Trial Title:
Hyperpolarized 13C MRI for Cancer Immunotherapy
NCT ID:
NCT05805358
Condition:
Gynecologic Cancer
Cervical Cancer
Endometrial Cancer
Ovarian Cancer
Conditions: Official terms:
Ovarian Neoplasms
Uterine Cervical Neoplasms
Endometrial Neoplasms
Conditions: Keywords:
Carbon 13 pyruvate
Artificial intelligence
Ovarian Cancer
Cervical Cancer
Endometrial Cancer
Dynamic nuclear polarization
Magnetic resonance imaging
Computed tomography
Precision medicine
Metabolomics
Radiomics
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Health Services Research
Masking:
Single (Participant)
Intervention:
Intervention type:
Drug
Intervention name:
Hyperpolarized 13C-Pyruvate injection
Description:
DNP-MRI for splenic immune function evaluation through hyperpolarized 13C-Pyruvate
injection
Arm group label:
Next Generation Imaging Group
Other name:
Hyperpolarized 1-13C Pyruvate injection
Other name:
HP 13C-Pyruvate injection
Other name:
Dynamic Nuclear Polarization
Summary:
The investigators aim to develop an advanced imaging platform, such as dynamic nuclear
polarization (DNP) 13C-MRI, MR fingerprinting (MRF) and MR Relaxometry, which combines
with traditional anatomical contrast CT, MRI and PET, and integrate blood/urine
metabolomics methods. A comprehensive strategy to thoroughly analyze the immune
activation of spleen pattern, microstructure, cell density, red blood cell iron content,
immune cell glycolysis and metabolic flow rate.
Detailed description:
The investigators plan a 3-year trial with a randomized, two-groups allocation
observational study design that will enroll 90 subjects with newly diagnosed or recurrent
gynecological cancer from Linkou Chang Gung Memorial Hospital (CGMH) receiving ICI
therapy for this prospective study. Standard cares, eg. MRI/CT/PET, are priorly required
for the first-line screening method, with tumor slides and routine blood work at the
initial visit. After being randomly assigned, 30 eligible subjects will be assigned to
the next-generation imaging group, and will receive two integrated examinations between
the baseline and 2 weeks of immunotherapy-the integrated examination of DNP and
metabolomics.
Subjects in the next-generation imaging group will receive splenic DNP imaging, followed
by non-contrast-enhancing MRF at the lesion and MR Relaxometry, which provide
quantitative measurements of metabolism occurring within the spleen and within the cancer
cells, respectively. DNP is injected with 13C contrast agent hyperpolarized 13C pyruvate
(HP [1-13C] Pyruvate) intravenously in the arm, and the study drug is injected at a dose
of 0.43 ml/kg, which is labeled with the non-radioactive isotope 13C at the C1 position,
hyperpolarized 13C signals are obtained through MR spectrum acquisition, and then MRF
sequences are performed to obtain multi-parameter tissue characteristics. The general
imaging group will receive the same MR strategies but without spleen DNP scan.
All MRI sequences will be performed on a 3T clinical scanner (Discovery MR750w,GE
Healthcare, Milwaukee, USA) with a flexible surface 13C/1H multinuclear transmit-receive
coil (RAPID Biomedical, Bavaria, Germany) to cover the splenic region.
