A Phase I/II Study of [124I]mIBG PET/CT in Neuroblastoma

Study Overview
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Brief Summary
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This study aims to show that 3-dimensional PET/CT imaging with a new novel PET tracer (called [124I]mIBG) can detect as many or more sites of neuroblastoma (a type of childhood cancer) compared to the recommended 1-dimensional routine scans (called [123I]mIBG planar scintigraphy).

Detailed Description
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Neuroblastoma is the most common tumour of childhood after brain tumours. Approximately half of cases are high risk and despite extensive treatments outcome is very poor. More than 60% of high risk patients suffer relapse or further spread of their disease and long-term survival is below 10%. Existing imaging techniques are not sensitive enough to accurately assess the level of risk which is critical in determining the best choice of treatment. This study will compare a new type of imaging against the existing imaging techniques. The new scans use a new tracer called [124I]mIBG which is taken up by the cancer tissue much more than by normal tissues. This tracer can be used with a 3D imaging technique called PET/CT to pinpoint where the disease has spread and quantify the amount of disease. Patients will be those scheduled to have an [123I]mIBG scan for routine care during a planned break in treatment.

Official Title
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A Cancer Research UK Phase I/II Study to Compare [124I]Meta-Iodobenzylguanidine (mIBG) Positron Emission Tomography/Computerised Tomography (PET/CT) to [123I]mIBG Imaging in Patients With Metastatic Neuroblastoma

Conditions
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Metastatic Neuroblastoma

Intervention / Treatment
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* Drug: [124I]meta-Iodobenzylguanidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven Stage 4 neuroblastoma as defined by the International Neuroblastoma Staging System (INSS). Aged ≥ 1 year at the time that written informed consent is given. Planned to undergo conventional [123I]mIBG planar scintigraphy for routine clinical care of neuroblastoma. Life expectancy of at least 12 weeks. World Health Organisation (WHO) performance status of 0, 1 or 2 for patients aged > 12 years old or Lansky play scale score of ≥ 50% for patients aged ≤ 12 years old. Written (signed and dated) informed consent from patient ≥ 16 years old and/or parent or legal guardian for patients <16 years old and the patient be capable of co-operating with scanning requirements. (N.B. Written or verbal assent as appropriate should be sought from all patients who are under 16 years old). Exclusion Criteria: Treatment with any medications contra-indicated with mIBG scanning as listed in Appendix 4 of the trial protocol. For example, decongestants containing pseudoephedrine, phenylpropalomine and phenylephrine, sympathomimetics, cocaine, antihypertensives, tricyclic antidepressants. These drugs should be stopped before administration as indicated in this list (usually for four biological half-lives to allow almost complete wash-out but refer to list). Stage 4S neuroblastoma as defined by the INSS. Any anti-cancer treatment planned between the routine [123I]mIBG imaging and the [124I]mIBG PET/CT scan on Day 2. Anti-cancer treatments can be started only after the Off-Study assessment on Day 3 to Day 7, see schedule of assessments in Section 7. N.B. Patients should not be enrolled in the study if their participation will delay their subsequent treatment for neuroblastoma. Female patients who are pregnant or lactating. At high medical risk because of non-malignant systemic disease including active uncontrolled infection. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV). Patients with known hypersensitivity to mIBG. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical study. Clinical Criteria for [124I]mIBG imaging One or more disease foci observed on conventional [123I]mIBG planar scintigraphy. Disease foci will initially be identified by a Nuclear Medicine physician at the investigational site. ≥ 3kg at the time of the [124I]mIBG imaging to agree with the paediatric EANM guidelines. Haematological and biochemical indices within the ranges below: For patients ≤16 years old, haematological and biochemical indices within the following ranges: Haemoglobin ≥ 7.0 g/dl (N.B transfusions will be allowed); Absolute neutrophil count ≥ 0.2 x 10^9/L (N.B. G-CSF support will be allowed); Platelet count ≥ 10 x 10^9/L (N.B. transfusions will be allowed); Serum bilirubin ≤ 2.5 x upper limit of normal (ULN); Alanine amino-transferase (ALT), aspartate amino-transferase (AST), and/ or alkaline phosphatase (ALP) ≤ 5 x ULN; and Calculated creatinine clearance using revised Schwartz formula ≥ 60 mL/min/1.73m^2. For patients >16 years old, haematological and biochemical indices within the following ranges: Haemoglobin ≥ 8.0 g/dl (N.B transfusions will be allowed); Absolute neutrophil count ≥ 0.5 x 10^9/L (N.B. G-CSF support will be allowed); Platelet count ≥ 50 x 10^9/L (N.B. transfusions will be allowed); Serum bilirubin ≤ 2.5 x upper limit of normal (ULN); Alanine amino-transferase (ALT), aspartate amino-transferase (AST), and/ or alkaline phosphatase (ALP) ≤ 5 x ULN; and Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73m^2. Menarchal female patients must have a negative serum or urine pregnancy test before administration of [124I]mIBG Solution for Injection on Day 1 and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intra-uterine device and condom, diaphragm with spermicidal gel and condom) to be effective from Day 1 and for 7 days afterwards. Male patients with partners of child-bearing potential must agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] from Day 1 and for 7 days afterwards. Male patients with pregnant or lactating partners must agree to use barrier method contraception (e.g. condom plus spermicidal gel) to prevent exposure to the foetus or neonate.

