
patients receive between 3 and 4 cycles. MIBG-I131 is administered intravenously to an 
inpatient, being discharged when reaching limits of radiological exposure recommended 
by the National Nuclear Energy Commission (invariably, 24 hours). The dose of 200mCi 

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per application for up to 4 doses of MIBG-I131 used in this protocol is the same used in 
routine at the institution and is also used in other PPRT treatments. This dose is safe and 
practiced by the service for at least a decade. 
Clinical and toxicity assessments will take place every 2 weeks with medical 
history, physical examination and general laboratory until resolution of toxicities 
(usually 30 days after treatment). Imaging exams (chest, abdomen and pelvis CT scans) 
and 5-HIAA dosage in 24-hour urine (functioning tumors) will be performed at the 
beginning of treatment, and every 3 months until progression or exit from the study. 
Symptom assessment will be conducted using quality of life questionnaires that will be 
administered before treatment and every 3 months until progression. Toxicities will be 
measured in all medical visits through CTCAE version 5.0. Consultations, laboratory and 
imaging tests are already part of the treatment routine of these patients. The extra 
routine interventions, that is, the study, are the MIBG-I131 scintigraphy exam, the 
treatment with MIBG-I131 and the quality-of-life assessments. 
Clinical data will be prospectively collected in an electronic database (REDCap) 
and will include sex, age, primary tumor site, performance scale status, functionality, 
metastatic disease duration, metastasis sites, degree of liver impairment, comorbidities, 
previous treatments, scores of quality of life results and toxicity. 
 
Study population 
 
 
Research participants will be recruited from the Clinical Oncology outpatient 
clinics and must meet all the inclusion criteria and none for exclusion. 
 
Inclusion criteria 
• Age greater than or equal to 18 years. 
• Well-differentiated metastatic NET from GEP, unknown primary with hepatic 
metastases or advanced/metastatic lung, inoperable, with no possibility of curative 
treatment. 
• MIBG-I131 scintigraphy with positive expression in at least one lesion that presents 
significant uptake and compatible with therapeutic effectiveness. 

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• Disease with radiological progression (at least 10% tumor volume growth) in the last 
12 months or with clinical and biochemical progression to functional NET according to 
clinical judgment. 
• Progression or intolerance to previous standard treatments according to scenario 
(private [somatostatin analogue, everolimus] or public [somatostatin analogue]). 
• Measurable disease. 
• ECOG performance scale 0 to 2. 
• Adequate organic function as defined by the following criteria: 
- Aspartate serum aminotransferase (AST), alanine serum aminotransferase (ALT) ≤ 2.5 
times the upper limit of normal of the local laboratory (ULN-LL); 
- Total serum bilirubin ≤ 2.0 x ULN-LL; 
- Absolute neutrophil count ≥ 1,500/mm3; 
- Platelet count ≥ 100,000/mm3; 
- Hemoglobin ≥ 9.0 g/dL; 
- Estimated creatinine clearance using the MDRD equation ≥ 60ml/min 
- Informed consent form signed by the patient or legal representative. 
 
Exclusion Criteria 
• Patients already treated with MIBG-I131. 
• History of serious clinical or psychiatric illness that, due to clinical judgment, may pose 
a risk for participation in this study. 
• Patients being treated with other protocols with experimental drugs. 
• Patients who have had recent major surgery less than 4 weeks ago. 
• Patients who received chemotherapy or other cancer therapy less than 3 weeks ago. 
• Pregnant or lactating patients. 
• Another synchronic neoplasia that requires systemic treatment. 
 
MIBG-I131 Treatment 
 
MIBG scintigraphy: 
Scintigraphy with MIBG-I131 will be performed as the method of choice for 
research and identification of active anatomical sites of expression of norepinephrine 

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receptors; for the staging of PggF and for the assessment of theranostic eligibility of 
patients for treatment with high doses of MIBG-I131. 
All patients will receive and must follow preparation prior to the exam, making 
use of iodized solutions to block the physiological uptake of eventual free iodine by the 
thyroid. Patients will be interviewed prior to the administration of doses, obtaining 
information about the correct preparation and the possible use of drugs that could 
potentially interfere with the result. 
The exams will be performed 24 hours after the intravenous administration of 
1.0 mCi of MIBG-I131, using the GE Discovery 640 or 630 Gamma Camera equipment 
where images of the entire body and those associated with anatomy (Spect_CT) will be 
obtained, following the Nuclear Medicine protocols of the A.C.Camargo Cancer Center. 
The exam will be considered as presenting a positive result when the concentration 
observed in the 24-hour images is considered to be of moderate to severe degree and 
still in agreement with the target lesions to be treated. The results will be obtained 
through the individual reading of the exams by two or more nuclear physicians, with 
experience varying between 30 and 6 years, with doubts being resolved in consensus 
with the most experienced. 
 
