Window-of-Opportunity Trial of Ulixertinib for MAPK-Activated Gliomas

Inclusion Criteria

• •1. Be willing and able to provide written informed consent for the trial (by participant or legally authorized representative), and assent when applicable. Participants with cognitive impairment will be enrolled. Cognitive function will be assessed by the treating physician or designee through a neurological examination. The formal consent for such participants will be obtained from their legally authorized representative.
• •2. Surgical: Be 18 years of age or older on day of signing informed consent. Non-surgical: Be 12 years of age or older on day of signing informed consent.
• •\*Pediatric patients will be dosed at the RP2D of 260mg/m2 EVERY 12 HRS continuously for 28-day cycles. The pediatric maximal single dose is 450mg. Since the smallest tablet strength of ulixertinib is 150mg, dosing in subjects with a BSA \< 0.9m2 will be inaccurate. Therefore, only subjects with a BSA of ≥ 0.9m2 are eligible.
• •3. MAPK-activated gliomas, mixed glioma or glioneural tumors, including but not limited to those with mutations in BRAF, FGFR, PTPN11, somatic NF-1, NF-1 syndrome-associated gliomas, and recurrent oligodendrogliomas, CIC mutated. Somatic-only NF-1-mutated grade 3, 4 astroctyoma will not be included.
• •4. Mutational status requires a pathology report, genomic sequencing, or immunohistochemical report of a mutation or activation of the RAS/RAF/MEK/ERK pathway.
• •5. Prior resection or biopsy with confirmed diagnosis of glioma. Low grade gliomas patients (grade 1, 2) and oligodendroglioma (grade 2, 3) must have had prior radiation OR chemotherapy for the treatment of glioma. High grade glioma patients (grades 3 and 4 excluding oligodendroglioma) must have had prior radiation.
• •6. Have the following imaging and surgical criteria:
• •1. Surgical: Progressive disease per RANO low-grade glioma or high-grade glioma criteria depending on tumor grade AND presence of respectable tumor are required.
• •2. Non-surgical: Progressive disease per RANO low-grade glioma or high-grade glioma criteria depending on tumor grade.
• •7. Patients having undergone radiation are eligible as long as they are at least 12 weeks from radiation with evidence of disease progression per advanced brain tumor imaging \[(ABTI); includes spectroscopy and perfusion MR studies\] or biopsy.
• •8. Any number of prior relapses.
• •9. Be willing to provide tissue from an archival tissue sample.
• •10. Presence of archival tissue sample of at least 1 H\&E and 10 unstained slides. One tissue block will be requested but 10 unstained slides are acceptable if tissue block is not available.
• •11. Have a performance status of ≥ 60 on the KPS.
• •12. If patient is on steroids, patient must be on a stable or decreasing dose of steroids one week prior to screening MRI. Patients cannot be on more than 16mg of dexamethasone or equivalent per day.
• •13. Demonstrate adequate organ function as defined in the Table below. All screening labs should be performed within 14 days (+3 working days) of treatment initiation.
• •Organ System - Laboratory Value
• •Hematological Absolute neutrophil count (ANC) ≥ 1,500 /mcL
• •Platelets ≥ 100,000 /mcL
• •Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L
• •Renal
• •Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR
• •≥ 50 mL/min for patient with creatinine levels \> 1.5 X institutional ULN
• •Cardiac
• •LVEF ≥ 50%
• •Hepatic
• •Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN
• •AST (SGOT) and ALT (SGPT) ≤ 3.0 X ULN
• •Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN
• •\* Creatinine clearance should be calculated per institutional standard.
• •14. Female patients of childbearing potential should have a negative serum pregnancy test within 14 days (+ 3 working days) of study enrollment.
• •15. Male and female patients of childbearing potential agree to use highly effective contraception throughout the study and at least 90 days after the last study treatment administration.
• •16. Male patients should agree to use an adequate method of contraception during the course of the study and for 90 days after the last dose of the study drug.