Key Eligibility Criteria (Pre-Operative Screening)
Inclusion Criteria:
1. Adult patient who is aged 18-≤55 years of age
2. Has MRI features consistent with a high-grade glioma
3. Is planned for standard of care biopsy or surgery to investigate and/or treat this lesion
4. ECOG 0-1
5. Provides informed written consent
Exclusion Criteria:
1. Prior radiation or systemic treatment for glioblastoma
2. Multi-focal disease not likely to be encompassed within a standard radiotherapy field, infratentorial disease or leptomeningeal disease
3. Evidence of significant acute intracranial or intra-tumoural haemorrhage either by magnetic resonance imaging (MRI) or computerized tomography (CT) scan.
4. Serious intercurrent illness, as determined by the treating physician, that would compromise either patient safety or study outcomes.
Key Eligibility Criteria (Post-Operative Screening)
Inclusion Criteria:
1. Aged 18 to ≤55-years of age
2. Newly diagnosed patient with IDH-wildtype glioblastoma as per WHO 2021, or morphological features consistent with glioblastoma but pending confirmatory NGS or other profiling
3. ECOG 0-1
4. Consents to, and has sufficient tissue, for:
5. IHC for BRAF V600E, pan-TRK and MMR proteins
6. Further confirmatory NGS for NTRK fusions if pan-TRK IHC is positive
7. Life expectancy of at least 12 weeks
Exclusion Criteria:
1. Diagnostic biopsy/craniotomy more than 2-weeks prior to study screening such that insufficient time for molecular profiling
2. Prior radiation or systemic treatment for glioblastoma
3. Placement of Gliadel wafers or receipt of any other local investigational therapy at the time of surgery
4. Multi-focal disease not encompassed within a standard radiotherapy field, infratentorial disease or leptomeningeal disease
5. Evidence of significant acute intracranial or intra-tumoural haemorrhage either by magnetic resonance imaging (MRI) or computerized tomography (CT) scan
6. Serious intercurrent illness, as determined by the treating physician, that would compromise either patient safety or study outcomes
Key Eligibility Criteria (for patients being offered trial treatment)
Inclusion Criteria:
1. Newly diagnosed patients with IDH-wildtype glioblastoma as per WHO 2021
2. Able to provide written informed consent
3. Aged 18 to ≤55-years of age
4. ECOG 0-1
5. Adequate organ function as defined by
1. Hepatic: total bilirubin ≤2.0 × upper limit of normal (ULN); alanine transaminase (ALT) and aspartate transaminase (AST) ≤1.5 × ULN
2. Renal: estimated glomerular filtration rate (GFR) ≥60 mL/min
3. Bone marrow: platelets ≥100 × 109/L, absolute neutrophil count (ANC) ≥1.5 × 109/L, haemoglobin ≥9 g/dL
6. If the patient is a male or female with reproductive potential, the patient is willing to use an approved contraceptive method (e.g., intrauterine device \[IUD\], birth control pills, or barrier device) during and for three months after discontinuation of study drug
7. If the patient is a woman of childbearing potential, she has a negative serum pregnancy test within seven days prior to study enrollment
8. Life expectancy of at least 12 weeks
9. Patient is on stable or reducing dose of steroid within the first week of study enrolment, not exceeding a dose of dexamethasone 2 mg or equivalent
Exclusion Criteria:
1. Prior radiation or systemic anti-cancer treatment for glioblastoma or any glioma, including a history of lower grade glioma
2. Placement of Gliadel wafers or receipt of any other local investigational therapy at the time of surgery
3. Multi-focal disease not encompassed within a standard radiotherapy field, infratentorial disease or leptomeningeal disease
4. Evidence of significant acute intracranial or intra-tumoral haemorrhage either by magnetic resonance imaging (MRI) or computerized tomography (CT) scan as per clinician discretion. (Note: Patients with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin are not excluded).
5. Pregnant or breastfeeding at time of screening
6. Any significant concomitant disorder, including active bacterial, fungal, or viral infection, incompatible with participation in the study
7. History of another malignancy, except adequately treated non melanoma skin cancer or carcinoma in-situ of the cervix. Patients with prior malignancy are excluded unless they have been disease free for ≥ 2 years
8. Known history of HIV, hepatitis B or hepatitis C
9. Clinically significant gastrointestinal disorder that is expected to compromise absorption of oral medication, as determined by the treating physician for those receiving toral therapy
10. Any serious intercurrent illness, as determined by the treating physician, that would compromise either patient safety or study outcomes
11. Psychiatric illness or a social situation that would limit compliance with the study procedures requirements
12. QTc interval \> 470 milliseconds on screening ECG
