Phase 3 Randomized Double-Blind Placebo-Controlled Trial of Vorasidenib in Residual or Recurrent Grade 2 Glioma with IDH1/IDH2 Mutation

The primary objective of this study is to demonstrate the efficacy of **vorasidenib** based on radiographic progression-free survival (PFS) as assessed by the Blinded Independent Review Committee (BIRC) compared with placebo. This is evaluated in subjects with residual or recurrent Grade 2 oligodendroglioma and astrocytoma harboring an IDH1 or IDH2 mutation, who have undergone surgery as their sole treatment. The clinical relevance of this objective lies in its potential to provide a new therapeutic option for managing these specific gliomas, potentially improving patient outcomes by delaying disease progression.

Secondary objectives include:

• Demonstrating the efficacy of vorasidenib based on time to next intervention (TTNI) compared with placebo.
• Evaluating the safety and tolerability of vorasidenib.
• Assessing vorasidenib and placebo with respect to tumor growth rate (TGR) as determined by volume per BIRC.
• Evaluating efficacy based on objective response, complete response (CR) plus partial response (PR), time to response (TTR), time to CR+PR, duration of response (DoR), and duration of CR+PR, with response assessed per BIRC and the Investigator.
• Evaluating overall survival (OS) with vorasidenib and placebo.
• Assessing health-related quality of life (HRQoL) using the Functional Assessment of Cancer Therapy – Brain (FACT-Br) questionnaire.
• Evaluating progression-free survival (PFS) per Investigator assessment.
• Assessing the pharmacokinetics (PK) of vorasidenib and its circulating metabolite AGI-69460 in plasma.

The clinical trial involves a total of **269 participants** diagnosed with **residual or recurrent Grade 2 glioma** with an IDH1 or IDH2 mutation. The study population includes both male and female subjects, with an age range starting from 12 years and no upper age limit specified. Participants are required to have undergone at least one prior surgery for glioma, with the most recent surgery occurring between one and five years before randomization. The trial includes individuals who have not received any prior anticancer therapy, such as chemotherapy or radiotherapy, and who do not require immediate such treatments. Participants must have a confirmed IDH1 or IDH2 gene mutation and MRI-evaluable, measurable, non-enhancing disease. The trial population was selected based on these criteria, ensuring a focus on individuals with specific genetic mutations and surgical history. The study does not specify any particular lifestyle considerations such as diet or physical activity. Both vulnerable populations and individuals with a Karnofsky Performance Status (KPS) score of at least 80% are included, ensuring a diverse and representative sample of the affected population.

The clinical trial is a **Phase 3**, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of **vorasidenib** in subjects with residual or recurrent Grade 2 glioma with an IDH1 or IDH2 mutation. The trial aims to demonstrate the efficacy of vorasidenib based on radiographic progression-free survival (PFS) as assessed by the Blinded Independent Review Committee (BIRC) compared to placebo. The study involves the administration of vorasidenib in the form of film-coated tablets, with a maximum daily dose of 40 mg, over a treatment period of up to 96 weeks. The trial is expected to conclude by May 2028, with recruitment having commenced in February 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, prior surgery, and confirmed IDH1 or IDH2 mutation status. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy endpoints, including adverse events, serious adverse events, and laboratory parameters. The primary endpoint is radiographic PFS, while secondary endpoints include time to next intervention (TTNI), overall survival (OS), and various safety assessments. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement is up to 96 weeks, with conditions for early termination including significant adverse events or disease progression as determined by the investigator. Participants will be monitored for safety through vital signs, electrocardiograms (ECGs), and other clinical assessments. The trial will also involve pharmacokinetic (PK) sampling to determine plasma concentration-time profiles of vorasidenib and its metabolite AGI-69460. The study is conducted under strict adherence to ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **vorasidenib**, an experimental medication, in the form of a **film-coated tablet**. Vorasidenib is chemically synthesized and is identified by the product code S95032/AG-881. The trial utilizes two dosage forms of vorasidenib: 40 mg and 10 mg tablets. The medication is administered orally, with a maximum daily dose of 40 mg. The treatment period extends up to 96 weeks. Vorasidenib is designed to target residual or recurrent Grade 2 glioma with an IDH1 or IDH2 mutation, following surgical intervention as the sole prior treatment. Participant compliance with the dosing regimen is monitored throughout the study.

In addition to the experimental medication, the study employs a **placebo** control. The placebo tablets are designed to match the S95032 drug product in appearance, being white to off-white, round for the 10 mg dose, and oblong for the 40 mg dose. These placebo tablets are also administered orally. The use of a placebo is integral to maintaining the double-blind nature of the study, ensuring unbiased assessment of vorasidenib's efficacy compared to the placebo group.

The efficacy of vorasidenib in the clinical trial will be assessed primarily through **radiographic progression-free survival (PFS)** as evaluated by the Blinded Independent Review Committee (BIRC) using the modified Response Assessment for Neuro-oncology for Low-Grade Gliomas (RANO-LGG) criteria. This primary endpoint aims to demonstrate the efficacy of vorasidenib compared to placebo in subjects with residual or recurrent Grade 2 oligodendroglioma and astrocytoma with an IDH1 or IDH2 mutation.

Secondary efficacy endpoints include time to next intervention (TTNI), tumor growth rate (TGR), objective response, complete response plus partial response (CR+PR), time to response, time to CR+PR, duration of response, duration of CR+PR, overall survival (OS), and Functional Assessment of Cancer Therapy-Brain (FACT-BR) scores. Additionally, PFS will also be assessed by the investigator. These endpoints will provide a comprehensive evaluation of the treatment's impact on disease progression and patient quality of life.

Data collection will involve serial or sparse blood sampling at specified time points to determine plasma concentration-time profiles and pharmacokinetic (PK) parameters of vorasidenib and its circulating metabolite AGI-69460. Safety assessments will include monitoring adverse events, serious adverse events, and adverse events leading to discontinuation or death, as well as evaluating safety laboratory parameters, vital signs, 12-lead electrocardiograms (ECGs), left ventricular ejection fraction (LVEF), and Karnofsky Performance Scale (KPS) or Lansky Play-Performance Scale (LPPS) scores. These assessments will ensure a thorough evaluation of both the efficacy and safety of the treatment throughout the trial duration.