Inclusion Criteria:
1. Ability of patient to understand character and individual consequences of the clinical trial
2. Written informed consent
3. Age ≥ 18 years
4. Patients present with unequivocal first, second or third recurrence of a histologically and molecularly confirmed IDH1R132H-mutated astrocytoma WHO grade 2, 3 and 4 recurrent and/or progressive after radiotherapy and chemotherapy
5. Availability of pre-study MRI (not older than 3 months) of latest tumor recurrence
6. Availability of tumor tissue from the most recent glioma-directed surgical intervention (FFPE bulk or cryo tissue)
7. Patients have received radiotherapy and alkylating chemotherapy
8. Patients are at least six months off radiotherapy and at least 4 weeks off chemotherapy prior to screening MRI prior to baseline
9. Patients must be candidates for complete or partial on-trial resection and the on- trial resection must be postponable for six weeks
10. Patients should be immunocompetent (i.e. no concomitant treatment with dexamethasone (or equivalent), or receive stable/decreasing steroid levels not exceeding 2 mg/day dexamethasone (or equivalent) during the last 3 days prior to baseline)
11. Karnofsky Performance Status ≥ 70
12. Adequate bone marrow function:
1. absolute neutrophil counts (ANC) ≥ 1.5 x 109/L,
2. hemoglobin ≥ 9 g/dL,
3. platelets ≥ 100 x 109/L
13. Adequate renal function: serum creatinine ≤ 2.0 x ULN, or creatine clearance \> 30 mL/min
14. Adequate hepatic function:
1. 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)
2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at or below ULN.
3. Alkaline phosphatase (ALP) ≤ 2.5 x ULN.
15. Postmenopausal or evidence of non-childbearing status. For women of childbearing potential negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at baseline as well as highly effective forms of contraception have to be in place thereafter.
16. Female patients of childbearing potential and male patients with partners of childbearing potential who are sexually active must agree to the use of two forms of contraception in combination (male condom and one highly effective method). These should be started immediately after signing the informed consent form and continued throughout the period of study treatment plus 6 months after EOT.
Exclusion Criteria:
1. Presence of 1p19q co-deletion (Per local assessment, q)
2. Patient is unable to swallow oral medication
3. Patient is unlikely to cooperate in the study
4. Known hypersensitivity to any of the components of vorasidenib
5. Known hypersensitivity to any of the components of the IDH1 vaccine (IDH1-vac)
6. Ongoing use of medications that are CYP2C8, CYP2C9, CYP2C19, or CYP3A substrates with a narrow therapeutic index.
7. Relevant lactose intolerance
8. Any prior treatment with vorasidenib or any other IDH inhibitor
9. Any prior treatment with IDH1-vac
10. Pregnancy and lactation
11. Current participation in another interventional study or participation in other clinical trials or their observation period during the last 30 days before the first administration of the IMP(s).participation in non-interventional registries or epidemiological studies is allowed
12. Have received prior systemic anticancer therapy (other than surgery) within 4 weeks (or 6 weeks for nitrosoureas) of the start of study treatment. In addition, the first dose of study treatment should not occur before a period of 28 days or ≥5 half-lives of any prior investigational agent have elapsed, whichever is longer
13. Any use of immunosuppressive medication until 4 weeks prior to baseline, except for the following:
1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
2. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
14. Patients with history or presence of HIV and/or HBV/HCV positivity (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
15. Active infection requiring systemic therapy.
16. Patients who have received a live, attenuated vaccine within 4 weeks prior to the first administration of the study drug(s)
17. Clinically significant (i.e., active) cardiovascular disease: Cerebral vascular accident/stroke (\< 6 months prior to baseline), myocardial infarction (\< 6 months prior to baseline), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
18. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
19. Have a heart-rate corrected QT interval using the formula of Bazett or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome). Subjects with bundle branch block and prolonged QTcF are permitted with approval of the Medical Monitor.
20. 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), or 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).
21. Concurrent active malignancy except for a) curatively resected nonmelanoma skin cancer or b) curatively treated carcinoma in situ. Subjects with previously treated malignancies are eligible provided they have been disease-free for 3 years at Baseline
22. Have LVEF \<40% by echocardiogram (ECHO) (or by other methods according to institutional practice) obtained within 28 days before the start of study treatment.