Treatment with high-dose MIBG-I131 
MIBG-I131 is a radioactive drug that emits Beta particles (0.61 MeV of energy) 
with a physical half-life of 8 days and a gamma-ray emitter of 364 keV of energy (which 
allows the performance of imaging tests), where metaiodobenzylguanidine is a 
norepinephrine analogue. MIBG-I131 is selectively concentrated in tissues enriched by 
adrenergic innervation (mainly tissues of neuroectodermal origin, which include 
neuroectodermal neoplasms such as NET. MIBG-I131 enters cells through diffusion 
passive or by neuronal uptake mechanism and is stored in neuro-secretory granules. 
Unlike noraepinephrine, MIBG-I131 is not metabolized, which allows its intracellular 
retention for many days, making its theranostic use feasible; it is excreted in its entirety 
via the urinary tract. The mechanism of antitumor action occurs by the emission of 
ionizing radiation from the decay of I131; 90% of this radiation comes from the emission 
of Beta radiation, which has an average penetration of 0.5 mm in the tissues. 

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The main adverse effect of MIBG-I131 is myelotoxicity, which occurs between 4 
to 6 weeks after MIBG-I131, with variable frequency according to heterogeneous studies 
(20-70% of all grades). Acute adverse events are of low intensity and include mild nausea 
and fatigue, elevated blood pressure (described in patients with PggF). Late events: 
hypothyroidism could occur if preventive measures described below are not taken; 
Persistent myelosuppression is uncommon and has been described in pre-treated 
patients with many previous regimens and chemotherapy (this treatment is uncommon 
in TNE); myelodysplasia, renal dysfunction or any other organ are considered to be rare 
and have no proven causality. The absolute contraindications are severe renal failure 
that requires dialysis, pregnancy/lactation and life expectancy less than 3 months; 
Relative contraindications are: moderate renal failure, refractory and resistant urinary 
tract infection, myelosuppression (serum platelet levels less than 100,000/mm3 and 
total leukocytes less than 3,000/mm3). Given the teratogenic potential, women of 
childbearing potential should undergo contraceptive measures during and for at least 4 
months after treatment. 
MIBG-I131 is administered at a dose of 200mCi intravenously every 8 weeks for 
up to 4 cycles. Laboratory tests are performed every 15 days, with a focus on assessing 
myelotoxicity. Laboratory blood tests within the appropriate results (see “inclusion 
criteria”) allow the administration of the next cycle. In the case of any toxicity with a 
degree equal to or greater than 3 or intolerable and persistent grade 2 toxicity, the next 
course of treatment will not be administered until the toxicity is grade 1 or resolves. If 
the toxicity does not resolve or becomes grade 1 within 8 weeks, the next cycle is not 
administered, and treatment is stopped. 
 
Administration protocol with MIBG-I131 
The treatments will be carried out in the Radioisotope Therapy Unit of the 
A.C.Camargo Cancer Center, which complies with the regulatory standards of the CNEN 
(National Nuclear Energy Commission) for treatments with radioisotopes and is part of 
the institutional routine. 
After admission, patients will be evaluated by anamnesis, will receive 
radiological safety instructions and sign the consent form for the procedure, then be 

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prepared with venepuncture, placement of infusion and hydration equipment with 
saline, medication with antiemetics (ondansetron) and the collection of control exams. 
The dose of MIBG-I131 provided by IPEN (Energy and Nuclear Research Institute - 
CNEN -SP) will be unpacked and its content and radioactive activity checked by the 
Nuclear Physician responsible for the procedure. The verified and authorized dose will 
be connected to the infusion equipment properly shielded from radiation and 
administered slowly between 45 and 180 minutes, under constant heart rate and blood 
pressure monitoring. Increases in blood pressure should be followed by stopping or 
slowing down the administration of the dose or/and using beta-blockers until 
normalization. The discharge will occur after the rate of radiological exposure produced 
by the patient is reduced to outpatient levels, which occurs within a maximum of 24 
hours. 
The bone marrow is the organ that receives the highest dose of unwanted 
radiation originating from the procedure, and during follow-up in cases of any toxicity 
with a degree equal to or greater than 3 or intolerable and persistent degree 2 toxicity, 
the next treatment cycle will not be administered until the toxicity is grade 1 or resolves; 
if it does not run within 8 weeks, treatment is stopped. Women of childbearing potential 
should use contraception for 6 months and men should consider using a sperm bank. 
Thyroid protection is recommended so that it does not absorb radioactive iodine, 
with the ingestion of potassium chloride syrup twice a day, which begins 72 hours before 
MIBG-I131 and continues for 72 hours after treatment. This procedure is routine in the 
Nuclear Medicine service. 
Guidance on hospital discharge, the participant/patient and their family 
members/caregivers on safety and radiation protection will be done according to the 
institution's routine. 
 
