This is an open-label, multi-center, Phase 0/2 trial designed to enroll up to 78 total participants with suspected newly diagnosed glioblastoma (nGBM) who are scheduled for surgical resection to accrue at least 14 participants in Arm A and 10 participants in Arm B. The trial will evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of BGB-58067.

The study is composed of a Phase 0 and expansion Phase 2 component. The Phase 0 primary endpoint will be suppression of symmetric dimethylarginine (SDMA) in tumor tissue measured by immunohistochemistry (IHC). The Phase 2 primary endpoint will be 12-month overall survival rate (OS12).

The Phase 0 secondary endpoint will be to characterize the PK of BGB-58067 in tumor tissue, plasma, and cerebrospinal fluid (CSF). The Phase 2 secondary endpoints will include assessing the safety profile of BGB-58067 and evaluating clinical efficacy of BGB 58067 using overall survival (OS) and the 6-month progression-free survival rate (PFS6) estimated by Kaplan-Meier (K-M) methods.

PHASE 0 Participants with nGBM will receive a high dose of BGB-58067 prior to surgical resection. The first 5 participants will receive a smaller dose of BGB-58067 to characterize tumor penetration and PD effects at that dose.

Participants without histologically confirmed diagnosis of GBM after the craniotomy will be replaced.

Methylthioadenosine phosphorylase (MTAP) -deletion will be determined using IHC on gadolinium (Gd) enhancing tumor tissue collected during resection, which may be supported by retrospective analysis of next-generation sequencing results.

Participants with tumors demonstrating PD response will be eligible to enroll into the Phase 2 component. A positive PD response will be defined as a ≥ 50% decrease in SDMA expression relative to baseline biopsy tissue, if available. In the absence of a pretreatment biopsy, an H-score of 70 or below will be deemed as a positive PD response.

Eligible participants will then be allocated into one of two Arms based on methylated-DNA-protein-cysteine methyltransferase (MGMT) status (methylated vs unmethylated). Participants with unmethylated tumors will be enrolled into Arm A and participants with methylated tumors will be enrolled into Arm B.

Participants that do not proceed to the Phase 2 component will receive treatment per treating physician's recommendation. All participants will complete the end of treatment visit, safety follow-up, and survival monitoring.

PHASE 2 ARM A Participants with unmethylated-MGMT and MTAP-deleted GBM demonstrating a positive PD response will continue BGB-58067 treatment concurrently with standard of care upfront radiotherapy (RT).

Following completion of RT, participants will receive adjuvant monotherapy with BGB-58067 administered continuously. Study visits, safety assessments, and cycle numbering during adjuvant therapy will follow a fixed days cycle calendar. Participants will receive BGB-58067 until disease progression, unacceptable toxicity or death, withdrawal of consent, loss to follow up, or study termination by the sponsor.

ARM B Participants with methylated-MGMT and MTAP-deleted GBM demonstrating a positive PD response will continue BGB-58067 treatment concurrently with standard of care upfront RT and temozolomide (TMZ).

Following completion of RT, participants will continue BGB-58067 dosing. If a transition period occurs between completion of concurrent therapy and initiation of adjuvant TMZ, BGB-58067 dosing may be continued to maintain uninterrupted exposure.

Adjuvant therapy will then begin with BGB-58067 administered on a continuous dosing schedule combined with TMZ. Study visits, safety assessments, and cycle numbering during adjuvant therapy will follow a fixed days cycle calendar. BGB-58067 will have no planned off-days during TMZ cycles.

Following completion of TMZ therapy, BGB-58067 may be administered at the same dose received during adjuvant TMZ therapy until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow up, or study termination by the sponsor.

ALL PARTICIPANTS. All participants will return to the clinic for safety monitoring following BGB-58067 treatment discontinuation and will be contacted approximately every 3 months for up to 24 months for survival data collection. The start of follow-up for long-term survival will begin after the safety follow-up visit. MRI scans and review in guidance with RANO criteria will occur approximately every 2-3 months, per standard of care, to monitor disease progression.

Longitudinal biomarker analysis through liquid biopsy may be conducted to characterize genomic and/or transcriptomic changes from circulating tumor cells (CTCs) or cell free DNA (cfDNA) isolated from CSF collected during Phase 0 surgery, during Phase 2, or at recurrent craniotomy. At the treating investigator's discretion, an Ommaya reservoir or shunt may be placed during Phase 0 surgery to access CSF from the resection cavity. CSF samples will be collected during Phase 2 only if a participant has the Ommaya reservoir in place.

Additional biomarker analysis may be conducted using surgical tissue. If the participant undergoes repeat craniotomy for recurrence or disease progression, to enable longitudinal sample collection and analysis, IVY will request samples from the resected tumor, CSF, or blood to help identify possible resistance mechanisms.

Inclusion Criteria:

• 1. Suspected newly diagnosed glioblastoma according to 2021 WHO criteria who have not received any tumor directed intervention other than biopsy.

• 2. Has measurable disease (preoperatively), defined as at least one contrast-enhancing lesion with two perpendicular measurements of at least 1 cm.

• 3. Age ≥ 18 at time of consent.

• 4. Has a performance status of ≤ 2 on the ECOG scale.

• 5. Has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility):

  1. Adequate Bone Marrow Function Absolute neutrophil count ≥ 1500/μL (≥ 1.5 x 109/L) Platelets (at time of surgery) ≥ 100,000/μL (≥ 100 x 109/L) Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without erythropoietin dependency and without pRBC transfusion within prior 2 weeks.)
  2. Adequate Hepatic Function Total Bilirubin ≤ 1.5x ULN (Participants with Gilbert's syndrome with a total bilirubin ≤ 3x ULN and direct bilirubin ≤ 1.5x ULN will be permitted.) AST (SGOT) ≤ 2.5x institutional ULN (Participants with liver metastases with ALT < 5x ULN will be permitted) ALT (SGPT) ≤ 2.5x institutional ULN (Participants with liver metastases with ALT < 5x ULN will be permitted.)
  3. Adequate Renal Function eGFR ≥ 60 mL/min/1.73 m2 (Calculated as individualized eGFR using the CKD-EPI formula [2021]) If measured or calculated GFR (e.g., creatinine clearance; mGFR) is required or used: ≥ 60 mL/min
  4. Adequate Metabolic Function Albumin ≥ 2.8 g/dL
  5. Adequate Coagulation INR or PT and aPTT ≤ 1.5x ULN

• 6. For females of childbearing potential:

  1. Must have a confirmed negative serum pregnancy test (β-hCG) before starting study treatment (within 24 hours of first dose of study treatment); in rare cases where hCG is suspected to be elevated in the absence of pregnancy (e.g., due to a tumor producing hCG), an ultrasound must be performed to rule out possible pregnancy.
  2. Must use a highly effective method of contraception (with a failure rate of <1% per year and low user dependency) for at least 28 days prior to treatment, and agree to use such a method during study participation and for an additional 6 months after final study drug administration.
  3. Agrees not to breastfeed starting at screening, during study participation, and for 6 months after final study drug administration.
  4. Agrees not to donate eggs (ova, oocytes) for the purpose of reproduction starting at screening, during study participation, and for 6 months after final study drug administration.

• 7. For females of non-childbearing potential, is no longer of childbearing potential due to surgical, chemical, or natural menopause.

• 8. For males:

  1. Agrees not to donate sperm starting at screening, during study participation, and for 3 months after final study drug administration.
  2. Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agrees to remain abstinent starting at screening, during study participation, and for 3 months after final study drug administration.

OR Must use a male condom and their female partner must use an additional highly effective method of contraception (with a failure rate of <1% per year and low user dependency) starting at screening, during study participation, and for 3 months after final study drug administration.

• 9. Agrees to adhere to protocol defined Lifestyle Considerations throughout study duration.
• 10. Able and willing to comply with scheduled visits, treatment plans, laboratory tests and other procedures.
• 11. Understands the informed consent document and has voluntarily agreed to participate by giving written informed consent (personally or via legally authorized representative(s), and assent if applicable). Written informed consent for the protocol must be obtained prior to any screening procedures. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness.

Exclusion Criteria:

• 1. Unable to undergo MRI of the brain with intravenous (IV) contrast.

• 2. Has a known active systemic bacterial infection (on IV antibiotics or has fever > 38.5°C at time of initiating study treatment) or fungal infection, or has a detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [e.g., hepatitis B surface antigen positive]). NOTE: Screening of viral infection is not required for enrollment.

• 3. Has cardiovascular abnormalities including:

  1. LVEF < 50%
  2. History of prolonged QTc, or QT interval corrected for heart rate using Fridericia's formula (QTcF) prolongation > 480 msec, except for right bundle branch block.
  3. Uncontrolled/symptomatic or significant cardiovascular conditions within 6 months prior to enrollment, including but not limited to any of the following: cardiac angioplasty or stenting, unstable angina pectoris, myocardial infarction, stroke/transient ischemic attack, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, New York Heart Association (NYHA) class III or IV congestive heart failure, pericarditis, atrial fibrillation or other arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes).

• 4. Has symptomatic or radiographic leptomeningeal disease.

• 5. Has other known concurrent severe psychiatric and/or uncontrolled medical condition that, in the investigator's judgment, would cause unacceptable safety risks, contraindicate participation in the clinical study, or compromise compliance with the protocol.

• 6. Has received prior treatment with another investigational drug or other intervention within 5 half lives of the investigational product, whichever is longer.

• 7. Has received prior treatment with another PRMT5 inhibitor.

• 8. Has known allergic reactions to components of BGB-58067.

• 9. Patients who require ongoing treatment with a strong CYP3A or CYP2C8 inhibitor or inducer, ≤ 5 half-lives or ≤ 14 days, whichever is shorter or known. Consider using alternative medications, per Investigator judgment.

• 10. Has received a live/attenuated vaccine within 30 days of anticipated first treatment. The use of inactivated seasonal influenza vaccines (e.g., Fluzone®) will be permitted.

• 11. Is pregnant or breastfeeding.