Ages Eligible for Study
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Minimum Age: 1 Year

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm Trial<br>This was a single arm trial, all patients were to undergo the same assessments and interventions. | Drug: [124I]meta-Iodobenzylguanidine<br>* Single intravenous administration of [124I]mIBG Solution for Injection on Day 1 with a maximum radioactive dose of 1.42 MBq/kg (±10%) and a maximum injected dose of 50 MBq [124I]mIBG equating to a maximum chemical dose of 10 micrograms of stable mIBG. The activity to paediatric patients will be scaled by weight based upon the EANM paediatric dose card (Lassmann et al., 2007). This will result in an activity between 10 MBq and 50 MBq depending on the patient's weight.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Number of Lesions Detected as Positive by [123I]mIBG Planar Scintigraphy Which Are Also Considered Positive With [124I]mIBG PET/CT. | Analysis of [124I]mIBG PET/CT and [123I]mIBG planar scintigraphy was performed retrospectively by four specialist observers. The analysis was performed and observers were blinded to each others scores. The observers subsequently reviewed the lesions identified and, where there was a difference in their separate scores, they returned to the images in order to reach an agreed consensus score. The number of lesions identified as positive by this consensus scoring (all lesions with a SIOPEN score of 4 or 5) were used to meet the primary objective. | [124I]mIBG PET/CT imaging on Day 1, three to 21 days after routine [123I]mIBG imaging and before the start of any new anti-cancer therapy. A minimum interval of 72 hours was required between injection of [123I]mIBG tracer and the [124I]mIBG PET/CT scan. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the Number of Lesions Detected as Positive by [123I]mIBG SPECT Which Are Also Considered Positive With [124I]mIBG PET/CT. | Analysis of [124I]mIBG PET/CT and [123I]mIBG SPECT/CT was performed retrospectively by four specialist observers. The analysis was performed and observers were blinded to each others scores. The observers subsequently reviewed the lesions identified and, where there was a difference in their separate scores, they returned to the images in order to reach an agreed consensus score. The number of lesions identified as positive by this consensus scoring (all lesions with a SIOPEN score of 4 or 5) were used to meet the primary objective. | [124I]mIBG PET/CT imaging on Day 1, three to 21 days after routine [123I]mIBG imaging and before the start of any new anti-cancer therapy. A minimum interval of 72 hours was required between injection of [123I]mIBG tracer and the [124I]mIBG PET/CT scan. | 
| Determining the Causality of Each Adverse Event to [124I]mIBG and Grading Severity According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Version 4.02. | Documenting Adverse Events (AEs), Serious Adverse Events (SAEs), Dose Limiting Toxicities (DLTs) (Graded According to NCI-CTCAE Version 4.02) and Laboratory Parameters and Determining Their Causality in Relation to [123I]mIBG and [124I]mIBG. | Safety data was collected from the date of written informed consent and continued for seven days after administration of [124I]mIBG. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroblastoma, Positron emission tomography, 124-iodine, Meta-Iodobenzylguanidine