Vorasidenib Guided by AGX PET in Recurrent/Low-grade Glioma

The goal of this prospective, single-arm, open-label clinical trial is to evaluate whether 18F-AGX PET imaging can be used to assess early treatment response and metabolic changes in adult patients with recurrent or residual WHO 2021 grade 2-3 IDH-mutant diffuse glioma receiving Vorasidenib therapy. IDH-mutant diffuse gliomas often show slow tumor growth, making early treatment response difficult to evaluate using conventional structural imaging such as magnetic resonance imaging (MRI). Clinical endpoints such as progression-free survival (PFS) and overall survival (OS) typically require long follow-up periods to detect treatment effects. Therefore, the development of sensitive and noninvasive imaging methods for early evaluation of therapeutic response is needed. This study aims to determine whether metabolic changes detected by 18F-AGX PET during Vorasidenib treatment are associated with tumor structural changes and clinical outcomes. The main questions it aims to answer are: * Whether early changes in tumor metabolic activity measured by 18F-AGX PET, including percentage change in maximum tumor-to-background ratio (TBRmax), are associated with changes in tumor growth rate (TGR) measured by MRI during treatment. * Whether early metabolic response detected by 18F-AGX PET imaging after initiation of Vorasidenib treatment can predict subsequent disease progression or tumor growth dynamics. Participants enrolled in this study will receive oral Vorasidenib once daily for 12 treatment cycles (28 days per cycle), with dosing based on body weight. Participants will: * Undergo baseline MRI and 18F-AGX PET imaging following surgery for recurrent or residual disease. * Receive oral Vorasidenib continuously for 12 cycles. * Undergo MRI scans at baseline and during treatment cycles 1, 2, 3, 6, 9, and 12 to assess structural tumor changes. * Undergo 18F-AGX PET/CT scans at baseline and during treatment cycles 1, 2, 3, 6, and 12 to assess metabolic tumor activity. * Provide serial blood samples for laboratory safety monitoring, including hematologic and biochemical testing. * Undergo magnetic resonance spectroscopy (MRS) to quantify intratumoral 2-hydroxyglutarate (2-HG) levels as an indicator of IDH mutation-associated metabolic activity. Participants will be followed for imaging-based disease progression using RANO criteria and for treatment-related adverse events during the study period. This study will evaluate the feasibility of using 18F-AGX PET imaging as a noninvasive imaging biomarker for early response assessment in IDH-mutant diffuse glioma patients receiving targeted IDH inhibition therapy with Vorasidenib.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. Histologically or molecularly confirmed WHO 2021 grade 2 or 3 IDH1/2-mutant diffuse glioma with recurrent or residual disease
2. At least one measurable non-enhancing lesion (≥1 cm × ≥1 cm) on postoperative T2/FLAIR MRI
3. Eligible for Vorasidenib treatment
4. Age ≥18 years
5. Karnofsky Performance Status (KPS) score ≥80
6. Adequate hematologic function
7. Adequate renal function
8. Adequate hepatic function
9. Ability to provide written informed consent

Exclusion Criteria:

1. Prior treatment with radiotherapy, chemotherapy, or IDH inhibitors
2. Known contraindications to Vorasidenib
3. Contraindications to PET/CT imaging
4. Uncontrolled hyperglycemia
5. Pregnancy or breastfeeding
6. Inability to undergo repeated intravenous injections
7. Known hypersensitivity to imaging agents or study-related medications
8. Use of strong CYP1A2 inhibitors or CYP2C19 or CYP3A substrates with narrow therapeutic index
9. Any serious comorbid condition that may interfere with study participation or safety

• BACKGROUNDGalldiks N, Werner JM, Stetter I, Puhr HC, Nakuz TS, Stoffels G, Albert NL, Langen KJ, Lohmann P, Preusser M. Evaluation of early metabolic changes following vorasidenib using FET PET in patients with IDH-mutant gliomas. Neurooncol Adv. 2024 Nov 29;6(1):vdae210. doi: 10.1093/noajnl/vdae210. eCollection 2024 Jan-Dec. PMID 39737092
• BACKGROUNDCloughesy TF, van den Bent MJ, Touat M, Blumenthal DT, Peters KB, Ellingson BM, Clarke JL, Mendez J, Yust-Katz S, Welsh L, Mason WP, Ducray F, Umemura Y, Nabors B, Holdhoff M, Hottinger AF, Arakawa Y, Sepulveda JM, Wick W, Soffietti R, Perry J, Giglio P, de la Fuente M, Maher E, Bottomley A, Tron AE, Yi D, Zhao D, Pandya SS, Steelman L, Hassan I, Wen PY, Mellinghoff IK; INDIGO trial investigators. Vorasidenib in IDH1-mutant or IDH2-mutant low-grade glioma (INDIGO): secondary and exploratory endpoints from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2025 Dec;26(12):1665-1675. doi: 10.1016/S1470-2045(25)00472-3. Epub 2025 Oct 29. PMID 41175888