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.
- - We will not select for CIC mutation in oligodendrogliomas in the surgical cohort as
an inclusion criteria but will check CIC mutation status on the recurrent tissue for
two main reasons; 1-CIC mutation is particularly enriched in recurrent OD (Barthel,
Johnson et al.
2019) and not newly diagnosed disease, 2- Recurrence happens after
more than 10 years and even longer in patients previously treated with radiation and
chemotherapy (Bell, Zhang et al. 2020), therefore confirmation of CIC mutation based
on archival tissue at the time of diagnosis is very challenging.
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.
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.
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
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.
Exclusion criteria. 1. Treatment with bevacizumab less than 3 months prior to enrollment.
2. Presence of implanted chemotherapy. Previously resected implanted chemotherapy is
not excluded.
3. 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.
4. Patient currently participating in a study of an investigational agent or using an
investigational device for therapeutic purposes.
5. Patient has a diagnosis of severe immunodeficiency or is receiving systemic
immunosuppressive therapy (except for steroids) within 7 days of study entrance.
6. 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.
7. 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.
8. Has an active infection requiring systemic therapy.
9. 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.
10. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
11. Is pregnant, breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit.
12. Has contraindication for undergoing MRIs.
13. Is not a candidate for non-emergent surgical resection.
14. Is taking prohibited concomitant medications (Appendix 5) and is unable to
discontinue these medications prior to study enrollment.
15. A history or current evidence/risk of retinal vein occlusion or central serous
retinopathy
