NICI Study: Non-Invasive Chemistry Imaging in the Whole Human Body

Study Overview
=================
Brief Summary
-----------------
Patients suffering metastasized gastrointestinal cancer often receive ineffective treatments for prolonged periods of time as therapy non-response, which is hard to detect, cannot be determined earlier than nine weeks following start of therapy. Current therapy evaluation strategies primarily focus on morphological changes via RECIST criteria. However, morphological changes are subjected to prior physiological and metabolic alterations. Therefore, the NICI project's ambition is to lay the foundations of a new area of research: the study of human biology using non-invasive chemistry imaging. For this, NICI aims to unite two areas of research: metabolomics and magnetic resonance (MR). Metabolomics studies body functions through the measurements of metabolites; MR imaging (MRI) and spectroscopy (MRS) can provide 3D images of the body and measure metabolite and lipid content respectively. Previous studies show that phospholipid metabolites in particular the cell membrane precursors i.e. phosphomonoesters (PME), and the cell membrane degradation products i.e. phosphodiesters (PDE) are valuable biomarkers in therapy assessment. With this NICI approach, the consortium aims at reducing the nine weeks period before therapy efficacy evaluation to three weeks or less. By validating the powerful new MRS(I)-visible biomarkers in a patient cohort, a non-invasive technology can be developed for dynamically mapping biochemical processes in the whole human body and pave the way for individualized medicine.

Detailed Description
-----------------
Patients suffering metastasized gastrointestinal cancer often receive ineffective treatments for prolonged periods of time as therapy non-response, which is hard to detect, cannot be determined earlier than nine weeks following start of therapy. Current therapy evaluation strategies primarily focus on morphological changes via RECIST criteria. However, morphological changes are subjected to prior physiological and metabolic alterations. Therefore, the NICI project's ambition is to lay the foundations of a new area of research: the study of human biology using non-invasive chemistry imaging. For this, NICI aims to unite two areas of research: metabolomics and magnetic resonance (MR). Metabolomics studies body functions through the measurements of metabolites; MR imaging (MRI) and spectroscopy (MRS) can provide 3D images of the body and measure metabolite and lipid content respectively. Previous studies show that phospholipid metabolites in particular the cell membrane precursors i.e. phosphomonoesters (PME), and the cell membrane degradation products i.e. phosphodiesters (PDE) are valuable biomarkers in therapy assessment. With this NICI approach, the consortium aims at reducing the nine weeks period before therapy efficacy evaluation to three weeks or less. By validating the powerful new MRS(I)-visible biomarkers in a patient cohort, a non-invasive technology can be developed for dynamically mapping biochemical processes in the whole human body and pave the way for individualized medicine. Primary objective • In this study the investigators will investigate whether biochemical imaging of change (Δ, figure 1) in the metabolic phospholipid ratios of PME and PDE between baseline and after 2 weeks of therapy are predictive for RECIST progression in gastrointestinal cancer patients after the first 9 week treatment period. Secondary objectives: In this study the investigators will investigate whether biochemical imaging of change (Δ, figure 1) in the metabolic phospholipid ratios of PME and PDE between baseline and after 2 weeks of therapy are predictive for progression free survival (PFS) and overall survival (OS) in gastrointestinal cancer patients.. Investigate whether biochemical imaging of the metabolic phospholipid ratios of PME and PDE at baseline of therapy are predictive for RECIST progression after the first 9-week treatment period, and for PFS and OS in gastrointestinal cancer patients. Investigate whether biochemical imaging of change (δ, figure 1) in the metabolic phospholipid ratios of PME and PDE after a 9-week treatment period are predictive for RECIST progression following that treatment period, and for PFS and OS in gastrointestinal cancer patients. Exploratory multi variable analysis for the development of a prediction model to predict resistance to treatment within 3 weeks after the start of chemotherapy with the use of all chemistry imaging data including all MR detectable nuclei and clinical parameters. Study population: The aim of this study is to include a total of 150 patients with metastatic gastrointestinal cancer before start of palliative chemotherapy containing fluoropyrimidine with or without platinum. Of each of the following tumour types approximately 50 patients will be included: colon-, pancreatic and gastro-oesophageal cancer. Intervention: Participants will undergo multiple 7T MR imaging sessions which include advanced 31P MRSI techniques, before start of palliative chemotherapy and during treatment until progression of disease or until week 54. Main study parameters/endpoints: Study parameters include; metabolic ratios of the phospholipids PME and PDE from the area under the curve (AUC) of the corresponding spectral peaks, size measurements from CT and MRI scans, coded radiology reports, clinical patient data, e.g. chemotherapy details extracted from clinical notes which are coded before storage to preserve anonymity. Main endpoint is defined by the RECIST progression criteria after every nine weeks for which chemical imaging its predictive value is investigated in the primary objective. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients will be asked for eight extra hospital visits to undergo 7T MRI of approximately one hour per session (8x 1 hour). MRI is a safe non-invasive technique without use of ionizing radiation and so far, extensive research has not shown any side-effects of the high magnetic field used in 7T MRI, resulting in low inherent risks for the participants. Patients' therapy is not delayed by participation in this study and patients with MRI contraindications are excluded from participation (Refer to 3.3 Exclusion Criteria).

