Multiparametric Metabolic and Hypoxic PET/MRI Imaging for Brain Cancer

Overseen by Jonathan McConathy, MD, PhD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: University of Alabama at Birmingham

Must not be taking: Bevacizumab, Investigational drugs

Disqualifiers: Recurrent glioma, Pregnancy, Renal dysfunction, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This feasibility study will assess the clinical potential of a new imaging approach to detect viable high grade glioma (HGG) in pediatric and adult patients after standard of care radiation therapy (RT) with or without concurrent temozolomide (TMZ). Study participants will undergo simultaneous positron emission tomography/magnetic resonance imaging (PET/MRI) with O-(\[2-\[F-18\]fluoroethyl)-L-tyrosine (FET, amino acid transport) and 1H-1-(3-\[F-18\]fluoro-2-hydroxypropyl)-2-nitroimidazole (FMISO, hypoxia) at the time of standard of care imaging after completion of RT. The presence of viable tumor at this time point will be assessed on a per patient basis. Study participants will be followed clinically and with standard of care (SOC) imaging for up to 2 years after completion of PET/MRI to determine the nature of lesions seen on investigational imaging and to obtain patient outcome data. The imaging data will also be used to develop a semi-automated workflow suitable for implementation in clinical trials and standard of care PET/MRI studies.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have used bevacizumab or an investigational drug within 3 months before the imaging study.

What data supports the idea that Multiparametric Metabolic and Hypoxic PET/MRI Imaging for Brain Cancer is an effective treatment?

The available research shows that Multiparametric Metabolic and Hypoxic PET/MRI Imaging, using a substance called FET, is effective in diagnosing and assessing brain cancer. Studies indicate that FET PET imaging can help doctors see how well a treatment is working for patients with brain cancer, especially when other imaging methods like MRI might not be as clear. This imaging technique is particularly useful for identifying the return of cancer and distinguishing it from changes caused by treatment. While the research focuses on its diagnostic capabilities, it suggests that FET PET imaging is a valuable tool in managing brain cancer treatment. ^{1 2 3 4 5}

What safety data exists for O-(2-[18F]Fluoroethyl)-L-tyrosine (FET) in brain cancer treatment?

The safety data for O-(2-[18F]Fluoroethyl)-L-tyrosine (FET) in brain cancer treatment is supported by multiple studies. These studies have investigated its transport mechanism, uptake kinetics, and biodistribution in both preclinical and clinical settings. FET has been shown to provide high contrast between tumor tissue and benign tissue, with low accumulation in healthy brain tissue, indicating a favorable safety profile. It has been widely adopted in neuro-oncology for its diagnostic potential and has replaced other tracers in many centers due to its logistic advantages and clinical results. ^{4 6 7 8 9}

Is the treatment in the trial 'Multiparametric Metabolic and Hypoxic PET/MRI Imaging for Brain Cancer' promising?

Yes, the treatment is promising because it combines PET and MRI imaging to better understand brain cancer. This approach helps doctors see how the cancer is using energy and how much oxygen it has, which can help in planning more effective treatments. ^{1 10 11 12 13}

Research Team

Jonathan McConathy, MD, PhD

Principal Investigator

University of Alabama at Birmingham

Eligibility Criteria

This trial is for pediatric and adult patients with newly diagnosed high-grade gliomas who have completed standard radiation therapy. Participants must be 10 years or older, have a life expectancy over 12 weeks, and can undergo PET/MRI without anesthesia. Women of childbearing age need a negative pregnancy test. Exclusions include pregnancy, significant kidney issues, recurrent glioma, recent use of certain drugs like bevacizumab, or any condition that may hinder study completion.

Inclusion Criteria

I have a high-grade glioma and have received or am receiving radiation.

Females with childbearing potential must have a negative urine β-hCG test on the day of procedure or a serum beta-hCG test within 48 hours prior to the administration of FET or FMISO

I am at least 10 years old.

Exclusion Criteria

My kidney function is significantly impaired.

Inability to complete PET/MRI scans

My brain tumor has come back after treatment.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

PET/MRI Imaging

Participants undergo FET and FMISO PET/MRI imaging to assess viable high grade glioma

2 weeks

2 visits (in-person)

Follow-up

Participants are monitored clinically and with standard of care brain MRI for progression-free survival (PFS) and overall survival (OS)

24 months

Regular visits (in-person)

Treatment Details

Interventions

• O-(2-[18F]Fluoroethyl)-L-tyrosine (Amino Acid Transport Inhibitor)

Trial Overview The study tests a new imaging method using simultaneous PET/MRI with two tracers: FET to track amino acid transport and FMISO for hypoxia in tumors post-radiation therapy. The goal is to detect viable brain tumors after treatment and develop an automated workflow for future clinical trials and care standards.

Participant Groups

Group I: PET imaging of system L amino acid transport with FET and hypoxia imaging with FMISO Experimental Treatment 1 Intervention

The participant will have a plastic peripheral intravenous (IV) catheter placed in the arm for Positron emission tomography (PET) tracer and MR contrast administration. FET O-(\[2-\[18F\]fluoroethyl)-L-tyrosine and FMISO 1H-1-(3-\[18F\]fluoro-2-hydroxypropyl)-2-nitroimidazole will be produced by the UAB Cyclotron PET Production Facility. PET/MRI will be performed using a GE Signa PET/MRI system in the AIF with specific imaging protocols for FET and FMISO studies. Upon completion of imaging, the peripheral IV catheter will be removed. The participant will be asked to urinate to reduce bladder dose after completion of each PET acquisition.Patients enrolled in the study will be followed clinically and with standard of care brain MRI. PFS and OS will be monitored for up to 24 months after completion of FET and FMISO PET/MRI studies.

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Kierstin Kennedy

University of Alabama at Birmingham

Chief Medical Officer since 2022

MD

S. Dawn Bulgarella

University of Alabama at Birmingham

Chief Executive Officer since 2023

BSc in Commerce and Business Administration from the University of Alabama, MS in Health Administration from the University of Alabama at Birmingham

Findings from Research

In a study of 10 patients with recurrent high-grade glioma treated with bevacizumab/irinotecan, (18)F-FET PET identified 60% of patients as metabolic responders, while MRI only showed a complete response in 10% and partial response in 50%, indicating that (18)F-FET PET may be more sensitive in detecting treatment responses.

Responses detected by (18)F-FET PET were significantly associated with longer progression-free survival (9 months vs. 3 months) and overall survival (23 months vs. 3.5 months), suggesting that this imaging technique provides critical prognostic information that complements MRI assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response assessment of bevacizumab in patients with recurrent malignant glioma using [18F]Fluoroethyl-L-tyrosine PET in comparison to MRI. Galldiks, N., Rapp, M., Stoffels, G., et al.[2022]

In a study of 98 patients with gadolinium-negative gliomas, dynamic 18F-FET PET imaging revealed distinct time activity curve (TAC) patterns that correlated with patient survival, with 5-year survival rates of 85% for increasing TACs, 47% for mixed TACs, and 19% for decreasing TACs.

The study found that TAC measurements serve as a strong independent biomarker for prognosis, regardless of tumor grade or IDH mutation status, highlighting their potential utility in guiding treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dynamic 18F-FET PET is a powerful imaging biomarker in gadolinium-negative gliomas. Kunz, M., Albert, NL., Unterrainer, M., et al.[2020]

In a study of 124 glioma patients, (18)F-FET PET demonstrated a higher diagnostic accuracy (93%) for detecting tumor progression or recurrence compared to conventional MRI (85%), particularly when specific uptake criteria were met.