Security Assessments 
 
Baseline Assessments: 
After signing the informed consent form, patients will be submitted to the 
baseline eligibility assessment (see Table 2). 

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Within 6 weeks of the first treatment dose: search for noraepinephrine expression by 
MIBG-I131 scintigraphy. If positive, eligibility is confirmed, and the following procedures 
are: 
• Within 4 days of D1C1: Medical history, including previous diagnosis and treatment, 
history of other diseases (active and resolved), medications in use and general 
demographic data. Complete physical examination, ECOG performance index (PS) and 
vital signs. 
• Within 4 days of the first treatment dose, laboratory tests will be performed: blood 
count, urea, creatinine, ALT, AST, total bilirubin, sodium, potassium, and pregnancy test 
for women of childbearing age; these patients will be oriented to contraception. 
• Baseline imaging exams performed within 8 weeks of the first treatment dose will be 
accepted: CT scan (or MRI, if applicable) of the abdomen, pelvis and chest. 
• For patients with functioning NET, it will be accepted that baseline tumor marker 
exams have been performed within 8 weeks of the first treatment dose (eg 5HIAA in 24-
hour urine). 
 
With the exception of MIBG scintigraphy, which is used routinely for patients 
with PggF (but not TNE), all of the above tests are already part of the routine in the 
treatment of NET at A.C.Camargo Cancer Center. 
 
Safety assessments during treatment: 
Patients will be evaluated clinically and with laboratory tests (Table 2) every 15 
days between treatment cycles and after completion until resolution of any adverse 
treatment effects. +/- 3 days window will be allowed. 
 
• Complete physical examination, measurement of vital signs, weight measurement, 
ECOG, use of medications. 
• Assessment of adverse events. 
• Laboratory evaluation: blood count, urea, creatinine, ALT, AST, total bilirubin, sodium, 
potassium, and others, if clinically indicated. 
 

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To grade toxicities we will use the CTCAE 5.0 criteria. Patients who have 
intolerable grade 2 or grade 3 toxicity that the investigator deems to be related to MIBG-
I131 will have their treatment cycle delayed to grade 1 or resolution. If there is no 
reduction in the intensity of the adverse event to grade 1 within 8 weeks, treatment is 
discontinued. 
 
All adverse effects will be graded and assessed whether or not they are related 
to treatment. If there is no CTCAE 5.0 classification for an adverse event, the degree of 
severity of mild, moderate, severe and life threatening will be used. 
 
An adverse event for the purposes of this protocol is the appearance of (or 
worsening of pre-existing) undesirable sign(s), symptom(s) or medical condition(s) that 
occurs(s) after signature. informed consent, even if the event is not considered to be 
related to the drug(s) under study. The occurrence of adverse events should be obtained 
through indirect questions asked to the patient at each visit during the study. Adverse 
events can also be detected when they are reported voluntarily by the patient during or 
between visits or through physical examination, laboratory tests or other assessments. 
 
Whenever possible, each adverse event should be assessed to determine: 
1. Severity (mild, moderate, severe and life threatening) or (CTCAE 5.0 grade) 
2. Its relationship to each drug under study (suspected / not suspected) 
3. Its duration (initial and final dates or if they continue in the final exam) 
4. Conduct adopted (no conduct adopted; study drug dosage adjusted/ 
temporarily interrupted; study drug permanently discontinued due to the referred 
adverse event; concomitant medication administered; non-drug therapy administered; 
hospitalization / prolonged hospitalization). 
Patients requiring hospitalization should be immediately identified by the 
investigators in the study who monitor all patients. 
 
