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A dose of Fluorodopa F 18, 3-6 MBq/Kg (0.08-0.16 mCi/kg), will be injected intravenously into the subject under the direct supervision of the radiology sub-investigator. Then, the PET imaging procedure will begin and proceed for up to 70 minutes after injection. An abdominal CT image will be made using intravenous contrast. Both images, PET and CT, will be co-localized by the radiologist for interpretation.

Fluorodopa F 18

Deborah Rafferty, PhD

Paul Thornton, MD

Low blood sugars are known to cause brain damage in newborn babies. One of the most common causes of low blood sugars persisting beyond the new born period is a condition called congenital hyperinsulinism (HI). This is a disease whereby the pancreas secretes too much insulin and causes low blood sugars. Twenty to forty percent of these babies will have brain damage. There are two forms of this disease. In one form only a small part of the pancreas makes too much insulin (focal HI) and in the other, the whole pancreas make too much insulin (diffuse HI). Another very similar disease is insulinoma which occurs after birth, but also causes hyperinsulinism. If a surgeon could know which part of the pancreas has the focal lesion he could remove it and cure the patient.

The purpose of this study is to investigate whether a new investigational drug called Fluorodopa F 18, when used with a PET scan, can find the focal lesion and guide the surgeon to remove it, thus curing the patient and preventing further brain damage.

Congenital Hyperinsulinism (HI) is a disorder of insulin secretion that causes profound hypoglycemia leading to significant morbidity. It is the most common form of persistent neonatal hypoglycemia, and the most dangerous. Inappropriate insulin secretion causes not only hypoglycemia but also inability to release free fatty acids from adipose tissue and inability to release glycogen from the liver. Hence the brain is deprived of all the major fuel sources (glucose, beta-hydroxybutyrate and lactate) for energy thus leading to the high incidence of brain damage. In up to 50% of cases of congenital hyperinsulinism, medical therapy fails and surgical resection of the pancreas is necessary. Previous techniques developed to differentiate those patients with focal HI in whom surgery could result in a cure are very invasive and put the infants at risk for hypoglycemic brain damage or arterial thrombosis.

It is known that the beta cells in the pancreatic islets, similar to other neuroendocrine tissues, contain amino acid decarboxylase (AADC). Beta cells take up L-Dopa and convert it into dopamine by AADC. It was proposed that as other neuroendocrine tumors such as phaeochromocytoma and carcinoid tumors express AADC and can be very easily visualized using Fluorodopa F 18 PET then so also would the pancreas be easily and accurately visualized. After initial reports demonstrated the effectiveness, safety and accuracy, there have been now over 200 patients with HI reported in the literature who have had Fluorodopa F 18 PET scans with suggestions that referral to major HI centers for Fluorodopa F 18 PET CT is now an integral part of standard of care management of patients with HI that require surgery. Fluorodopa F 18 PET scanning for patients with Hyperinsulinism is now established in Europe and Australia, and has close to 95% sensitivity. When linked to Computed Tomography (CT) image of the pancreas, Fluorodopa F 18 PET allows the surgeon to image the pancreas in three dimensions, to even more accurately identify the site of the focal lesion, increasing the chance of a sufficient partial pancreatectomy to cure the patient.

Similarly, insulinomas are neuroendocrine cell tumors that are typically benign (90%) and very rare occurring in 1-4 per million of the population with \> 50% occurring in adults \>age 25 years. Biochemical differentiation of insulinomas from congenital hyperinsulinism may be aided by the use of the pro-insulin:insulin ratio, by the age of presentation and by the history. The standard of care for insulinoma is to remove them once identified, rather than long term medical treatment. Current imaging techniques include CT scan pancreas, endoscopic ultrasound of the pancreas and MRI pancreas however despite using these modalities in some patients the insulinoma may not be found. 18F-DOPA has been shown to be superior than MIBG scanning for neuroendocrine tumors such as phaeochromocytoma, but there is very little data in patients with insulinoma. Moreover, patients with MEN 1 and insulinoma may have more than one tumor, which if missed with conventional imaging could result in failure to cure with surgery.

The objectives of this study are:

1. To determine, using Positron Emission Tomography, whether or not the uptake of a radiopharmaceutical agent, Fluorodopa 18F (18F-DOPA) produced in a cyclotron located at a distance far from the imaging center will produce qualitatively adequate pancreatic images in patients with congenital hyperinsulinism
2. To determine, using direct comparisons, whether or not Fluorodopa 18F Positron Emission Tomography (18F-DOPA PET) combined with Computed Tomography (CT) will produce pancreatic images matching the gold-standard of histopathological findings at surgery for partial or complete pancreatectomy in the treatment of patients with congenital hyperinsulinism
3. To determine, using direct comparisons, whether or not Fluorodopa 18F Positron Emission Tomography (18F-DOPA PET) combined with Computed Tomography (CT) will produce pancreatic images matching the gold-standard of histopathological findings at surgery for insulinomas
4. To determine the best way to interpret the 18F-DOPA PET scans comparing SUV max:SUV sub max at a ratio of the current 1.5, a suggested 1.3 and by using visual inspection of the images.

