This is an open-label, multi-center Phase 0/1b study that will enroll up to 18 participants with recurrent WHO grade 4 glioblastoma (rGBM) IDH-wildtype (IDH-WT), Arm A, and 12 participants with presumed newly-diagnosed WHO grade 4 glioblastoma (nGBM) IDH-WT, Arm B. The trial will be composed of a Phase 0 component (subdivided into Arms A and B), and an Expansion Phase 1b. Patients with tumors demonstrating a positive pharmacokinetic (PK) response in the Phase 0 component of the study will graduate to an Expansion Phase that combines therapeutic dosing of quisinostat plus standard-of-care fractionated radiotherapy (RT).

Eligible participants (rGBM in Arm A and nGBM in Arm B) will enroll in the Phase 0 study and receive quisinostat prior to a planned resection. Arm A includes a 3+3 design to determine optimal time interval (OTI) of final dose prior to surgery. Further rGBM participants and nGBM participants will enroll at OTI once established. Blood, tumor, and cerebrospinal fluid (CSF) samples will be collected during surgery, and blood and CSF samples will be collected after surgery, to measure the amount of drug that is present in the samples. Participants with tumors demonstrating PK response will continue with therapeutic dosing of quisinostat treatment on Monday, Wednesday, Friday of 5-day cycles after surgery concurrently with their standard of care (SOC) fractionated RT. Participants will continue to receive quisinostat and SOC RT for their physician-directed duration of RT, (2-3 weeks for rGBM and 5-6 weeks form nGBM).

The Phase 0 Primary Objective is to evaluate concentration of quisinostat in gadolinium-non-enhancing tumor tissue, and the Expansion Phase Primary Objective is to determine the 6-month progression free survival (PFS6) rate in rGBM participants who had positive PK response in Phase 0.

The Phase 0 Secondary Objective is to evaluate concentration of quisinostat in CSF, and the Expansion Phase Secondary Objectives are to monitor safety and tolerability of quisinostat and examine overall survival (OS) in participants.

Inclusion Criteria:

• For Arm A: Participants who have had a prior resection of diagnosed glioblastoma, IDH wildtype (2021 WHO grade 4), defined as participants who have progressed on or following standard therapy, which includes maximal surgical resection, temozolomide, and fractionated radiotherapy. Participants will also need to have radiation planned as part of the post-surgical treatment plan; OR, for Arm B only: Participants undergoing resection for a suspected newly diagnosed WHO Grade 4 glioblastoma, IDH wildtype. Participants will also need to have radiation planned as part of the post-surgical treatment plan.
• Participants must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm.
• Provision of signed and dated, written informed consent (personally or by the legally authorized representative, if applicable) prior to any study specific procedures, sampling and analyses.
• Age ≥18 at time of consent
• Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology Group (ECOG) scale.
• Ability to swallow oral medications.
• Participant has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility):
• Participants with tumor-induced seizures must be well-controlled on a stable anti-epileptic treatment.
• Participants must be willing to receive prophylaxis with levetiracetam for the duration of study drug administration (or alternative anti-epileptic if agreed with Medical Monitor).
• Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or participant who is no longer of childbearing potential due to surgical, chemical, or natural menopause.
• For females of reproductive potential: use of highly effective contraception and agreement to use such a method during study participation until the end of treatment administration and for 16 weeks after the last dose of study drug.
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner until the end of treatment administration and for 16 weeks after the last dose of study drug.
• Agreement to adhere to Lifestyle Considerations throughout study duration.

Exclusion Criteria:

• Pregnancy or lactation.
• Known allergic reactions to components of the quisinostat.
• Known to have active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis, as determined by the investigator.
• Known active systemic bacterial infection (requiring intravenous [IV] antibiotics or fever >38.5°C at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening of viral infection is not required for enrollment.
• The participant has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
• Any of the following cardiac criteria: cardiac dysfunction defined as myocardial infarction within six months of study entry, NYHA Class II/III/IV heart failure, unstable angina or unstable cardiac arrhythmias; mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 electrocardiograms (ECGs) (QTc interval will be calculated using Fridericia's formula); any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, e.g., complete left bundle branch block, third degree heart block; any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age (patients stable on concomitant medications known to prolong the QT interval may be allowed to participate in the study provided that their mean resting corrected QT interval (QTcF) is < 450 msec in males or < 470msec in females at baseline and after discussion with the Principal Investigator); use of medications that may cause Torsades de Pointes.
• History or presence of myopathy or raised creatine kinase (CK) > 5 x upper limit of normal (ULN) on 2 occasions at screening.
• Participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30 ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
• Prior therapy with histone-deacetylase inhibitor therapy; more than 3 prior lines of therapy.
• Treatment with strong inhibitors or inducers of CYP3A4 within 2 weeks prior to receiving study drug.
• Prior treatment with pneumotoxic drugs, e.g. busulfan, bleomycin, within the past year. If prior therapy in lifetime, then excluded if history of pulmonary toxicities from administration. Patients who have received treatment with nitrosoureas (e.g., BCNU, CCNU) in the year before study entry without experiencing lung toxicity are allowed on study.
• Treatment with another investigational drug or other intervention within 5 half-lives of the investigational product, whichever is longer.
• With the exception of alopecia, any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0) Grade 1 at the time of starting study treatment and patients with chronic Grade 2 unresolved toxicities may be eligible following discussion with the Principal Investigator.