A Study of Mirdametinib in People With Central Nervous System Tumors

Exclusion Criteria

Subjects who meet any of the following criteria will not be enrolled in the study:

General criteria

1. Is pregnant or nursing

2. Is participating in another interventional study at the same time; participation in non-therapeutic registries is allowed

   Medical and Therapeutic criteria

3. Receipt of tumor directed therapy (chemotherapy, targeted therapy, biologic, investigational) within 28 days or 5 half-lives (whichever is shorter) before the first dose of mirdametinib.

4. Concomitant use of medications that strongly induce CYP3A

5. History of allergic reaction to the study agent(s), compounds of similar chemical or biologic composition to the study agent (s) (or any of its excipients).

6. Evidence of serious active infections. Patients are allowed to enroll if they have been fever free for at least 48 hours

7. Uncontrolled or severe intercurrent medical condition

8. Have significant active cardiac disease within 6 months before the start of treatment, including New York Heart Association Class III or IV congestive heart failure, atrial fibrillation, myocardial infarction, unstable angina and/or stroke.

9. Have significant active ophthalmologic disease within 6 months before the start of treatment, including central retinal vein occlusion

10. Has a history of or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator

11. Cohort A only: Patients with documented driver mutations outside of the MAPK pathway are not eligible for this study. These are uncommon and include mutations in ALK, RET, CSF1R, NTRK, and other kinases20 .

On Study Guidelines:

Physicians should consider the following when evaluating if the patient is appropriate for this study:

• Cohorts A and B: Patients with cytopenias, renal impairment or hepatic impairment deemed the direct result of disease and therefore amenable to improvement with mirdametinib treatment may be enrolled at the discretion of the treating investigator
• Cohort A: There is no prior therapy requirement given the poor CNS efficacy of standard therapies, morbidity of neurohistiocytosis, and the available data about safety and efficacy in nine patients treated with mirdametinib.
• The effects of mirdametinib on the developing human fetus are unknown. For this reason, female participants of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 6 weeks following the completion of study therapy. Male participants with female partners of reproductive potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 3 months following the completion of study therapy. Should a participant become pregnant or suspect pregnancy while participating in this study, they should inform their treating physician immediately.