DNP-MRI:
To comply with the Good Manufacturing Practice (GMP) of pharmaceuticals, [1-13C]pyruvate
for human will be prepared in the ISO 8 clean room and ISO 5 laminar flow in the
Department of Nuclear Medicine, Chang Gung Memorial Hospital at Linkou, Taiwan. The
premixed [1-13C]pyruvic acid/12.5 mM Electronic Paramagnetic Agent (Electronic
Paramagnetic Agent; EPA; AH111501, GE Healthcare, Oslo, Norway) will be packed into a
sterile pharmacy Kit (Sterile Fluid Path; SFP, GE Research Circle Technology) and
polarized in the polarizer (SPINlab, GE Research Circle Technology) at 0.7 - 0.8 K and a
magnetic field of 5 T for at least 2 - 3 hrs. After being quickly dissolved in heated
water, it will pass through an EPA filter to remove excess EPA and be mixed with
neutralization medium (NaOH/TRIS/EDTA) in the receiver, and then automatically detected
by optical measurement in the QC machine (GE GE Research Circle Technology), including
pyruvate concentration, EPA concentration, pH, temperature, volume, and polarization
level, while simultaneously drawing a solution containing hyperpolarized [1-13C]pyruvate
through a 0.2 μm terminal filter (ZenPure, Manassas, Virginia) into an administration
syringe (Medrad, Warrendale, Pennsylvania) to ensure sterility. After the responsible
physician checks that the QC parameters meet the criteria, the patient will be injected
intravenously at a dose of 0.43 mL/Kg at a flow rate of 5 mL/s, and then flushed with 20
mL of physiological saline. Terminal filter integrity (Threshold = 50 psi) will be
checked immediately after dispensing.
During 13C-MRI scanning, a set of image detections will be performed first for
positioning, and then the 13C signal will be calibrated, including gradient shimming, 13C
center frequency confirmation (calculated from the 1H center frequency) and emission gain
optimization (using the Bloch-Sieger sequence ), after a 30-second delay from injection,
the following rapid 13C sequence will be performed, which will take approximately 2-3
minutes:
1. Pulse acquisition of 13C spectra: flip angle = 10°; TR = 2000 ms; slice thickness =
30 mm; read bandwidth = 5000 Hz; spectral collection points 2048; repetition = 14;
acquisition time = 2000 ms; time-resolved Rate = 2000 ms.
2. 13C metabolite-specific imaging of pyruvate, lactate, and alanine (spectral-spatial
RF pulses followed by helical readout): TR = 250 ms; TE = N/A; in-plane spatial
resolution = 10 x 10 mm^2; matrix size = 128 x 128 mm^2; field of view = 22 x 22
cm^2; slice thickness = 20 mm; flip angle = 15°/30°/30° (pyruvate/lactate/alanine);
acquisition time = 250 ms; time resolution = 1000 ms.
3. 13C chemical shift imaging: TR = 80ms; TE = N/A; in-plane spatial resolution = 25 x
25 mm^2; matrix size = 8 x 8 mm^2; field of view = 20 x 20 cm^2; slice thickness =
20 mm ; Flip angle = 15°; Acquisition time = 80 ms.
DWI:
The clinical MR study will continue after 13C DNP with the original scanner and will use
single-echo planar technique with fat suppression (repetition time ms/echo time ms:
3300/79; number of signal averages: 4; slice thickness: 4 mm ; gap; 1 mm; matrix: 128x128
mm^2; field of view 20 x 20 cm^2). The highest b-value of 1000 sec/mm^2 has been chosen
to optimize the signal-to-noise ratio. Diffusion-weighted gradients are applied
orthogonally for slice selection, phase encoding and readout direction, and the slope
will be calculated from the logarithmic decay curve of signal intensity versus b-value
(Syngo, Siemens, Erlangen, Germany).
MR Fingerprinting (MRF):
MAGiC (MAGnetic resonance image Compilation) will use 2D fast spin echo based
multi-saturation delayed multi-echo acquisition. Steady-state free precession (SSFP) is
used for MRF acquisition with acquisition traces interleaved using 89 under sampled
golden angle helices, sampling bandwidth = ±250 kHz, TR = 9 ms, TE = 2.2 ms, NEX = 1 and
979 frames . B0 and B1 are not included in the sequence but slice outlines are included
to improve T2 accuracy, other imaging parameters used in MAGiC and MRF scans are: FOV =
22 x 22 mm^2; matrix = 256 x 256; slice thickness = 4 mm, 1 mm gap; 20 pieces. Time
intervals of scan are approximately 4 minutes and 3.6 minutes, respectively.