Criteria suspension of treatment: 
Patients may interrupt study treatment for one or more of the following reasons: 

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• Disease progression (documented by images and defined by the RECIST 1.1 
criteria). 
Clinical progression, based on the investigator's assessment 
• Death. 
• Intolerable or persistent adverse event (s) of grade 2 or higher. 
• Withdrawal of consent by the patient. 
• Need for new cancer therapy and / or surgery. 
 
Effectiveness and Follow-up Assessments: 
For evaluation of efficacy, patients will undergo imaging tests (chest, abdomen 
and pelvis tomography or abdomen and pelvis resonance) at baseline (within 8 weeks 
of starting treatment) and every 12 weeks (+/- 5 days) until progression or withdrawal 
from the study. Patients will also be evaluated for signs and symptoms that may be 
related to disease progression. Patients who present clinical progression, according to 
the investigator's judgment, but without radiological progression, will be able to 
discontinue the treatment and continue the image evaluation until progression; 
however, if new treatment is instituted, the last date of receipt of MIBG-I131 will be the 
censorship date in the progression-free survival analysis. 
After documenting progression or leaving the study for other reasons, patients 
will be followed up by the investigator or another oncologist from the Clinical Oncology 
team for symptom control, image monitoring and possible future therapies. The patient 
continues to be cared for at the A.C.Camargo Cancer Center, if desired. 
 
Quality of Life Assessment: 
The quality-of-life assessment will be conducted by two questionnaires from the 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire group, composed of the general questionnaire EORTC QLQ-C30 and its 
specific domain for TNE, the QLQ-GINET21, both available in Portuguese of Brazil by 
cross-cultural validation.14 
The QLQ – C30 general quality of life questionnaire was developed for cancer 
patients and is one of the most used in clinical cancer research, having already been 
applied by more than 80,000 cancer patients. Version 3 is the one currently used.16 It is 

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multidimensional, can be self-administered and consists of 30 questions that assess the 
patient in the last two weeks. The questionnaire addresses general questions about 
cancer, such as symptoms, side effects of treatment, psychological suffering, physical 
functioning, social interaction, sexuality, body image, global health, quality of life and 
satisfaction with medical care, regardless of the type of cancer. It is a generic quality of 
life document for cancer, composed of 30 questions that define the general quality of 
life, through five functional scales (physical, role/performance, cognitive, emotional and 
social), three symptom scales (fatigue, pain and nausea/vomiting) and six simple items 
(dyspnea, insomnia, loss of appetite, constipation, diarrhea and financial difficulties). 
The scale in this questionnaire constitutes the following score: 1 (no), 2 (little), 3 
(moderately), and 4 (a lot), except the global health scale. This consists of 2 questions 
that ask the individual to rate their general health and quality of life in the last week, 
through a score from 1 to 7, 1 being terrible and 7 being excellent. Scores are calculated 
separately for each of the scales (functional, QOL and symptoms), ranging from zero - 
100.17 On the Global Health and functionality scale, the higher the score, the better the 
quality of life. In the symptom scales, the higher the score, the worse the score. In order 
to know the calculation in each scale, the average score in each of the scales is 
performed. After this average we make the linear transformation for the score to be 0-
100, according to the formulas below: 
- Gross score or Raw Score (RS): adds the score of each item and divides it by the 
number of items 
- S score for functional scales: {1 - (RS - 1) / variation} x 100 
- S score for symptom scale: {(RS - 1) / variation} x 100 
- S-score for general health status / general quality of life: {(RS - 1) / variation} x 
100 
The variation is generally 3, since the items score from 1 to 4, except for the 
global health and quality scales that score a maximum of 7 and, therefore, there is a 
general variation of 6. 
The complement of the QLQ-C30 for TNE, the QLQ-GINET21 questionnaire, is 
composed of 5 multi-item scales that address common symptoms in patients with NET, 
such as gastrointestinal and endocrine, concerns about illness, social role and symptoms 
of treatments; it also contains five items that assess weight loss/gain, bone/muscle pain, 

18 
 
sexual function. The methodology for calculating the scores is the same as that used by 
the questionnaire QLQ-C30.18 
Missing data often occurs in questionnaire studies. Researchers will try to 
minimize missing data by providing guidance to study participants. However, if it still 
occurs, several imputation methods can be used, and there is no standard method. The 
most common is to calculate the average of the scale of the answered items and use this 
average to input the missing value, provided that at least 50% of the items of that scale 
have been answered.19 This will be the method used in this study to treat possible 
missing data. When missing data occurs in single items, they should be excluded from 
the analysis. 
The EORTC quality of life questionnaires will be applied at the baseline (within 4 
days of treatment) and every 12 weeks (window of +/- 5 days) until the study leaves. 
The administration should preferably be on the day of the image, and always before the 
patient knows the result of the exam (so that the result does not influence the responses 
to the questionnaires) and by a trained investigator. 
The total time to complete the QLG-C30 and LQL-GINET21 is approximately 20 
to 30 minutes. The patient himself will complete the questionnaires; however, he may 
be helped by an investigator, if in doubt. In the end, it will be inserted in a closed 
envelope to ensure confidentiality and privacy. 
 
