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

18F-AGX PET for Evaluation of Vorasidenib Response and Tumor Metabolic Changes in Low-grade IDH-Mutant 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Glioma; Diffuse Glioma; Recurrent Gliomas
• Intervention / Treatment: Drug: Oral Vorasidenib administered once daily for up to 12 treatment cycles (28 days per cycle) as IDH-targeted therapy in participants with recurrent or residual IDH-mutant diffuse glioma.

Detailed Description

Diffuse gliomas harboring mutations in isocitrate dehydrogenase (IDH1 or IDH2) represent a biologically distinct subgroup of central nervous system tumors characterized by the accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). Mutant IDH enzymes catalyze the reduction of α-ketoglutarate to 2-HG, leading to widespread epigenetic dysregulation, impaired cellular differentiation, and altered tumor metabolism. These metabolic alterations are considered key drivers of glioma tumorigenesis and progression.

Vorasidenib is an oral, brain-penetrant, dual inhibitor of mutant IDH1 and IDH2 enzymes that has demonstrated clinical activity in patients with IDH-mutant diffuse glioma. By selectively inhibiting mutant IDH enzymatic activity, Vorasidenib reduces intratumoral 2-HG production and is expected to modify tumor metabolic processes. However, due to the relatively slow growth kinetics of IDH-mutant gliomas, conventional structural imaging techniques such as magnetic resonance imaging (MRI) may not detect treatment-related changes in tumor size during the early phases of therapy. As a result, reliance on morphologic imaging alone may delay the identification of therapeutic response or disease progression.

Metabolic imaging approaches have the potential to provide earlier indicators of biological treatment effects. Magnetic resonance spectroscopy (MRS) has been used to quantify intratumoral 2-HG concentrations in vivo as a surrogate of mutant IDH activity. While MRS-based measurements may reflect pharmacodynamic effects of IDH inhibition, its sensitivity and spatial resolution may limit its utility for longitudinal monitoring of treatment response in clinical practice.

Positron emission tomography (PET) imaging using radiolabeled tracers enables the quantitative assessment of tumor metabolism and has been shown to detect treatment-related metabolic changes that precede morphologic alterations observed on MRI. Amino acid PET tracers such as 18F-FET and 18F-FDOPA have demonstrated the ability to identify early metabolic responses in glioma patients undergoing systemic therapy, with metabolic response correlating with clinical outcomes in some studies.

18F-AGX is a novel PET radiotracer designed to selectively bind to IDH-mutant glioma cells. Preclinical studies have demonstrated that 18F-AGX crosses the blood-brain barrier and exhibits increased uptake in IDH-mutant glioma models compared with IDH wild-type tumors. In experimental settings, treatment with Vorasidenib has been associated with reductions in tracer uptake that parallel decreases in intratumoral 2-HG levels, suggesting that 18F-AGX PET imaging may serve as a noninvasive indicator of target engagement and metabolic response.

This clinical study is designed to evaluate the feasibility of using 18F-AGX PET imaging to monitor metabolic changes in patients with recurrent or residual IDH-mutant diffuse glioma receiving Vorasidenib therapy. Longitudinal multimodal imaging will be performed during treatment to assess temporal changes in tumor metabolic activity and structural characteristics.

PET imaging will be conducted following intravenous administration of 18F-AGX. Quantitative image analysis will be performed using tumor-to-background uptake metrics derived from standardized uptake values (SUV). Regions of interest will be defined on PET images with reference to co-registered MRI data to allow for spatial correlation between metabolic and structural tumor features.

MRI will be performed using standardized acquisition protocols to assess tumor morphology, including T2-weighted and FLAIR sequences. MR spectroscopy may be performed to quantify intratumoral 2-HG concentrations as a complementary metabolic biomarker associated with mutant IDH activity.

Serial laboratory testing will be conducted throughout the study to monitor participant safety during Vorasidenib treatment. Adverse events will be assessed according to applicable clinical research standards.

Imaging-based disease status will be evaluated using established neuro-oncology response assessment criteria. Participants may receive additional standard-of-care interventions if clinically indicated during or after completion of the treatment period.

The results of this study are intended to provide preliminary clinical data on the use of 18F-AGX PET imaging as a noninvasive method for detecting early metabolic response in IDH-mutant diffuse glioma patients undergoing targeted IDH inhibition therapy.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zhifeng Shi, MD; Phone Number: +86 21 64280718; Email: shizhifeng@fudan.edu.cn
• Study Contact Backup: Name: Shan Jiang, MD; Phone Number: +86 21 64280718; Email: jsscosmos@gmail.com

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 201100
      • Huashan Hospital
      • Contact: Zhifeng Shi, MD; Phone Number: +86 21 64280718; Email: shizhifeng@fudan.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vorasidenib Treatment with 18F-AGX PET Assessment; Participants receive oral Vorasidenib once daily for up to 12 treatment cycles (28 days per cycle). Serial 18F-AGX PET imaging and MRI assessments are performed during treatment to evaluate metabolic and structural tumor changes associated with IDH-targeted therapy.	Drug: Oral Vorasidenib administered once daily for up to 12 treatment cycles (28 days per cycle) as IDH-targeted therapy in participants with recurrent or residual IDH-mutant diffuse glioma.; Positron emission tomography (PET) imaging performed using the investigational IDH-targeted radiotracer 18F-AGX to assess metabolic tumor activity during Vorasidenib treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Tumor Metabolic Activity Assessed by 18F-AGX PET	Percentage change from baseline in maximum tumor-to-background ratio (TBRmax) measured by 18F-AGX PET imaging during Vorasidenib treatment.	Up to 12 treatment cycles (approximately 12 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Growth Rate Assessed by MRI	Change in tumor growth rate derived from serial volumetric measurements on T2/FLAIR MRI sequences during treatment.	From baseline to the end of Cycle 12 (each cycle is 28 days; approximately 12 months)
Diagnostic Accuracy of 18F-AGX PET for IDH Mutation Detection	Sensitivity, specificity, positive predictive value, and negative predictive value of 18F-AGX PET imaging for detecting IDH mutation status compared with histopathologic diagnosis.	At baseline imaging assessment
Incidence of Treatment-Related Adverse Events	Frequency and severity of treatment-related adverse events during Vorasidenib treatment.	From the first dose of Vorasidenib to the end of Cycle 12 (each cycle is 28 days; approximately 12 months)

Collaborators and Investigators

• Sponsor: Huashan Hospital
• Collaborators: SCU West China Lecheng Hospital
• Investigators: Principal Investigator: Zhifeng Shi, MD, Huashan Hospital

Publications and helpful links

General Publications

• Galldiks 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.
• Cloughesy 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.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: March 5, 2026
• First Submitted That Met QC Criteria: March 9, 2026
• First Posted (Actual): March 13, 2026

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Positron Emission Tomography; Vorasidenib; IDH Mutation; Treatment Response
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: HIM-2025-0674

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: It is currently undecided whether individual participant data (IPD) collected in this study will be made available to other researchers. Any future data sharing will be subject to approval by the institutional review board and in accordance with applicable regulatory requirements governing the use and transfer of human subject research data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No