Fluorodopa F 18 in Congenital Hyperinsulinism and Insulinoma

The Use of Fluorodopa F 18 Positron Emission Tomography Combined With Computed Tomography in Congenital Hyperinsulinism and Insulinoma

Positron Emission Tomography will be used to determine whether or not the uptake of a radiopharmaceutical agent, Fluorodopa F 18, produced in a cyclotron located at a distance far from the imaging center will produce qualitatively adequate pancreatic images in patients with congenital hyperinsulinism

Investigators will directly compare pancreatic images from Fluorodopa F 18 PET combined with Computed Tomography versus the gold-standard of histopathological findings at surgery in subjects who received a partial or complete pancreatectomy

Investigators will compare SUV max to SUV sub max at a ratio of the current 1.5, a suggested 1.3 and by using visual inspection of the images.

Cook Children's Health Care System

Pharmaceutical Solutions

Pasireotide

Hormones

Hormone Antagonists

Pasireotide 0.6Mg Solution for Injection will be given once per study visit

Pasireotide 0.6Mg Solution for Injection

Saline Solution injection will be given once per study visit

Saline Solution

Erika Brutsaert, M.D., M.P.H.

This is a small controlled pilot study to assess the effect of subcutaneous pasireotide on preventing hypoglycemia due to hyperinsulinism, including congenital hyperinsulinism and insulinoma.

Pasireotide is a somatostatin analog with affinity for several somatostatin receptors including those on pancreatic beta cells; when activated these receptors affect the secretion of glucagon and insulin. Pasireotide is also known to decrease glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) secretion. Hyperglycemia is a well-documented adverse effect of pasireotide in its approved indications for treatment of Cushing's disease and acromegaly.

In light of this, the investigators hypothesize that pasireotide may be an effective therapy for hypoglycemia due to hyperinsulinism. Therefore a small controlled pilot study to assess the effect of subcutaneous (s.c.) pasireotide on preventing hypoglycemia due to hyperinsulinism over 7 hours of observation in both fasting and fed states is proposed.

Pasireotide in Hyperinsulinemic Hypoglycemia

Pasireotide for Prevention of Hypoglycemia in Patients With Hyperinsulinemic Hypoglycemia

Collection of safety and adverse event data

Occurence, frequency and severity of hypoglycemia (serum glucose \< 55 mg/dL)

Insulin, GLP-1, glucagon and cortisol levels

Novartis Pharmaceuticals

Montefiore Medical Center

Symptoms and General Pathology

Syndrome

Beckwith-Wiedemann Syndrome

Congenital Abnormalities

Abnormalities, Multiple

Chromosome Disorders

Genetic Diseases, Inborn

Fetal Thalidomide Syndrome

18F-DOPA

Susan Becker, RN, BSN, CCRC

Lisa States, MD

This purpose of this study is to determine the ability of an 18F-fluoro-L-dihydroxyphenylalanine (18F-DOPA) PET (Positron Emission Tomography) scan to detect a focal lesion of hyperinsulinism and determine the location in patients with congenital hyperinsulinism, Beckwith Wiedemann Syndrome and suspected insulinoma. Safety data will be collected.

Patients with hyperinsulinemic hypoglycemia are at risk for neurological damage due to hypoglycemia. Early surgical intervention can be preventative. F-DOPA PET may be able to detect of a focal lesion prior to surgical intervention and be used during surgical planning to guide the surgical procedure.

18F-L-Fluoro-DOPA PET/CT Scan Localization of Focal Pancreatic Lesions in Subjects With Hyperinsulinemic Hypoglycemia

Expanded Access Use of 18F-L-Fluoro-DOPA PET/CT Scan Localization of Focal Pancreatic Lesions in Subjects With Hyperinsulinemic Hypoglycemia

Children's Hospital of Philadelphia

Principal Investigator

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Fluorodopa F 18 in Congenital Hyperinsulinism and Insulinoma	NCT02021604	Congenital Hype... Insulinoma	Fluorodopa F 18	- 18 Years	Cook Children's Health Care System
Pasireotide in Hyperinsulinemic Hypoglycemia	NCT03053284	Congenital Hype... Insulinoma Hyperinsulinism	Pasireotide 0.6... Saline Solution	18 Years - 70 Years	Montefiore Medical Center
18F-L-Fluoro-DOPA PET/CT Scan Localization of Focal Pancreatic Lesions in Subjects With Hyperinsulinemic Hypoglycemia	NCT01916148	Congenital Hype... Beckwith-Wiedem... Insulinoma	18F-DOPA	-	Children's Hospital of Philadelphia
Fluorodopa F 18 in Congenital Hyperinsulinism and Insulinoma	NCT02021604	Congenital Hype... Insulinoma	Fluorodopa F 18	- 18 Years	Cook Children's Health Care System
Fluorodopa F 18 in Congenital Hyperinsulinism and Insulinoma	NCT02021604	Congenital Hype... Insulinoma	Fluorodopa F 18	- 18 Years	Cook Children's Health Care System
Fluorodopa F 18 in Congenital Hyperinsulinism and Insulinoma	NCT02021604	Congenital Hype... Insulinoma	Fluorodopa F 18	- 18 Years	Cook Children's Health Care System

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