Statistical plan 
 
Descriptive statistics will be used to report population characteristics, binary 
outcomes and adverse events. The Kaplan-Meyer method will be used to report time-
to-event variables and the reverse Kaplan-Meyer method will be used to calculate the 
follow-up time for patients. For the analysis of quality of life, we will report the 
proportion of patients who increase the sum of the total score by at least 10% at 3 and 
6 months after treatment - improvement of at least 10% is considered to be clinically 
significant by patients.15 We will also evaluate whether the global score varies and how 
much varies during the study for each patient; this analysis will be carried out in 
percentage and descriptively. The scores will be calculated according to the instruction 
manual of the EORTC group.16 The quality-of-life analysis will be carried out using the 

19 
 
intention to treat method, where patients who do not respond will be considered “non-
responders” in terms of the effectiveness of the treatment. 
Missing data in the questionnaires will be dealt with as described in the section 
above "Quality of Life Assessment". 
The study sample will be 22 patients. For this calculation, we considered the 40-
month disease control rate H0 to be 40% (placebo arm of phase III studies in TNE, such 
as the RADIANT417 study), H1 to 67%. Two-tailed type I error margin of 10%, power of 
80% and loss of follow-up / non-adherence of 10% were considered. 
We estimated a 40% screening failure (40% positivity on MIBG-I131). 
All analyzes will be by intention to treat. Patients who receive at least one dose 
of MIBGI131 will be evaluated for toxicity and efficacy. 
 
Study time 
 
About 35 to 40 patients with metastatic NET are treated annually at the 
A.C.Camargo Cancer Center. Therefore, we estimate to recruit the study population in a 
maximum period of 2 years and have the first assessment in 3 years. 
 
Ethical Considerations 
 
The study will be carried out in accordance with the protocol, the Good Clinical 
Practice guidelines of the International Harmonization Conference (ICH GCP) and the 
applicable local laws and regulatory requirements. The informed consent form (IC) must 
comply with ICH GCP guidelines, local regulatory regulations and legal requirements. 
The investigator must ensure that each patient in the study, or their legal representative, 
is fully informed about the nature and objectives of the study and possible risks 
associated with participation. The investigator will obtain written consent from each 
patient before any specific study activity is performed. The investigator will retain one 
copy of each consent form signed by the patient. It will be emphasized that participation 
is voluntary, and that the patient has the right to refuse participation or leave in the 
middle of the study whenever he wishes. This will not affect subsequent patient care. 
Female patients will be instructed not to become pregnant during treatment, being 

20 
 
instructed to use contraceptive methods if they are of childbearing age, as has been 
done in the routine. There is a risk of loss of confidentiality, if patient data is identified, 
however, all reasonable measures will be taken to prevent this from happening. 
The protocol will be approved by the Local Ethics Committee. The study will be 
registered with the international clinical trial registration database ClinicalTrial.gov. 
 
Study Funding and Sponsorship 
 
The patient will not incur any costs in relation to the MIBG-I131 scintigraphy exam 
or treatment with MIBG-I131, which will be paid for by the Brentani Prize and will be 
carried out at the Dept. Nuclear Medicine, under the supervision of Dr. Eduardo 
Nobrega. Everything else (laboratory tests, hormone dosages produced by TNE, 
conventional imaging tests, medical consultations) is not part of this protocol as it is 
already part of the routine treatment of patients with NET at the A.C.Camargo Cancer 
Center, both in the Unified Health System and in the supplementary/private health 
sector. For this study, insurance against risks of serious adverse events and / or requiring 
medical intervention (complementary exams, hospitalization or emergency at 
A.C.Camargo Cancer Center) will be contracted due to an adverse event related to 
treatment with MIBG-I131. 
 
