A Study of NST-628 in Recurrent Grade 4 Glioma

Inclusion Criteria:

* 1\. Diagnosed with Grade 4 glioma, who have progressed on or following standard of care therapy, including maximal safe resection (biopsy allowed if resection was deemed unsafe) and concurrent chemoradiation.
* 2\. Has sufficient archival or biopsy brain tumor tissue available to confirm eligibility, and the tissue must have an H-Score \> 150 for pERK.
* 3\. Is clinically indicated for tumor resection and has measurable disease (preoperatively), defined as at least one contrast-enhancing lesion with two perpendicular measurements of at least 1 cm.
* 4\. Age ≥ 18 at time of consent.
* 5\. Has a performance status of ≤ 2 on the ECOG scale.
* 6\. Able to swallow oral medications without crushing or chewing.
* 7\. Has adequate bone marrow and organ function as defined by the laboratory values below (as assessed by the local laboratory for eligibility). Participants not meeting one or more of the laboratory criteria below may still be considered eligible at the discretion of the investigator if the abnormality is not deemed clinically significant, is attributable to the underlying disease or concurrent medications, or if the investigator determines that study participation is appropriate based on an assessment of the potential risks and anticipated benefits. The rationale for eligibility outside of the specified laboratory parameters must be documented in the participant's source records.
* 8\. For women of childbearing potential: a. 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. b. Must use highly effective contraception (with a failure rate of \< 1% per year and low user dependency) for at least 28 days prior to study treatment, and agree to use such a method during study participation and for an additional 6 months after final study drug administration. c. Agrees not to breastfeed starting at screening, during study participation, and for an additional 6 months after final study drug administration. d. Agrees not to donate eggs (ova, oocytes) for the purpose of reproduction starting at screening, during study participation, and for an additional 6 months after final study drug administration.
* 9\. For women of non-childbearing potential, is no longer of childbearing potential due to surgical, chemical, or natural menopause.
* 10\. For men: a. Agrees not to donate sperm starting at screening, during study participation, and for an additional 6 months after final study drug administration. b. 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 6 months after final study drug administration, or; must use a male condom (even if vasectomized) to ensure effective contraception/prevent delivery of the study drug via seminal fluid starting at screening, during study participation, and for an additional 6 months after final study drug administration.
* 11\. Agrees to adhere to protocol defined Lifestyle Considerations starting at screening during study participation.
* 12\. Able and willing to comply with scheduled visits, treatment plans, laboratory tests, and other procedures.
* 13\. Understands the informed consent document and voluntarily agrees to participate by providing written informed consent (personally or via a legally authorized representative, with assent if applicable). Written informed consent must be obtained before any screening procedures. If consent cannot be expressed in writing, consent must be formally documented and witnessed, preferably by an independent, trusted witness.

Exclusion Criteria:

* 1\. Has extracranial disease, or evidence of leptomeningeal disease.
* 2\. Has a history or current evidence of significant retinal pathology associated with an increased risk of RVO, including any of the following: a. History of RVO; b. Visible retinal pathology as assessed by ophthalmic examination, such as: i. Evidence of new optic disc cupping; ii. Evidence of new peripheral visual field defects; iii. Intraocular pressure \> 21 mmHg; iv. Evidence of retinal detachment.
* 3\. Has a history or evidence of CV risk, including any of the following: a. QT interval corrected for heart rate using the Fridericia's formula, QTcF ≥ 470 msec; b. History or evidence of current, clinically significant, uncontrolled arrhythmias (those that would require a pacemaker and are not normalized by medication: symptomatic A-fib, clinically significant 2nd or 3rd degree heart block, other clinically significant supraventricular arrhythmias, any obvious ventricular arrhythmias); c. History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to Study Day 1; d. NYHA Class II or higher congestive heart failure; e. Treatment-refractory hypertension, defined as systolic blood pressure \> 140mmHg and/or diastolic \> 90mmHg despite anti-hypertensive therapy; f. Presence of intracardiac defibrillator or pacemaker.
* 4\. Has a history or current evidence of pneumonitis or ILD within 6 months of Day 1.
* 5\. Has received more than 2 lines of prior systemic therapy.
* 6\. Has received chemotherapy, radiation, gene therapy, vaccine therapy, or anti-cancer antibodies/antibody-drug conjugates within 28 days prior to Day 1, or ongoing treatment-related AEs Grade \> 1 per NCI-CTCAE v5.0 (excluding alopecia) at the time of starting study treatment. Individuals with chronic Grade 2 unresolved toxicities might be deemed eligible following discussion with the Sponsor-Investigator.
* 7\. Has received prior treatment with another investigational drug or other intervention within 14 days or 5 half-lives of the investigational product (whichever is less) of Day 1, or a longer period if clinically indicated.
* 8\. Has undergone a minor surgical procedure ≤ 5 days or major surgical procedure ≤ 21 days, prior to Day 1.
* 9\. Has a known infection with HIV, HBV, or HCV; individuals with laboratory evidence of cleared HBV or HCV infection are permitted. Serologic status reflecting active HBV or HCV: HbsAg or hepatitis B PCR positivity. Individuals who are anti-HBc positive and HbsAg negative will need to have a negative HBV PCR result to be eligible; HCV PCR positivity. Subjects who are HCV antibody positive will need to have a negative PCR result to be eligible.
* 10\. Has serious and/or uncontrolled preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study (e.g., substance abuse, psychiatric disturbance, uncontrolled intercurrent illness).
* 11\. Women who are pregnant or breastfeeding.