VorAsidenib With Lomustine In Patients With rEcurrent IDH-mutaNT Glioma Harboring IDH1 and/or IDH2 Mutations

Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible for enrollment: 1. Age ≥18 years. 2. Karnofsky performance status score of ≥ 60%. 3. Be able to understand and willing to sign informed consent or assent as determined by local requirements. 4. Be willing to comply with scheduled visits, treatment plans, and laboratory tests, including serial peripheral blood sampling and during the study. 5. Must have recurrent IDH-mutant oligodendroglioma or astrocytoma grade 2-4 harboring IDH1 and/or IDH2 mutation per WHO 2021 criteria (Louis et al, 2021). 6. Must have IDH1 (IDH1 R132H/C/G/S/L mutation variants tested) and/or IDH2 (IDH2 R172K/M/W/S/G mutation variants tested) mutation(s) as determined by standard of care local testing. 7. Must have available 1p/19q and tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) status available from a pathological report as per standard of care local testing. 8. Have presence of measurable disease based on RANO2.0 criteria AND imaging review meeting definition of progression of disease as per RANO2.0 criteria (see Section 10.1.1 for more information). o Note: Contrast enhancing disease will be allowed. 9. Participants must have received appropriate standard of care treatment options (in the opinion of the treating investigator) with at least 1 prior surgery (biopsy, subtotal resection, gross-total resection) and 1 prior treatment (radiation, chemotherapy). o Note: Prior exposure to IDH-inhibitors will be allowed. 10. Have expected survival of ≥3 months. 11. Sexually active fertile subjects and their partners must agree to use a highly effective method of contraception prior to study entry, during the course of the study, and for 90 days after the last dose of vorasidenib or 3.5 months after the last dose of lomustine, (whichever is later). Females of reproductive potential should be advised to use effective non-hormonal contraception during treatment with vorasidenib, since vorasidenib can redner some hormonal contraceptives ineffective. An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods. 12. Female subjects of childbearing potential (FOCBP) must not be pregnant or breastfeeding at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: o Permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff. 13. Must have normal organ and marrow function as defined below: * Hemoglobin ≥ 9.0 g/dL * Absolute neutrophil count ≥ 1,500/mcL * Platelet count ≥ 100,000/mcL * Serum total bilirubin ≤1.5 × upper limit of reference range (ULN); if \>1.5 × ULN and due to Gilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN * Aspartate aminotransferase (AST) at or below ULN * Alanine aminotransferase (ALT) at or below ULN * Alkaline phosphatase (ALP) ≤2.5 X institutional ULN * Serum creatinine ≤ 2.0 × ULN, OR Creatinine clearance \> 40 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation: (140 - Age) × (Weight in kg) × (0.85 if female) / 72 × Serum Creatinine 14. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better. 15. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within six (6) months are eligible for this trial. 16. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. 17. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Exclusion Criteria: 1. Patients who have not recovered to grade 0 or 1 or pre-treatment baseline from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia. 2. Presence of extracranial metastatic or leptomeningeal disease. 3. Have had any prior anticancer therapy within 28-days of treatment other than surgery (biopsy, sub-total resection, gross- total resection) for treatment of glioma including systemic chemotherapy, radiotherapy, vaccines, small-molecules, IDH inhibitors, investigational agents, laser ablation, etc. 4. Early progression prior to 3 months from completion of radiotherapy. 5. Have features assessed as high-risk by the Investigator, including: * Brainstem involvement either as primary location or by tumor extension * Clinically relevant functional or neurocognitive deficits due to the tumor in the opinion of the Investigator (deficits resulting from surgery are allowed) * Uncontrolled seizures (defined as persistent seizures interfering with activities of daily life AND failed 3 lines of antiepileptic drug regimens including at least 1 combination regimen). 6. Concurrent active malignancy except for: * Curatively resected non-melanoma skin cancer * Curatively treated carcinoma in situ. * Note: Subjects with previously treated malignancies are eligible provided they have been disease-free for 3 years at Screening. 7. Are pregnant or breastfeeding. 8. Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous. 9. Have a known hypersensitivity to any of the components of vorasidenib or lomustine. 10. Have a heart-rate corrected QT interval using Fridericia's formula (QTcF) ≥450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome). o Note: Subjects with bundle branch block and prolonged QTcF are permitted with approval of the principal investigator. 11. Are taking therapeutic doses of steroids at a dexamethasone equivalent of \> 4mg/day for signs/symptoms of glioma. o Note: Subjects taking physiologic doses (defined as equivalent of ≤10 mg prednisone daily) for medical conditions not related to glioma will be permitted. 12. Are taking any medications that are cytochrome CYP2C19, or CYP3A substrates with a narrow therapeutic index or strong inhibitors of CYP1A2. (Subjects should be transferred to other medications before receiving the first dose of study drug.) 13. Are unable to swallow pills or have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other condition that limits the ingestion or gastrointestinal absorption of drugs administered orally. o Note: Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential). 14. Previous treatment with bevacizumab for the treatment of glioma with therapeutic intent, or with bevacizumab as supportive therapy (e.g., edema reduction) within six (6) weeks (42 days) of initiation of study treatment. 15. Have any other acute or chronic medical or psychiatric condition, including recent (within 12 months of C1D1) or active suicidal ideation or behavior, or a laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.