This is a three parallel cohort, open-labeled, non-randomized, multicenter study. All three cohorts will enroll independently.

Group A will be composed of newly-diagnosed, elderly patients with Isocitrate dehydrogenase 1 (IDH1) gene non mutant (IDH1R132H) and O-6-methylguanine-DNA methyltransferase (MGMT) promoter-unmethylated anaplastic astrocytoma or glioblastoma who will receive TG02 and radiotherapy (RT).

Group B will be composed of newly-diagnosed, elderly patients with IDH1R132H-non mutant and MGMT promoter-methylated anaplastic astrocytoma or glioblastoma who will receive TG02 and temozolomide.

For both Groups A and B, there will be a classical 3+3 dose escalation and an expansion phase in the study. Up to a total of 24 evaluable patients in Group A and up to a total of 12 evaluable patients in Group B (up to 36 evaluable patients for Groups A and B).

Group C patients will be composed of patients initially diagnosed with IDH1R132H-non-mutant anaplastic astrocytoma or glioblastoma at first relapse post TMZ/RT-->TMZ therapy who will receive TG02.

Specifics for groups A and B

• Newly diagnosed glioblastoma or anaplastic astrocytoma, IDH1R132H-non-mutant by immunohistochemistry locally assessed, with formalin-fixed, paraffin-embedded (FFPE) tissue available for central MGMT testing and optional biomarker studies (treatment allocation will be performed based on centrally assessed MGMT result)
• Tumor debulking surgery, including partial resection
• Age > 65 and considered non-eligible for combination therapy (TMZ/RT→TMZ) in Investigator's opinion
• No prior RT with overlap of radiation fields with the planned RT in this study (Group A)
• No prior therapy for glioblastoma or anaplastic astrocytoma before surgery
• Brain MRI within 14 days before the first dose of TG02

Specifics for group C

• IDH1R132H-non-mutant glioblastoma or anaplastic astrocytoma at first relapse with tissue available from first surgery. [Per 2016 World Health Organization (WHO) classification, in patients older than 55 years of age at diagnosis with a histological diagnosis of glioblastoma, without a pre-existing lower grade glioma and with non-midline tumor location, immunohistochemical negativity for IDH1R132H suffices for classification as glioblastoma. In all other instances of diffuse gliomas, lack of IDH1R132H immunopositivity should be followed by IDH1 and isocitrate dehydrogenase 2 (IDH2) sequencing to detect or exclude other less common IDH mutations.]
• Brain MRI at the time of progression or 14 days before the first dose of TG02 and availability of last brain MRI before progression diagnosis for upload to the EORTC Imaging Platform for post-hoc central review of progression
• Diagnosis of recurrence more than 3 months after the end of RT for initial treatment
• Intention to be treated with standard TMZ/RT→TMZ for initial treatment (at least one dose of TMZ administered; RT alone or chemotherapy alone as initial treatment are not permitted)
• No discontinuation of TMZ for toxicity during first-line treatment
• No RT or stereotactic radiosurgery is allowed for the treatment of first recurrence prior to enrollment in this study
• Patient may have been operated for recurrence. If operated:
• surgery completed at least 2 weeks before initiation of TG02 and patients should have fully recovered as assessed by investigator. Criteria for full recovery include absence of active post-operative infection, recovery from medical complications (CTCAE grade 0 and 1 acceptable), and capacity for adequate fluid and food intake
• residual and measurable disease after surgery is not required but surgery must have confirmed the recurrence
• a post-surgery MRI should be available within 72 hours; the post-surgery MRI can be used as baseline if performed within 2 weeks prior to registration. If not, a baseline MRI has to be done within 2 weeks prior to registration
• For non-operated patients: recurrent disease must be at least one bi-dimensionally measurable contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal diameters of 10 mm, visible on 2 or more axial slices 5 mm apart, based on a MRI scan done within 2 weeks prior to registration
• Age ≥ 18 years

All groups

• Karnofsky Performance Score (KPS) of 60-100
• Recovered from effects of debulking surgery, postoperative infection and other complications of surgery (if any) (CTCAE grade 0 and 1 acceptable)
• Adequate bone marrow, renal and hepatic function within the following ranges within 7 days before the first dose of TG02:
• white blood cell (WBC) ≥ 3 x109/L
• absolute neutrophil count (ANC) ≥ 1.5x109/L
• Platelet count of ≥ 100 x109/L independent of transfusion
• Hemoglobin ≥ 10 g/dl or ≥ 6.2 mmol/L
• Bilirubin ≤ 1.5 × upper limit of normal (ULN)
• Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN
• Cockcroft-Gault calculated or measured creatinine clearance of ≥ 30 mL/min
• No use of enzyme-inducing anti-epileptic drugs (EI-AED) within 7 days prior to the first dose of TG02
• Life expectancy > 8 weeks
• No history of ventricular arrhythmia or symptomatic conduction abnormality in past 12 months prior to registration
• No congestive heart failure (New York Heart Association Class III to IV, see Appendix C), symptomatic ischemia, uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to enrollment
• No 12-lead ECG with a prolonged corrected QT interval (QTc) interval (males: > 450 ms; females: > 470 ms) as calculated by the Fridericia correction formula despite balancing of electrolytes at registration and/or discontinuing any drugs (for a time period corresponding to 5 half-lives) known to prolong QTc interval
• No known contraindication to imaging tracer or any product of contrast media
• No MRI contraindications
• No concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, hypertension, coronary artery disease) that, in the opinion of the Investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study
• No known human immunodeficiency virus infection or acquired immune deficiency syndrome
• No previous other malignancies, except for any previous malignancy which was treated with curative intent more than 3 years prior to enrollment, or adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix
• No pregnant women. Negative serum or urine pregnancy test within 72 hours prior to the first dose for women of childbearing potential (WOCBP). Nursing must be discontinued at least 1 hour before first dose.
• For men of reproductive potential and WOCBP, adequate contraception must be used throughout the study and for 6 months thereafter. For this study, acceptable methods of contraception include a reliable intrauterine device or a spermicide in combination with a barrier method. Hormonal forms of birth control (oral, implantable, or injectable) may only be used if combined with another highly effective form of birth control such as a spermicide combined with a barrier method
• Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments
• Ability to take oral medication
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Before patient registration, written informed consent must be given according to International Conference on Harmonization ICH) / Good Clinical Practice (GCP), and national/local regulations.