Official Title
-----------------
NICI Study: Non-Invasive Chemistry Imaging in the Whole Human Body

Conditions
-----------------
Gastrointestinal Cancer Metastatic

Intervention / Treatment
-----------------
* Radiation: MRI/Spectroscopy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with liver metastasis of gastrointestinal cancer, with histological or cytological proof of metastasis or a high suspicion on CT imaging. Tumour size ≥ 1cm. WHO-performance score 0-2. Scheduled for first- or second-line palliative chemotherapy containing capecitabine combined with oxaliplatin (CAPOX) or fluorouracil combined with oxaliplatin and folinic acid (FOLFOX). Written informed consent. Exclusion Criteria: Any psychological, familial, sociological, or geographical condition potentially hampering adequate informed consent or compliance with the study protocol. Contra-indications for MR scanning, including patients with a pacemaker, cochlear implant or neurostimulator; patients with non-MR compatible metallic implants in their eye, spine, thorax or abdomen; or a non-MR compatible aneurysm clip in their brain; patients with claustrophobia.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: • In this study we will investigate whether biochemical imaging of change (Δ, figure 1) in the metabolic phospholipid ratios of PME and PDE between baseline and after 2 weeks of therapy are predictive for RECIST progression in gastrointestinal cancer patients after the first 9 week treatment period.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Imaging<br>Participants will undergo multiple 7T MR imaging sessions which include advanced 31P MRSI techniques, before start of palliative chemotherapy and during treatment until progression of disease or until week 54. | Radiation: MRI/Spectroscopy<br>* Participants will undergo multiple 7T MR imaging sessions which include advanced 31P MRSI techniques, before start of palliative chemotherapy and during treatment until progression of disease or until week 54.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PME/PDE-ratio from Area Under the Curve (AUC): predictive | The primary outcome measure in this study is the PME/PDE-ratio (PME/PDE) resulting from the AUC of the metabolite peaks in the acquired metabolic images e.g. spectra. This measure is used to calculate changes in the metabolic phospholipid-ratios of PME and PDE (ΔPME/PDE) between baseline and after 2 weeks of therapy. In addition, this outcome measure is used to investigate secondary objectives including PME/PDE at baseline as a sole predictor (see Outcome Measure 3). | 36 months | 
| Change in PME/PDE (ΔPME/PDE): predictive | The second primary outcome measure to investigate the discriminative ability of PME/PDE is the ΔPME/PDE between baseline and after 2 weeks of therapy. This measure is used to investigate the primary objective whether biochemical imaging of change in the metabolic phospholipid-ratios of PME and PDE (ΔPME/PDE) between baseline and after 2 weeks of therapy are predictive for RECIST progression in gastrointestinal cancer patients after the first 9 week treatment period. In addition, this outcome measure is also used to investigate secondary objectives which includes different time periods over which ΔPME/PDE is measured. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PME/PDE at baseline: predictive | This secondary measure is used investigate the secondary objective whether biochemical imaging of PME/PDE at baseline of therapy is predictive for RECIST progression after the first 9-week treatment period, and for PFS and OS in gastrointestinal cancer patients. PME/PDE at baseline results from the AUC of the metabolite peaks in the acquired metabolic images e.g. specta (see also Outcome Measure 1). | 36 months | 
| Prediction model | Exploratory multi variable analysis for the development of a prediction model to predict resistance to treatment within 3 weeks after the start of chemotherapy with the use of all chemistry imaging data including all MR detectable nuclei and clinical parameters. Multi-variable analysis of clinically relevant data to investigate the feasibility of a dynamic prediction model will use all chemical imaging data, size measurements from CT, conventional 7T MR imaging scans, coded radiology reports, clinical patient data, e.g. chemotherapy details extracted from clinical notes which are coded before storage to preserve anonymity, choice of therapy, progression free survival (PFS) and overall survival (OS) and metastasis origin. | 36 months | 
| (Δ)PME/PDE predictive significance | To investigate to what extent baseline PME/PDE and (ΔPME/PDE) over all different time periods is predictive of PFS and OS, we will use standard survival analysis techniques (e.g. Cox regression, accelerated failure time models) and estimate the C-index as measure of discriminative ability. | 36 months | 
| Response to treatment | This outcome measure results from conventional therapy evaluation defined by RECIST progression. It is used in the primary and secondary objectives as the gold standard for the therapy evaluation predictors assessed in this study (ΔPME/PDE, PME/PDE, etc.) | 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
gastrointestinal cancer, human biology, non-invasive chemistry imaging, MR imaging, spectroscopy