Patient case: 50-year-old male with glioblastoma; genetic feature: IDH1 (R132H)

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

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.
  ...

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%
  -  Tumor tissue from any surgery prior to the study enrollment for genomic analysis.
  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.

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 tumor tissue available (block or 15 unstained slides) for analysis.
  -  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.

Relevance to patient case: not relevant