The use of (18)F-FET PET not only improved sensitivity (93%) and specificity (100%) but also effectively distinguished between true tumor progression and treatment-related changes, making it a valuable tool in glioma management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma. Galldiks, N., Stoffels, G., Filss, C., et al.[2022]

The study evaluated 393 patients and found that [(18)F]-fluoro-ethyl-l-tyrosine (18F-FET) PET has a high sensitivity of 87% for detecting high-grade brain tumors, indicating it is effective for identifying aggressive tumor types.

However, the specificity of 68% is limited due to tracer uptake in non-tumor brain lesions and disrupted blood-brain barriers, suggesting that while 18F-FET PET is useful, it may also yield false positives in certain conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma. Hutterer, M., Nowosielski, M., Putzer, D., et al.[2021]

The study involved 47 glioma patients and 63 lesions, demonstrating that combined 18F-fluorethyltyrosine (FET)-PET/MRI is effective in distinguishing between tumor recurrence and treatment-related changes, with a high area under the curve (AUC) of 0.89 for multiparametric analysis.

Static PET showed the highest sensitivity (80%) and specificity (85%) for identifying recurrence, while the multiparametric approach improved diagnostic accuracy, particularly when high specificity was required.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis of glioma recurrence using multiparametric dynamic 18F-fluoroethyl-tyrosine PET-MRI. Pyka, T., Hiob, D., Preibisch, C., et al.[2019]

L-[18F]FET is rapidly taken up by SW 707 colon carcinoma cells through the specific amino acid transport system L, demonstrating a significant accumulation factor of 3.0 to 5.0, while D-[18F]FET showed no accumulation.

In vivo studies in tumor-bearing mice revealed that L-[18F]FET has a half-life of 94 minutes in plasma and exhibits higher uptake in tumors compared to other organs, indicating its potential as an effective tracer for tumor imaging and therapy monitoring using PET.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-L-tyrosine in vitro and in vivo. Heiss, P., Mayer, S., Herz, M., et al.[2022]

The newly developed 18F-labeled amino acid tracer, 18F-FET, shows high radiochemical purity (over 95%) and stability for at least 6 hours, indicating its safety for use in medical imaging.

In preclinical studies, 18F-FET demonstrated significantly lower uptake in normal brain tissues compared to tumors, providing clearer images of brain tumors than the commonly used 18F-FDG, suggesting its efficacy as a PET tracer for tumor imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Synthesis and preliminary studies of O-(2-[18F] fluoroethyl)-L-tyrosine as a positron emission tomography imaging agent]. Dang, YH., Wang, SZ., Cheng, X., et al.[2016]

PET imaging with the amino acid analogue [18F]FET has proven effective in brain tumor diagnostics, providing critical information for tumor delineation, therapy planning, and monitoring treatment responses.

[18F]FET shows low accumulation in benign lesions and healthy brain tissue, allowing for clear differentiation between tumor and non-tumor areas, which has led to its preference over shorter-lived tracers like [11C]MET in many Western European medical centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current trends in the use of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) in neurooncology. Stegmayr, C., Stoffels, G., Filß, C., et al.[2021]

The study found that O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) is taken up significantly more by malignant thymoma cells compared to normal tissues, indicating its potential as a tumor imaging tracer.

In both mice and human studies, 18F-FET showed a clear biodistribution pattern, with tumor uptake being notably higher than in muscle tissue, suggesting its efficacy in distinguishing tumors from healthy organs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) uptake in mouse thymoma cells, and its biodistribution in mice and human volunteers. Abe, K., Hayashi, K., Sasaki, M., et al.[2016]

This study compared BOLD and TOLD MRI techniques with the radiotracer [18F]FMISO in tumor-bearing rats, revealing that both MRI methods can provide insights into tumor oxygenation and correlate with hypoxia levels indicated by PET imaging.

