Simultaneous Hyperpolarized [1-13C]Pyruvate and 18F-FDG PET/MRS in Cancer Patients

Study Overview
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Brief Summary
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Prospective phase 2a clinical trial to demonstrate proof-of-concept for simultaneous hyperpolarized [1-13C]pyruvate and 18F-FDG for positron emission tomography (PET) and MRS (magnetic resonance spectroscopy) in a PET/MR scanner in patients with cancer.

Detailed Description
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PET imaging with 18F-FDG is a well established method for non invasively assessing the intracellular glucose accumulation. 18F-FDG PET is used in many applications with diagnosing and staging of patients with cancer being one of the primary indications. Once internalized into the cell, 18F-FDG is phosphorylated to the metabolically inactive 18F-FDG-6-phosphate. Therefore it is not possible to determine what happens to the downstream glucose metabolites. In particular, it is not possible to determine the conversion into lactate, which is upregulated in many cancers. The upregulation of lactate conversion in cancers, even in presence of oxygen, is known as the Warburg effect. Hyperpolarized [1-13C]pyruvate MRS makes is possible to circumvent this limitation. The technique makes is it possible to follow the downstream fate of the glycolysis intermediate, pyruvate, and in particular makes is is possible to non-invasively and in in real time measure the glycolytic conversion of pyruvate into lactate as a direct measure of the Warburg effect. When using a PET/MR scanner, it is possible to simultaneous measure the glucose influx with 18F-FDG and the conversion of pyruvate into lactate with hyperpolarized [1-13C]pyruvate. In this way, the two modalities provide complementary information on the in vivo glycose metabolism. The prospective phase 2a project will include up to 15 patients diagnosed with breast cancer or gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) of all grades (G1, G2, G3). The aim is to demonstrate proof-of-concept for the feasibility of simultaneous acquisition of hyperpolarized [1-13C]pyruvate MRS and 18F-FDG PET imaging in a PET/MR scanner in cancer patients to allow for simultaneous measurements of overall tumor pyruvate-to-lactate conversion parameters on MRS and glucose influx with 18F-FDG on PET. Included patients are injected with a standard dose of radioactive 18F-FDG. Subsequent dynamic PET acquisition is performed for up to 90 minutes after injection on an area-of-interest covering pre-specified tumor lesion(s). Regional anatomical magnetic resonance imaging (MRI) is performed, including diffusion weighted imaging (DWI) and contrast enhanced imaging (DCE). MRS/MRSI is performed following the injection(s) of hyperpolarized [1-13C]Pyruvate. When available, resected tumor tissues samples from surgical specimens or biopsies obtained in relation to routine clinical procedures will be collected and analyses of enzymes and markers of glycolytic metabolism will be performed ex vivo and compared with the in vivo data from PET/MRS.

Official Title
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Phase IIa Clinical Trial: Feasibility Study on Non-Invasive Simultaneous Hyperpolarized [1-13C]Pyruvate Magnetic Resonance Spectroscopy and 18F-FDG PET (hyperPET) for Metabolic Imaging in Patients With Cancer

Conditions
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Breast Cancer, Neuroendocrine Tumors, Neuroendocrine Carcinoma, Neuroendocrine Carcinoma Metastatic

Intervention / Treatment
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* Drug: 18F-FDG
* Drug: Injection of hyperpolarized [1-13C]Pyruvate
* Procedure: PET/MR/MRS/MRSI scanning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with breast cancer or gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) grades G1, G2 or G3 Measurable solid tumor of at least 1.5 cm Capable of understanding the patient information in Danish and giving full informed consent Exclusion Criteria: Pregnancy Breast-feeding Weighs above 140 kg and/or with abdominal circumference exceeding the gantry of the PET/MR coil (120 cm) History of allergic reaction attributable to compounds of similar chemical or biologic composition to 18F-FDG or pyruvate Patients who are unable to lie in the MR scanner for up to 90 minutes Pace-maker Metallic implantations within the past 6 weeks Non-MR compatible implants Claustrophobia Participants who have not fasted for a minimum of 4 hours prior to the planned scan time

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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Injection of 18F-FDG and injections of hyperpolarized [1-13C]Pyruvate and subsequent PET/MRI/MRS scan | Drug: 18F-FDG<br>* Injection of 4 MBq/kg of 18F-FDG followed by dynamic positron emission tomography (PET) imaging<br>* Other names: [18F]F-FDG;Drug: Injection of hyperpolarized [1-13C]Pyruvate<br>* Injection of one bolus of 0.43 ml/kg of approximately 250 mM hyperpolarized [1-13C]Pyruvate followed by magnetic resonance spectroscopy (MRS) / magnetic resonance spectroscopy imaging (MRSI). After a 5-30 min pause, injection of a second bolus of 0.43 ml/kg of approximately 250 mM hyperpolarized [1-13C]Pyruvate followed by MRS / MRSI.<br>Procedure: PET/MR/MRS/MRSI scanning<br>* Regional dynamic PET acquisition for up to 90 minutes following 18F-FDG injection is performed focused on a region-of-interest (ROI). Anatomical magnetic resonance imaging (MRI) is performed in the ROI, including diffusion weighted imaging (DWI) and contrast enhanced imaging (DCE). MRS/MRSI is performed following the injections of hyperpolarized [1-13C]Pyruvate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole-tumor lactate/pyruvate ratio measured with MRS | Whole-tumor lactate/pyruvate ratio measured with MRS in regions-of-interest covering the tumor lesion(s) following injection of hyperpolarized [1-13C]Pyruvate | Up to 10 minutes after injection of hyperpolarized [1-13C]Pyruvate | 
| Whole-tumor glucose uptake measured with PET (static) | Whole-tumor standardized uptake values (SUV): SUVmean and SUVmax measured with PET in regions-of-interest covering the tumor lesion(s) approximately 60 minutes after injection of 18F-FDG | Approximately 60 minutes after injection of 18F-FDG | 
| Whole-tumor glucose uptake measured with PET (dynamic) | Whole-tumor glucose influx rate constant (Ki) derived from dynamic PET in regions-of-interest covering the tumor lesion(s) following injection of 18F-FDG | Up to 90 minutes after injection of 18F-FDG | 
| Correlation between whole-tumor lactate/pyruvate ratio measured with MRS and tumor glucose uptake measured with PET (static) | Correlation between whole-tumor lactate/pyruvate ratio measured with MRS and whole-tumor SUVmean and SUVmax measured with PET in regions-of-interest covering the tumor lesion(s) | Approximately 60 minutes after injection of 18F-FDG | 
| Correlation between whole-tumor lactate/pyruvate ratio measured with MRS and tumor glucose uptake measured with PET (dynamic) | Correlation between whole-tumor lactate/pyruvate ratio measured with MRS and whole-tumor Ki measured with PET in regions-of-interest covering the tumor lesion(s) | Up to 90 minutes after injection of 18F-FDG | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between measurements of in vivo glycolytic markers based on PET/MRS and enzymes involved in glycolytic metabolism based on ex vivo analyses | Ex vivo measurements of enzymes, regulatory proteins and transporters involved in glucose and pyruvate/lactate transcellular transport and in glycolysis on resected matched tumor tissue samples (if available) and the correlation with the primary endpoints (whole-tumor lactate/pyruvate ratio, SUVmax, SUVmean, and Ki) | Up to 90 minutes after injection of 18F-FDG |