Global innovation potential and for A.C.Camargo Cancer Center 
 
PRRT therapies have been shown to be highly effective in NET and today they are an 
active area of research with the development of new radiopharmaceuticals. There is a 
scientific rationale to test MIBG-I131 prospectively and with an adequate methodology, 
in addition to assessing the impact on patients' quality of life for the first time. If the 
study is positive, it has the potential to change national and international guidelines for 
the treatment of NET, helping many patients and giving visibility to the institution. In 
addition, the incorporation of MIBG-I131 as a therapeutic strategy in the treatment 
protocols for NET in the A.C.Camargo Cancer Center will allow that, after the study, the 
institution will be able to offer MIBG-I131 to supplementary health patients, recovering 
the costs invested in the study MIBNET. 

21 
 
 
Potential for cost-effectiveness 
 
Treatment with MIBG-I131, in addition to being available at SUS for the treatment 
of patients with PggF, appears to offer significant disease control for patients with NET. 
If the study is positive, it can be cost-effective, as we estimate that 67% of patients will 
obtain disease control lasting at least 12 months, which will provide time free of toxic 
therapies, with a low level of evidence and costly to patients and paying sources. In 
addition, in the absence of a clinical study, these toxic and ineffective therapies are used 
sequentially, so that each patient will do, in the period of 12 months, at least two of 
them. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

22 
 
Table 1. Treatments used in midgut NET or refractory lung, respective toxicities, efficacy 
and levels of scientific evidence9 
 
Treatment 
Disease 
control rate 
(%) 
Time of 
disease 
control 
(months) 
Common toxicities 
Evidence level 
Folfox/Capox 
0-10% 
4 – 6 
Peripheric neuropathy, 
diarrhea, nausea, 
vomiting, 
thrombocytopenia, 
anaemia 
Retrospective, 
heterogeneous 
population* 
Capecitabine/ 
Temozolomide 
0-10% 
4 – 6 
Nausea/Vomiting, 
diarrhea 
Retrospective, phase 
1/2 with 
heterogeneous 
population 
Interferon alpha 
(3 to 6 million 
units/week) 
20 – 30% 
(symptoms), 
50% 
(radiological) 
10 
Psychiatric disorders, 
immunes, fatigue, 
myopathy, 
myelosuppression 
Phase III for 
radiological control, 
retrospective studies 
for symptomatic 
control 
Debulking 
hepatic surgery 
(R2) 
50 – 90% (only 
symptoms) 
19 – 45 
Surgical risk compared to a 
hepatectomy 
Retrospective, 
heterogeneous 
population 
MIBG-I131  
63 – 80% 
12 – 24 
Myelosuppression 
Retrospective, 
heterogeneous 
population 
 
* neuroendocrine tumors of different origin, efficacy measured with distinct criteria 
 
 
 
 
 

23 
 
TABLE 2. Complete procedural summary of the study after signing the informed consent 
form 
 
Procedure 
Screening 
* 
Baseline 
evaluation 
D1 
** 
S2 
** 
S4 
** 
… 
** 
S8 
** 
S12 
** 
S16 
** 
… 
** 
S24 
** 
Every 
12 or 
8 
weeks 
Eligibility 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
MIBG scan 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
medical history 
and previous 
treatment  
x 
 
 
 
 
 
 
 
 
 
 
 
Therapeutic MIBG 
200mCi MIBG-
I131 IV 
administration 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
Clinical safety assessment 
Physical exam  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Vital signs, 
body weight 
and ECOG  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Signs and 
symptoms 
assessment  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Event 
Assessment  
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory safety assessment  
Hemogram 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Urea/creatinine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Bilirubin, 
AST/ALT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
NA, K 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
 
Pregnancy test 
in women of 
childbearing 
age 
 
x 
 
 
 
 
 
 
 
 
 
 
Image assessment  
CT of lung, 
abdomen and 
pelvis *** 
x 
 
 
 
 
 
 
x 
 
 
x 
x 
Tumor marker ** 
Specific 
hormone 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
Quality of life ** 
EORTC QLQ-
C30  
 
x 
 
 
 
 
 
x 
 
 
x 
x 
EORTC QLQ 
GINET21  
 
x 
 
 
 
 
 
x 
 
 
x 
x 
 
IV, intravenous; MIBG, metaiodobenzylguanidine 
* within 6 weeks of the first dose and within 4 working days of D1; 
** window of +/- 3 days 
*** baseline tests within 8 weeks of D1; Resonance of the abdomen and pelvis in special cases (allergy to iodinated 
contrast); window +/- 5 days 
 

24 
 
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25 
 
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