The findings suggest that regional variations in tumor oxygenation are important, as stronger correlations were found in well-perfused areas, highlighting the need for further research into the relationship between MRI signals and hypoxia in tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examining correlations of oxygen sensitive MRI (BOLD/TOLD) with [18F]FMISO PET in rat prostate tumors. Zhou, H., Chiguru, S., Hallac, RR., et al.[2020]

Increasing tumor oxygenation using carbogen did not significantly change overall (18)F-FDG uptake in tumors, indicating that general tumor metabolism may remain stable under different oxygen conditions.

However, in the most hypoxic regions of the tumor, (18)F-FDG uptake showed a significant 21% reduction with increased oxygenation, suggesting that enhancing tumor oxygen levels could improve the accuracy of (18)F-FDG imaging by highlighting areas of lower glucose metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of tumor oxygenation on (18)F-FDG (fluorine-18 deoxyglucose) uptake: a mouse study using positron emission tomography (PET). Chan, LW., Hapdey, S., English, S., et al.[2018]

The study used dynamic [18F]FMISO PET imaging in mice and human patients to assess tumor hypoxic fractions (HFs), revealing that the method of quantification significantly affects the results, with HFs ranging from 2% to 85% depending on the metric used.

Tracer kinetic modeling (K i and k 3) showed a stronger correlation with direct oxygen measurements compared to tissue-to-blood ratios (TBR), suggesting it may enhance the reliability of hypoxia quantification in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantification of Tumor Hypoxic Fractions Using Positron Emission Tomography with [18F]Fluoromisonidazole ([18F]FMISO) Kinetic Analysis and Invasive Oxygen Measurements. Kelada, OJ., Rockwell, S., Zheng, MQ., et al.[2019]

A new mathematical model has been developed to link anatomical MRI imaging with molecular PET imaging in glioblastoma multiforme (GBM), allowing for patient-specific virtual PET images that accurately reflect clinical scans.

This model incorporates factors like hypoxia and angiogenesis, providing insights into the tumor microenvironment and potentially improving our understanding of how these factors affect tracer activity and tumor behavior.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Applying a patient-specific bio-mathematical model of glioma growth to develop virtual [18F]-FMISO-PET images. Gu, S., Chakraborty, G., Champley, K., et al.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Response assessment of bevacizumab in patients with recurrent malignant glioma using [18F]Fluoroethyl-L-tyrosine PET in comparison to MRI. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Dynamic 18F-FET PET is a powerful imaging biomarker in gadolinium-negative gliomas. [2020]

3. England pubmed.ncbi.nlm.nih.gov

The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

[18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma. [2021]

5. Ireland pubmed.ncbi.nlm.nih.gov

Diagnosis of glioma recurrence using multiparametric dynamic 18F-fluoroethyl-tyrosine PET-MRI. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-L-tyrosine in vitro and in vivo. [2022]

7. China pubmed.ncbi.nlm.nih.gov

[Synthesis and preliminary studies of O-(2-[18F] fluoroethyl)-L-tyrosine as a positron emission tomography imaging agent]. [2016]

8. United States pubmed.ncbi.nlm.nih.gov

Current trends in the use of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) in neurooncology. [2021]

9. England pubmed.ncbi.nlm.nih.gov

O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) uptake in mouse thymoma cells, and its biodistribution in mice and human volunteers. [2016]

10. United States pubmed.ncbi.nlm.nih.gov

Examining correlations of oxygen sensitive MRI (BOLD/TOLD) with [18F]FMISO PET in rat prostate tumors. [2020]

11. England pubmed.ncbi.nlm.nih.gov

The influence of tumor oxygenation on (18)F-FDG (fluorine-18 deoxyglucose) uptake: a mouse study using positron emission tomography (PET). [2018]

12. United States pubmed.ncbi.nlm.nih.gov

Quantification of Tumor Hypoxic Fractions Using Positron Emission Tomography with [18F]Fluoromisonidazole ([18F]FMISO) Kinetic Analysis and Invasive Oxygen Measurements. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Applying a patient-specific bio-mathematical model of glioma growth to develop virtual [18F]-FMISO-PET images. [2021]