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

Glioma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03952598
• Other study ID #: 190096
• Secondary ID: 19-C-0096
• Status: Recruiting
• Phase: N/A
• Start date: October 16, 2019
• Est. completion date: December 31, 2025

Study information

• Verified date: March 15, 2024
• Source: National Institutes of Health Clinical Center (CC)
• Contact: NCI NOB Referral Group
• Phone: (866) 251-9686
• Email: ncinobreferrals[@]mail.nih.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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. ...

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 270
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• 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.

Related Conditions & MeSH terms

• Glioma
• Gliomas
• High Grade Glioma
• Low Grade Glioma
• Malignant Glioma

Intervention

Device:
• 3T MRI scanner
Research proton MRS (1H-MRS)followed by DW-MRI

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To monitor the quantitative levels of 2-hydroxyglutarate (2-HG) longitudinally in patients with IDH mutant gliomas via proton magnetic resonance spectroscopy (1H-MRS)	Changes in the level of 2-HG correlate with the occurrence of higher-grade transformation (HT) and/or development of hypermutator phenotype (HMP) in patients with IDH-mutant gliomas	5 years
Secondary	Determine the utility of 2-HG detection by 1H-MRS to predict higher-grade transformation (HT) and hypermutator phenotype (HMP) by correlating the 2-HG level with pathological diagnosis and tumor mutational load of the tumor tissue at time of rec...	Usefulness of 2-HG detection and its correlation with high grade transformation and HMP	at clinical disease recurrence

External Links

•   NIH Clinical Center Detailed Web Page