Studying the Biology of IDH-mutant Gliomas Via Longitudinal Observation of 2-hydroxyglutarate (2-HG) Using MR Spectroscopy

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Studying the Biology of IDH-mutant Gliomas Via Longitudinal Observation of 2-hydroxyglutarate (2-HG) Using MR Spectroscopy

Study Purpose

Background: Glioma is a type of brain cancer. Some of these tumors have gene mutations. These mutations can cause a substance called 2-HG to build up in the brain. This makes the tumors more aggressive. Researchers want to better understand 2-HG buildup in the brain. They hope this can help them design better ways to test for gliomas. Objective: To monitor the level of 2-HG in the brains of people with gliomas that have mutations in the IDH1 or IDH2 genes. Eligibility: People ages 18 and older with gliomas with mutations in the IDH1 or IDH2 genes. Design: Participants will be screened with: Medical and cancer history. Physical exam. Reviews of their symptoms and ability to perform normal activities. Blood and urine tests. MRI scan. Samples of their tumor from a past surgery. Documentation of their diagnosis and mutation status. Participants will have an initial evaluation. This will include repeats of screening tests. It will also include: Neurological exam. MRS and MRI scans of the brain: Participants will lie on a table that slides into a metal cylinder. A coil or soft padding will be placed around their head. They will have a contrast agent injected into a vein. Pictures will be taken of the brain. Participants will have follow-up visits every 2-6 month for the rest of their life. Visits will include scans.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

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INCLUSION CRITERIA:
- Patients must have histologically confirmed glioma with IDH1 or IDH2 mutation confirmed by DNA sequencing.

- Patients must have grade II, III or IV glioma.

- Patients must have measurable disease.

- Age greater than or equal to18 years.

Tumor biology of IDH-mutant gliomas are different in pediatric tumors. Therefore, children will be excluded from the study.

- Karnofsky performance greater than or equal to 60%.

- Patients must have normal kidney function as defined below: - creatinine within normal institutional limits OR.

- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients withcreatinine levels above institutional normal (Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl)).

- Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

- Subjects with any coexisting medical or psychiatric condition that is likely to interfere with study procedures and/or results (such as allergy to gadolinium contrast, metal implants and so on).

- Pregnant women are excluded because MRI contrast, planned to be used on this study, may be dangerous for the fetus.

Because there is an unknown but potential risk for adverse events in nursing infants secondary to using of MRI c ntrast, breastfeeding should be discontinued for 72 hours following study imaging.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT03952598
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	N/A
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	National Cancer Institute (NCI)
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Jing Wu, M.D.
Principal Investigator Affiliation	National Cancer Institute (NCI)
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	NIH
Overall Status	Recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Glioma, Gliomas, High Grade Glioma, Malignant Glioma, Low Grade Glioma
Study Website:	View Trial Website

Additional Details

Background:

- Glioma is the most common malignant brain tumor.

Genes coding for isocitrate dehydrogenase (IDH), a metabolic enzyme, are frequently mutated in gliomas, particularly lower-grade gliomas (LGGs). IDH mutation causes a unique tumor biology, including the accumulation of 2-hydroxyglutarate (2-HG), an oncometabolite, which in turn causes genomic hypermethylation and tumorigenesis.

- Despite having a better prognosis compared to their IDH WT counterparts, IDH-mutant LGGs undergo a slow but unremitting higher-grade transformation (HT) and eventually become high grade gliomas (HGGs).

A subset of patients with transformed HGGs develop a hypermutator phenotype (HMP), possibly related to previous treatment with alkylating agents and radiotherapy. The timeline for the development of HT and HMP is unpredictable and there is no known way to prevent them from happening, largely due to a lack of understanding their biological mechanisms and lack of a non-invasive approach for potential early detection.

- Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-HG in a tumor harboring IDH mutation.

There has been an increased interest in using quantitative 2-HG by MRS as a biomarker for IDH-mutant gliomas. This clinical study will allow a longitudinal monitoring of quantitative 2-HG by MRS in patients with IDH-mutant gliomas. We hypothesize that a significant increase in 2HG level is correlated with HT and/or HMP. The change in 2-HG level in conjunction with evaluation of tumor cellularity and other metabolite markers such as choline, creatinine and N-acetyl aspartate (NAA) will likely to provide insights into metabolic alterations that may correlate with HT/HMP and potentially provide the predictive biomarker for early detection of HT. Objective: -To monitor the quantitative levels of 2-hydroxyglutarate (2-HG) longitudinally in patients with IDH-mutant gliomas via proton magnetic resonance spectroscopy (1H-MRS). Eligibility:

- IDH 1 or 2 mutation confirmed by DNA sequencing.

- Age greater than or equal to18 years, KPS greater than or equal to 60% Design: - This is prospective observational study.

We will recruit at least 250 eligible patients in the next 5 years.

- The relationship between the occurrence of HT and the changes in 2-HG level using the proportional hazard model.

Arms & Interventions

Arms

Experimental: 1/Arm 1

Monitoring of quantitative levels of 2-hydroxyglutarate (2-HG) via proton magnetic resonance spectroscopy (1H-MRS)

Interventions

Device: - 3T MRI scanner

Research proton MRS (1H-MRS)followed by DW-MRI

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Bethesda, Maryland

Status

Recruiting

Address

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892

Site Contact

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

[email protected]

888-624-1937