Safety and Feasibility of First-line Avutometinib and Defactinib in Patients With Newly Diagnosed High-grade Gliomas

Inclusion Criteria:

* Patient must be able to provide written informed consent.
* ≥ 18 years of age
* Likely high-grade glioma based on frozen pathology in patients with no prior diagnosis of a glioma or astrocytoma.
* Patient appropriate for standard therapy for high-grade glioma that includes 6 weeks of radiation.
* Patient is not deemed at a high risk of symptomatic progression within 4 weeks by the treating physician and investigator team.
* Karnofsky Performance Scale (KPS) ≥ 70%.
* Post-operative MRI completed with 72 hours of surgery that includes FLAIR sequences
* Measurable disease per RANO 2.0 enhancing criteria. Leptomeningeal disease not allowed.
* Patient is on a tapering dose of steroids anticipated to be on a total daily dose of dexamethasone \< 2 mg for at least 5 days by start of study intervention.
* Willing to submit archival tumor sample if available
* Adequate organ and marrow function defined as:
* Ability to swallow and retain orally administered medications (no liquid suspensions available).
* Female participants of childbearing potential must have a negative serum pregnancy test prior to study start.
* Male participants must also be documented to be surgically sterile or agree to use adequate contraception and not to donate sperm
* Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with other malignancies must be disease-free for \> 2 years.
* Patients with human immunodeficiency virus (HIV) who are on effective antiretroviral therapy are eligible if the viral load was assessed as undetectable within 6 months prior to baseline.

Exclusion Criteria:

* Any prior glioma or astrocytoma, or any prior cancer diagnosis resulting in irradiation of the skull or scalp
* Significant bi-hemispheric disease or midline shift observed on post-operative MRI likely to result in rapid clinical deterioration
* Those who have undergone diagnostic biopsy only for suspected primary brain cancer.
* Those who are on other investigational agents at the time of screening and including patients on carmustine and/or gamma tiles
* History of clinically significant ophthalmologic disorders
* Impairment in gastrointestinal function or disease that may significantly alter the absorption of oral study drug
* Clinically significant cardiovascular disease
* History of recent (≤ 90 days) thromboembolic or cerebrovascular event
* Known history of any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or detectable virus.
* Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.
* Patients may not take any of the listed contraindicated medications for 7 days prior to the start of study drug, with the exception of dexamethasone; see section 5.6 "concomitant therapy":

  1. Warfarin
  2. Strong CYP2C9 or CYP3A4 inhibitors or inducers
  3. P-glycoprotein inhibitors or inducers
* Patients may not be on H2 blocker or PPI (Proton pump inhibitors) for 2 days prior to start of study drug.
* Subjects with a history of hypersensitivity to any of the active or inactive ingredients (hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the investigational products.
* Pregnant or breastfeeding
* Active or past medical history of interstitial lung disease (ILD)/pneumonitis, including drug-induced or radiation ILD/pneumonitis, pulmonary fibrosis, or adult respiratory distress syndrome (ARDS
* History of medically significant rhabdomyolysis