Inclusion Criteria:
* Age ≥18 years
* Histopathologically confirmed IDH-wildtype glioblastoma, WHO Grade 4, and variants including gliosarcoma as per WHO 2021 criteria (38).
* Prior treatment with radiotherapy with or without chemotherapy.
* Recurrent or progressive disease with no more than 2 prior relapses.
* Confirmed measurable disease per RANO 2.0 for GBM.
* Tumor is documented as IDH1/2 wildtype by direct DNA sequencing, provided that it is performed in a CLIA/CAP-certified laboratory.
* Availability of archival formalin fixed paraffin-embedded (FFPE) tumor tissue block or 20 unstained FFPE slides (5 μm thick) from any prior surgery for mutation testing and additional sequencing.
* Karnofsky Performance Status of ≥ 60.
* Candidate for surgical resection.
* Tumor tissue extending to cortical gray matter based on MRI.
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
* Women of child-bearing potential (WOCBP), defined as any individual assigned female at birth physiologically capable of becoming pregnant, must use highly effective contraception during study treatment and for 1 month after study discontinuation. Highly effective contraception is defined as either:
* True Abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
* Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
* Male Partner Sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male partner should be the sole partner for that participant.
* A barrier method defined as condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository along with a second contraceptive method as described below:
* Placement of an intrauterine device (IUD) or intrauterine system (IUS)
* Appropriate hormonal contraceptives (including any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent - including oral, subcutaneous, intrauterine
* Male subjects should agree to use a highly effective method of contraception starting with the first dose of study therapy through 3 months after the last dose of therapy. Male subjects must not donate semen for 3 months after the last dose of study treatment.
* Ability to understand and the willingness to sign a written informed consent document. (Providing consents in as many languages as possible is encouraged)
Exclusion Criteria:
* Laboratory values at the Screening Visit:
* ANC count \< 1,500/mm3; growth-factor support within 7 days for filgrastim or other short acting biosimilars or 21 days for pegfilgrastim or other long acting biosimilars to increase the ANC is not allowed.
* Platelets \<100,000/mm3;
* Hemoglobin \< 9 g/dL;
* Total bilirubin \> 2 × the upper limit of normal (ULN) (unless subject has documented history of Gilbert's Syndrome in which case subject may be enrolled if total bilirubin is less than 5 mg/dL, assuming all other criteria are fulfilled);
* Aspartate aminotransferase (AST \[SGOT\]) \> 1.5 x ULN;
* Alanine aminotransferase (ALT \[SGPT\]) \> 1.5 x ULN;
* Serum creatinine \> 1.5 mg/dL or a calculated creatinine clearance \< 60 mL/min; and
* Positive serum β-hCG test in any individual assigned female at birth and is of childbearing potential (defined as ≤ 50 years of age, or \> 50 years of age with a history of amenorrhea for ≤12 months prior to study entry).
* Has presence of diffuse leptomeningeal disease or extracranial disease.
* Prior treatment with troriluzole or riluzole
* From study treatment initiation, treatment with temozolomide less than 23 days, treatment with CCNU or BCNU less than 42 days, treatment with anti-VEGF therapy such as bevacizumab less than 6 months, or treatment with any cancer-directed systemic therapy less than 4 weeks or 5 half-lives, whichever is shorter. No wash-out period is required from tumor treating fields (TTF).
* Use of any investigational agents within 28 days of baseline or 5 half-lives from study initiation, whichever is shorter.
* Radiotherapy within 12 weeks prior to registration unless new enhancement is outside the radiation field (beyond the high-dose region of 80% isodense line) or evidence of viable tumor on histopathologic sampling.
* Presence of a clinically significant allergy, hypersensitivity, or toxicity of prior therapy, with the exception of alopecia or lymphopenia, that has not resolved to ≤ Grade 1 or pre-treatment baseline, as determined by National Cancer Institute CTCAE v 5.0.
* Major surgery within 28 days prior to initiation of study drug.
* Active or clinically unstable bacterial, viral, or fungal infection requiring systemic therapy.
* Any contraindication to MRI examination.
* Requires medications that are known to be strong inhibitors or inducers of CYP1A2 enzymes or anti-glutamergic agents (e.g., perampanel) or hepatotoxic drugs which may increase the risk of hepatotoxicity (e.g., allopurinol, methyldopa, sulfasalazine). A washout of 10 days or 5 half-lives, whichever is shorter, is required prior to study treatment initiation. Oral contraceptives which contain ethinyl estradiol (moderate CYP1A2 inhibitor) are allowed.
* Pregnant or lactating female.
* History of interstitial lung disease.
* Known history of hepatitis B, human immunodeficiency virus (HIV), or active hepatitis C infection requiring treatment with antiviral therapy. NOTE: HIV testing is not required in the absence of clinical suspicion.
* Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of study results and, in the Investigator's opinion, would make the subject inappropriate for entry into this study.
* Difficulty swallowing or malabsorption syndrome; refractory nausea and vomiting, chronic gastrointestinal (GI) disease or previous significant bowel resection with clinically significant sequelae that would preclude adequate absorption of study drug.
Moderate burden on patient
