Window-of-Opportunity Trial of Ulixertinib for MAPK-Activated Low-Grade Gliomas in Adults

To learn if the study drug, ulixertinib, can cross over the blood-brain barrier in patients with recurrent brain tumors

Primary Objective:

1. To evaluate the ability of ulixertinib to penetrate the BBB in patients with recurrent MAPK-activated LGG (ulixertinib tumor concentration, tumor/plasma ratio and tumor/cerebrospinal fluid (CSF) ratio)

Secondary Objectives:

1. To assess anti-tumor activity of ulixertinib for patients with recurrent lower grade

   MAPK-activated gliomas after surgical resection based on:
   1. Median progression-free-survival (mPFS)
   2. Objective response rate (ORR) at 12 months
   3. Disease control rate (DCR) at 12 months
   4. Duration of response (DOR)
   5. Time to response (TTR)
   6. Time to next intervention
2. To assess safety and tolerability of ulixertinib in MAPK-activated LGG

Eligibility Criteria:
Inclusion criteria:

1. Be willing and able to provide written informed consent for the trial. 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. Be 18 years of age or older on day of signing informed consent.
3. Have the following combined histological and molecular criteria:

   1. Cohort 1: World Health Organization recurrent grade 1, 2, 3 glioma and NF1 mutation (somatic and/or germline). NF1 mutation identified from prior tumor resection or from normal tissue samples (any CLIA certified NGS).
   2. Cohort 2: World Health Organization recurrent grade 2, 3 OD (IDH mutated, 1p19q codeleted)
4. Have had the following treatments:

   1. Cohort 1: prior resection or biopsy with confirmed diagnosis of glioma per above.

      Patient must have had prior radiation or chemotherapy for the treatment of glioma.
   2. Cohort 2: prior resection or biopsy with confirmed diagnosis of OD per above. Patient must have had prior radiation or chemotherapy for the treatment of OD.
5. Have the following imaging and surgical criteria:

   a. Progressive disease per RANO low-grade glioma or high-grade glioma criteria depending on tumor grade AND presence of non-enhancing respectable tumor are required. In cases that both non-enhancing and enhancing disease are present, collection of non-enhancing disease separate from enhancing disease should be deemed possible per the treating neurosurgeon.
6. 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.
7. Any number of prior relapses.
8. Be willing to provide tissue from an archival tissue sample.
9. 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.
10. Have a performance status of ≥ 60 on the KPS.
11. 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.
12. Demonstrate adequate organ function as defined in below Table. 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
13. Female patients of childbearing potential should have a negative serum pregnancy test within 14 days (+ 3 working days) of study enrollment.
14. 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
15. 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.

Exclusion criteria:

1. Treatment with bevacizumab less than 6 months since enrollment.
2. Tumor localized primarily to spinal cord.
3. Presence of implanted chemotherapy. Previously resected implanted chemotherapy is not excluded.
4. Less than 12 weeks from completing radiotherapy. Patients with proven progressive disease by biopsy or partial resection or with new lesions outside of the radiation field should not be excluded even if they are within 12 weeks of radiation.
5. Patient currently participating in a study of an investigational agent or using an investigational device for therapeutic purposes.

   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 a Creatinine clearance should be calculated per institutional standard.
6. Patient has a known history of Human Immunodeficiency Virus (HIV) (positive HIV 1/2 antibodies); HTLV1 and/or HTLV2; active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). Patients with prior HBV vaccination (anti-HBs positive, HBsAg negative, anti-HBc negative) will NOT be excluded.
7. Patient has a diagnosis of immunodeficiency or is receiving systemic immunosuppressive therapy (except for steroids) within 7 days of study entrance.
8. Patient has had prior chemotherapy or targeted small molecule therapy, within 3 weeks prior to study Day 1, or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

   1. Note: Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
   2. Note: If patient received major surgery (other than craniotomy), they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
9. Has a known additional malignancy that is progressing or requires active treatment.

   Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
10. Has an active infection requiring systemic therapy.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
13. Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit.
14. Has contraindication for undergoing MRIs.
15. Is not a candidate for non-emergent surgical resection.
16. Is taking prohibited concomitant medications (Appendix 5) and is unable to discontinue these medications prior to study enrollment.
17. A history or current evidence/risk of retinal vein occlusion or central serous retinopathy