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

• ClinicalTrials.gov Identifier: NCT03952598
• Recruitment Status: Recruiting
• First Posted: May 16, 2019
• Last Update Posted: May 10, 2024
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Glioma; Gliomas; High Grade Glioma; Malignant Glioma; Low Grade Glioma	Device: 3T MRI scanner	Not Applicable

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 270 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Studying the Biology of IDH-mutant Gliomas Via Longitudinal Observation of 2-Hydroxyglutarate (2-HG) Using MR Spectroscopy
• Actual Study Start Date: October 16, 2019
• Estimated Primary Completion Date: December 31, 2025
• Estimated Study Completion Date: December 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1/Arm 1; Monitoring of quantitative levels of 2-hydroxyglutarate (2-HG) via proton magnetic resonance spectroscopy (1H-MRS)	Device: 3T MRI scanner; Research proton MRS (1H-MRS)followed by DW-MRI

Outcome Measures

Primary Outcome Measures :

1. To monitor the quantitative levels of 2-hydroxyglutarate (2-HG) longitudinally in patients with IDH mutant gliomas via proton magnetic resonance spectroscopy (1H-MRS) [ Time Frame: 5 years ]
   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

Secondary Outcome Measures :

1. 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... [ Time Frame: at clinical disease recurrence ]
   Usefulness of 2-HG detection and its correlation with high grade transformation and HMP

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• 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.

Contacts and Locations

Contacts

Contact: NCI NOB Referral Group; (866) 251-9686; ncinobreferrals@mail.nih.gov

Contact: Jing Wu, M.D.; (240) 760-6036; jing.wu3@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office 888-624-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jing Wu, M.D.; National Cancer Institute (NCI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03952598
• Other Study ID Numbers: 190096; 19-C-0096
• First Posted: May 16, 2019
• Last Update Posted: May 10, 2024
• Last Verified: March 15, 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: .BTRIS: All IPD recorded in the medical record will be shared with intramural investigators upon@@@@@@request.@@@@@@dbGaP: All large scale genomic sequencing data will be shared with subscribers to dbGaP.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: BTRIS: Clinical data available during the study and indefinitely.@@@@@@dbGaP: Genomic data are available once genomic data are uploaded per protocol GDS plan for@@@@@@as long as database is active.
• Access Criteria: BTRIS: Clinical data will be made available via subscription to BTRIS and with the permission of@@@@@@the study PI.@@@@@@dbGaP: Genomic data are made available via dbGaP through requests to the data custodians.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):

Imaging; Higher-Grade Transformation; Biomarker for Cancer; High Grade Gliomas

Additional relevant MeSH terms:

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue