A Phase 0/2 Study of BGB-58067, an MTA Cooperative PRMT5 Inhibitor, in Newly Diagnosed Glioblastoma Patients With Methylthioadenosine Phosphorylase (MTAP) Deleted Tumors Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration With Pharmacodynamic (PD)-Triggered Expansion Cohorts
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.
• 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):
‣ 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.)
⁃ 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.)
⁃ 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
⁃ Adequate Metabolic Function Albumin ≥ 2.8 g/dL
⁃ Adequate Coagulation INR or PT and aPTT ≤ 1.5x ULN
• 6\. For females of childbearing potential:
‣ 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.
⁃ 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.
⁃ Agrees not to breastfeed starting at screening, during study participation, and for 6 months after final study drug administration.
⁃ 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:
‣ Agrees not to donate sperm starting at screening, during study participation, and for 3 months after final study drug administration.
⁃ 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.