Vorasidenib as daily maintenance therapy for adults with IDH‑mutant grade 2–3 astrocytoma

Inclusion Criteria:

* Before participant's enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations.
* Age ≥ 18 years
* Integrated diagnosis of astrocytoma, IDH-mutant, WHO CNS5 grade 2 or 3, per local assessment
* Documented IDH1 or IDH2 mutation based on local testing of tumour tissue
* At least 1 prior surgery for glioma (biopsy, partial resection, gross-total resection)
* Completed first-line standard of care radiotherapy (minimum 50.4 Gy, photons or protons allowed) followed by SoC adjuvant chemotherapy (i.e., either 4-12 cycles of temozolomide or 2-6 cycles of PCV).
* Adequate bone marrow function: absolute neutrophil counts ≥ 1.5 x 109/L, haemoglobin ≥ 9 g/dL, platelets 100 x 109/ L.
* Adequate renal function: serum creatinine ≤ 2.0 x ULN, or creatine clearance \> 40 mL/min, as calculated based on CKD-EPI 2021 formula.
* Adequate hepatic function:

  * Total bilirubin ≤ 1.5 × ULN (except for patients with Gilbert's syndrome who are excluded if total bilirubin \> 3.0 × ULN or direct bilirubin ≥1.5 × ULN)
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 x ULN.
  * Alkaline phosphatase (ALP) ≤ 2.5 x ULN.
* Recovered from any clinically relevant toxicity of the previous chemoradiotherapy cycle unless stable and manageable per investigator´s judgement
* WHO performance status 0-2
* Stable or decreasing corticosteroid dose, or no use of corticoids, for at least 7 days prior to enrollment.
* Baseline brain MRI available, as defined in the schedule of assessments
* Available FFPE tumour tissue from prior neurosurgery for central biobanking and translational research
* Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within two weeks prior to enrolment.
* Participants of childbearing / reproductive potential should use two adequate methods of birth control, including a highly effective method and a barrier method during the study treatment period and for at least 90 days after the last dose of treatment.

Exclusion Criteria:

* Presence of 1p19q co-deletion, per local assessment.
* Tumour recurrence or progression per RANO 2.0 criteria between first day of radiotherapy and enrolment, per local assessment
* Last chemotherapy dose of first line chemoradiotherapy less than 6 weeks or more than 12 weeks before enrolment
* Prior therapy with an IDH inhibitor or IDH vaccine
* Any prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
* Integrated diagnosis of astrocytoma, IDH-mutated, CNS5 WHO grade 4
* Pregnancy or breastfeeding
* Significant known active cardiac disease within 6 months before enrollment, including New York Heart Association Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.
* Known hypersensitivity to any of the components of vorasidenib.
* Ongoing use of medications that are CYP2C8, CYP2C9, CYP2C19, or CYP3A substrates with a narrow therapeutic index. Participants must be transferred to other medications before receiving the first dose of study drug.
* Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, known positive human immunodeficiency virus antibody results, or AIDS-related illness.

Participants with a sustained viral response to HCV treatment or immunity to prior HBV infection will be permitted. Participants with chronic HBV that is adequately suppressed by institutional practice will be permitted.

• Known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other condition that limits the gastrointestinal absorption of drugs administered orally.

Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential).

* Inability or known contraindication to undergo contrast media MRI.
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed and discussed with the patient before the enrolment in the trial.