Breast Cancer, Lymphoma, Neuroendocrine Carcinoma, Neuroendocrine Carcinoma Metastatic, Neuroendocrine Tumors, Sarcoma
Conditions
Brief summary
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
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, gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) of all grades (G1, G2, G3)., lymphomas or sarcomas 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.
Interventions
DRUG18F-FDG
Injection of 4 MBq/kg of 18F-FDG followed by dynamic positron emission tomography (PET) imaging
DRUGInjection of hyperpolarized [1-13C]Pyruvate
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.
PROCEDUREPET/MR/MRS/MRSI scanning
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.
Sponsors
Rigshospitalet, Denmark
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosed with breast cancer, gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NEN) grades G1, G2 or G3, lymphoma or sarcoma * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Whole-tumor lactate/pyruvate ratio measured with MRS | Up to 10 minutes after injection of hyperpolarized [1-13C]Pyruvate | Whole-tumor lactate/pyruvate ratio measured with MRS in regions-of-interest covering the tumor lesion(s) following injection of hyperpolarized \[1-13C\]Pyruvate |
| Correlation between whole-tumor lactate/pyruvate ratio measured with MRS and tumor glucose uptake measured with PET (dynamic) | Up to 90 minutes after injection of 18F-FDG | 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) |
| Correlation between whole-tumor lactate/pyruvate ratio measured with MRS and tumor glucose uptake measured with PET (static) | Approximately 60 minutes after injection of 18F-FDG | 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) |
| Whole-tumor glucose uptake measured with PET (dynamic) | Up to 90 minutes after injection of 18F-FDG | 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 |
| Whole-tumor glucose uptake measured with PET (static) | Approximately 60 minutes after injection of 18F-FDG | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation between measurements of in vivo glycolytic markers based on PET/MRS and enzymes involved in glycolytic metabolism based on ex vivo analyses | Up to 90 minutes after injection of 18F-FDG | 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) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tertiary (exploratory) Outcome Measure: Spatially mapped tumor lactate/pyruvate ratios measured with MRS | Up to 10 minutes after injection of hyperpolarized [1-13C]Pyruvate | Spatially mapped tumor lactate/pyruvate ratios measured with MRS in segmented regions-of-interest within the tumor lesion(s) following injection of hyperpolarized \[1-13C\]Pyruvate |
| Tertiary (exploratory) Outcome Measure: Correlation between spatially mapped lactate/pyruvate ratios measured with MRS and tumor glucose uptakes measured with PET (dynamic) | Up to 90 minutes after injection of 18F-FDG | Correlation between spatially mapped tumor lactate/pyruvate ratios measured with MRS and spatially mapped glucose influx rate constants (Ki) derived from dynamic PET in segmented regions-of-interest within the tumor lesion(s) |
| Tertiary (exploratory) Outcome Measure: Correlation between spatially mapped lactate/pyruvate ratios measured with MRS and tumor glucose uptakes measured with PET (static) | Approximately 60 minutes after injection of 18F-FDG | Correlation between spatially mapped tumor lactate/pyruvate ratios measured with MRS and spatially mapped SUVmean and SUVmax measured with PET in segmented regions-of-interest within the tumor lesion(s) |
| Tertiary (exploratory) Outcome Measure: Spatially mapped tumor glucose uptakes measured with PET (dynamic) | Up to 90 minutes after injection of 18F-FDG | Spatially mapped glucose influx rate constants (Ki) derived from dynamic PET in segmented regions-of-interest within the tumor lesion(s) following injection of 18F-FDG |
| Tertiary (exploratory) Outcome Measure: Spatially mapped tumor glucose uptakes measured with PET (static) | Approximately 60 minutes after injection of 18F-FDG | Spatially mapped SUVmean and SUVmax measured with PET in segmented regions-of-interest within the tumor lesion(s) approximately 60 minutes after injection of 18F-FDG |
Countries
Denmark
Outcome results
None listed