Gallium-68 Labeled LM3 PET/CT in Neuroendocrine Tumors

Study Overview
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Brief Summary
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LM3 is a novel somatostatin receptor antagonist, while Gallium-68 DOTATATE is a typical somatostatin receptor agonist, This study is to evaluate the safety, biodistribution, dosimetry, and lesion detection ability of Gallium-68 labeled somatostatin receptor antagonist LM3 for the diagnostic imaging of metastatic, well-differentiated neuroendocrine tumors using positron emission tomography / computed tomography (PET/CT). The results will be compared between antagonist Gallium-68 labeled LM3 and agonist Gallium-labeled DOTATATE in the same group of patients. It will also be compared between the two different antagonists, Gallium-68 DOTA-LM3 and Gallium-68 NODAGA-LM3, in two parallel-designed arms.

Detailed Description
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Patients with histologically confirmed metastatic, well-differentiated neuroendocrine tumors will be recruited in this study. All patients will be randomized into two groups: Gallium-68 NODAGA-LM3 group and Gallium-68 DOTA-LM3 group. The study will be divided into the following 2 parts: Part ONE, which will enroll 16 patients (8 in each group), focuses on the safety evaluation, biodistribution, and dosimetry. In Part A, patients will undergo serial whole-body PET/CT scans at multiple time points (5m, 10m, 20m, 40m, 1h, 2h) after administering 40ug/150-200MBq Gallium-68 NODAGA-LM3 or Gallium-68 DOTA-LM3 (according to their group). Part TWO, which will enroll 24 patients (12 in each group) and follows Part A study, focuses on lesion detection ability. In Part B, patients will undergo one whole-body PET/CT scan at 1 hour after administering 40ug/150-200MBq Gallium-68 NODAGA-LM3 or Gallium-68 DOTA-LM3 (according to their group). All patients need to do a Gallium-68 DOTATATE PET/CT scan (40ug/150-200MBq, 1h post-injection) for comparison on the next day.

Official Title
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A Prospective, Randomized, Double-blinded Study to Evaluate the Safety, Biodistribution, Dosimetry and Lesion Detection Ability of Gallium-68 Labeled LM3 for the Diagnostic Imaging of Metastatic, Well-differentiated Neuroendocrine Tumors Using PET/CT

Conditions
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Neuroendocrine Tumors