MR Relaxometry:
The iterative decomposition of water and fat with an echo asymmetry at least-square
estimation-iron quantification (IDEAL-IQ) sequence has the following parameters: TR 10
ms; TE 4.7 ms; echo number 6, ranging from 1.1 ms to 6.38 ms FOV 35-40 cm; matrix size
128 × 128; pixel bandwidth 325 Hz; flip angle 6; slice thickness 10 mm; space between
slices 5 mm. The scans are acquired during a breath-hold lasting less than 30 seconds.
R2* is calculated using the following formula: R2*IDEAL = -1.276 + 1.2366 * R2*GRE. R2*
is then converted to iron concentration (mg/g) using the widely used formula proposed by
Wood et al.: Iron concentration = 0.202 + 0.0254 x R2*
While there is no accepted normal range for spleen iron, 1.98 mg/g is suggested as an
upper limit, with 2.74 mg/g reported to be pathological. Splenic iron varies by age and
sex. Spleen iron content is higher in men than in women (men: 0.96 ± 0.34 mg/g, women:
0.87 ± 0.29 mg/g). In women, menopause is associated with 0.12 mg/g higher spleen iron.
It must be noted that the GRE echo time of abdominal MRI is insufficient to quantify iron
when iron exceeds the threshold (approximately 4 mg/g)
Metabolomics:
Plasma, urine and/or tissue samples collected from patients will be further analyzed by
1H high-resolution NMR (Bruker 600MHz NMR spectrometer) and LC-TOFMS (Waters Q-TOFMS)
located at the Clinical Metabolomics Center, Chang Gung Memorial Hospital. Standard
metabolomics software - GeneSpring MS, Markerlyn XS and Metaboanalyst, will also be used
for multivariate data analysis and presentation. The METLIN, HMDB, and KEGG databases
will be searched for an accurate set of features showing significant differences between
the groups of before and after immunotherapies. Compound predictions will be performed
using metabolite databases and formula generation software. Non-commercial and commercial
applications such as MetaboAnalyst for metabolomics studies are also available.
Laboratory examinations include routine inflammatory indices, such as erythrocyte
sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin, plasma antioxidant
index (TAC), cellular antioxidant index (GPX), DNA damage index (8-OHdG ) and lipid
oxidation and inflammation index (MPO); conventional metabolic indexes, such as LDH,
lactate and pyruvate; and immune function-related indexes, such as T Cell & B Cell, T
Cell Subset tests, HLA-B27, IL-6, a1-globulin and a2-globulin. If the patient has
undergone slides for histopathological diagnosis, tissue LDH and MCT protein expression
will also be determined.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Newly diagnosed or recurrent gynecological cancer confirmed by histology.
2. Age ≥ 20 years old.
3. Expected to receive immunotherapy.
Exclusion Criteria:
1. Suffering from other malignancies (excluding non-melanoma skin cancer).
2. History of splenic abnormalities (such as splenic damage, cirrhosis-related
splenomegaly or primary/metastatic splenic tumors).
3. Insufficient function of bone marrow, liver and kidney.
4. Contraindications to MRI studies (e.g. claustrophobia, cardiac pacemaker, metal
implants in the pelvis).
5. Uncontrolled concurrent diseases, including but not limited to kidney stones,
persistent or active infection, symptomatic heart failure, unstable angina, cardiac
arrhythmias, or mental illness/social situations that limit compliance with research
requirements.
6. Pregnant or lactating women.
Gender:
Female
Gender based:
Yes
Gender description:
Gynecological cancer
Minimum age:
20 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Chang Gung Memorial Hospital
Address:
City:
Taoyuan City
Zip:
333
Country:
Taiwan
Contact:
Last name:
Gigin Lin, MD, PhD
Phone:
886-3-3281200
Phone ext:
2575
Email:
giginlin@cgmh.org.tw
Contact backup:
Last name:
Kuan-Ying Lu, MS
Phone:
886-3-3281200
Phone ext:
2602
Email:
fantacy52317@gmail.com
Start date:
November 1, 2023
Completion date:
July 31, 2026
Lead sponsor:
Agency:
Chang Gung Memorial Hospital
Agency class:
Other
Collaborator:
Agency:
National Science and Technology Council
Agency class:
U.S. Fed
Source:
Chang Gung Memorial Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05805358
