Study of MIBG-I131 in Patients With Well Differentiated Neuroendocrine Tumors

Study Overview
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Brief Summary
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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 positive scan.

Detailed Description
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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.

Official Title
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Phase II Study of MIBG-I131 (Metaiodobenzylguanidine) in Patients With Well Differentiated Neuroendocrine Tumors and MIBG Positive Scan

Conditions
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Neuroendocrine Tumors

Intervention / Treatment
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* Radiation: MIBG-I131


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to 18 years Histological diagnosis of well-differentiated neuroendocrine tumor (NET) (typical and atypical lung carcinoids and NET of all gastroenteropancreatic sites according to World Health Organization (WHO) 2019 classification); metastatic/unresectable, with no possibility of curative treatment. MIBG-I131 positive scan in at least one lesion with uptake compatible with therapeutic effectiveness. Disease with radiological progression (at least 10 percent tumor volume growth) in the last 12 months before day 1 cycle 1. Intolerance due to toxicities or lack of access to standard treatments - [private context (somatostatin analog, everolimus) and public health system (somatostatin analog)]. Measurable disease Eastern Cooperative Oncology Group (ECOG) performance scale 0 to 2. Adequate organic function as defined by the following criteria: serum aspartate aminotransferase (AST), serum alanine 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 / mm^3; Platelet count ≥ 100,000 / mm^3; Hemoglobin ≥ 9.0 g / dL; Estimated creatinine clearance by the Modification of Diet in Renal Disease (MDRD) equation ≥ 60ml / min Term of free and informed consent signed by the patient or legal representative. Exclusion Criteria: Patients already treated with MIBG-I131. A history of serious clinical or psychiatric illness that, by clinical judgment, may involve participation risk in this study. Patients participating in other protocols with experimental drugs. Patients who underwent major recent surgery less than 4 weeks previously. Patients receiving chemotherapy or other oncologic therapy for less than 3 weeks. Pregnant or lactating patients. Another synchronous neoplasm that requires systemic treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 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 positive scan.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interventional<br>The participants will be submitted to metaiodobenzylguanidine 4 doses of 7.400 Mbq (million of Becquerels) (200 mCi). Each dose will be repeated with a minimum interval of 60 days. | Radiation: MIBG-I131<br>* Radiopharmaceutical<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) at 6 months after the end of treatment | Defined by absence of radiological progression in conventional imaging examinations by RECIST 1.1. | At 6 months after the end of MIBG-I131 (4 cycles - each cycle is 60 days) | 
| Quality of life measured by questionnaire | Quality of life questionnaire (QLQ), assessed by the European Organisation for Research and Treatment of Cancer Quality of Life for Neuroendocrine Tumors (EORTC QLQ-GINET21) (score ranging from 0 to 100, with higher scores meaning better state of the patient). Improvement in at least 10% of the baseline score will be considered positive. | At 6 months after the end of MIBG-I131 (4 cycles - each cycle is 60 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) at 3 months after the end of treatment | Defined by absence of radiological progression in conventional imaging examinations by RECIST 1.1. | At 3 months after the end of MIBG-I131 (4 cycles - each cycle is 60 days) | 
| 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. | Trough study completion, an average of 3 years | 
| Radiological response rate | Assessed by RECIST 1.1 criteria. | Trough study completion, an average of 3 years | 
| 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. | Trough study completion, an average of 3 years | 
| Quality of life measured by questionnaires | Quality of life questionnaire (QLQ), assessed by the European Organisation for Research and Treatment of Cancer Quality of Life for Neuroendocrine Tumors (EORTC QLQ-GINET21) (score ranging from 0 to 100, with higher scores meaning better state of the patient). Improvement in at least 10% of the baseline score will be considered positive. | Trough study completion, an average of 3 years | 
| Incidence of Treatment-related Adverse Events assessed by Common Terminology Criteria for Adverse Events (CTCAE) | Frequency of adverse events of grades 2 or more by CTCAE version 5.0. | Trough study completion, an average of 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MIBG-I131, Nuclear medicine, Treatment