Intervention / Treatment
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* Diagnostic Test: Gallium-68 NODAGA-LM3 PET/CT
* Diagnostic Test: Gallium-68 DOTA-LM3 PET/CT
* Diagnostic Test: Gallium-68 DOTATATE PET/CT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Patients of either gender, aged ≥ 18 years. Histologically confirmed diagnosis of Metastatic, well-differentiated neuroendocrine tumor. A diagnostic computed tomography (CT) or magnetic resonance imaging (MRI) of the tumor region within the previous 6 months prior to dosing day is available. At least 1 measurable lesion based on RECIST v1.1. Blood test results as follows (White blood cell: ≥ 3*10^9/L, Hemoglobin: ≥ 8.0 g/dL, Platelets: ≥ 50x10^9/L, Alanine aminotransferase / Aspartate aminotransferase / Alkaline phosphatase: ≤ 5 times upper limit od normal (ULN), Bilirubin: ≤ 3 times ULN) Serum creatinine: within normal limits or < 120 μmol/L for patients aged 60 years or older. Calculated Glomerular filtration rate (GFR) ≥ 45 mL/min. Exclusion Criteria: Known hypersensitivity to Gallium-68, to NODAGA, to DOTA, to LM3, to TATE or to any of the excipients of Gallium-68 DOTA-LM3, Gallium-68 NODAGA-LM3 or Gallium-68 DOTATATE. Presence of active infection at screening or history of serious infection within the previous 6 weeks. Therapeutic use of any somatostatin analog, including long-acting Sandostatin (within 28 days) and short-acting Sandostatin (within 2 days) prior to study imaging. If a patient is on long-acting Sandostatina, then a wash-out phase of 28 days is required before the injection of the study drug. If a patient is on short-acting Sandostatin, then a wash-out phase of 2 days is required before the injection of the study drug. Any neuroendocrine tumor-specific treatment between antagonist and agonist scans. Prior or planned administration of a radiopharmaceutical within 8 half-lives of the radionuclide used on such radiopharmaceutical including at any time during the current study. Pregnant or breast-feeding women. Current history of any malignancy other than neuroendocrine tumor; patients with a secondary tumor in remission of > 5 years can be included. Any mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gallium-68 NODAGA-LM3 group<br>Patients will undergo a Gallium-68 NODAGA-LM3 PET/CT as well as a Gallium-68 DOTATATE PET/CT. | Diagnostic Test: Gallium-68 NODAGA-LM3 PET/CT<br>* Twenty patients will take this intervention. They will be further divided into two sub-groups with the same interventional radiopharmaceutical (Gallium-68 NODAGA-LM3) but different scanning protocols (Protocol A and Protocol B). The first enrolled 8 patients will go with Protocol A, who will undergo serial whole-body PET/CT scans at multiple time points (5m, 10m, 20m, 40m, 1h, 2h) after administering 40ug/150-200MBq Gallium-68 NODAGA-LM3. Baseline safety assessment will be conducted right before the study. The following 12 patients will go with Protocol B, who will undergo a whole-body PET/CT scan at 1 hour after administering 40ug/150-200MBq Gallium-68 NODAGA-LM3.<br>Diagnostic Test: Gallium-68 DOTATATE PET/CT<br>* All patients have to do a Gallium-68 DOTATATE PET/CT scan (40ug/150-200MBq, 1h post-injection) for comparison on the next day of LM3 scan. Safety assessment and tolerability of the previous LM3 study will be conducted right before the study.<br>|
| Experimental: Gallium-68 DOTA-LM3 group<br>Patients will undergo a Gallium-68 DOTA-LM3 PET/CT as well as a Gallium-68 DOTATATE PET/CT. | Diagnostic Test: Gallium-68 DOTA-LM3 PET/CT<br>* Twenty patients will take this intervention. They will be further divided into two sub-groups with the same intervention radiopharmaceutical (Gallium-68 DOTA-LM3) but different scanning protocols (Protocol C and Protocol D). The first enrolled 8 patients will go with Protocol C, who will undergo serial whole-body PET/CT scans at multiple time points (5m, 10m, 20m, 40m, 1h, 2h) after administering 40ug/150-200MBq Gallium-68 DOTA-LM3. Baseline safety assessment will be conducted right before the study. The following 12 patients will go with Protocol D, who will undergo a whole-body PET/CT scan at 1 hour after administering 40ug/150-200MBq Gallium-68 DOTA-LM3.<br>Diagnostic Test: Gallium-68 DOTATATE PET/CT<br>* All patients have to do a Gallium-68 DOTATATE PET/CT scan (40ug/150-200MBq, 1h post-injection) for comparison on the next day of LM3 scan. Safety assessment and tolerability of the previous LM3 study will be conducted right before the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure[Safety and tolerability] | Measured in millimetre of mercury. | Within 1 hour prior to the administration of radiopharmaceuticals. | 
| Heart rate[Safety and tolerability] | Measured in beats per minute. | Within 1 hour prior to the administration of radiopharmaceuticals. | 
| Pulse oximetry[Safety and tolerability] | Measured in percentage. | Within 1 hour prior to the administration of radiopharmaceuticals. | 
| Electrocardiogram QT interval[Safety and tolerability] | 3-lead electrocardiogram | Within 1 hour prior to the administration of radiopharmaceuticals. | 
| Incidence of adverse effect[Safety and tolerability] | According to version 4.03 of the Common Terminology Criteria for Adverse Events. | From right after tracer injection to 24-hours post-injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum concentration achieved in units of Bq/ml) | Determination of Cmax for target lesion and discernible organs | From right after tracer injection to 2-hours post-injection | 
| Tmax (time to achieve Cmax) | Determination of Tmax for target lesion and discernible organs. | From right after tracer injection to 2-hours post-injection | 
| Standard uptake value (SUV) | Determination of SUV for detected lesions and discernible organs of 68Ga-DOTA-LM3, 68Ga-NODAGA-LM3, and 68Ga-DOTATATE scan. | From right after tracer injection to 2-hours post-injection | 
| Lesion numbers | Determination of lesion numbers of 68Ga-DOTA-LM3, 68Ga-NODAGA-LM3, and 68Ga-DOTATATE scan. | From right after tracer injection to 2-hours post-injection |