A Study of Mirdametinib in People With Central Nervous System Tumors

Inclusion Criteria

• •Demographic Characteristics
• •a. Be \> 18 years of age
• •General Criteria
• •1. Have Karnofsky Performance Status (KPS) of ≥ 70% or ECOG Performance Status of ≤ 2
• •2. Is able to understand and provide written informed consent for the trial prior to any study-specific procedures and is willing to comply with scheduled visits, treatment plans, procedures and laboratory tests. A legally authorized representative may consent on behalf of a subject who is otherwise unable to provide informed consent, if acceptable to and approved by the institutional review board.
• •Medical and Therapeutic Criteria
• •1. Have adequate bone marrow function, as determined by:
• •* Absolute neutrophil count (ANC) \>1,500/mm3
• •* Platelet count \>100,000 mm³
• •* Hemoglobin \>9.0 mg/dL
• •2. Have adequate hepatic function, as determined by:
• •* Total bilirubin ≤1.5 x ULN if baseline was normal or ≤1.5 x baseline if baseline was abnormal. Patients with previously documented Gilbert's Syndrome may have total bilirubin ≤3 x ULN.
• •* AST and ALT ≤3.0 x ULN if baseline was normal or ≤3.0 x baseline if baseline was abnormal
• •3. Have adequate renal function, as determined by:
• •o Creatinine clearance (CrCL) of ≥50 mL/min by the Cockcroft-Gault formula
• •CrCl (mL/min) = \[140 - age (years)\] x weight (kg) x 0.85 for female patients 72 creatinine (mg / dL)
• •4. Adequate cardiac function defined as follows
• •* Left ventricular ejection fraction \>50% as assessed by multi-gated acquisition or ultrasound or echocardiography and
• •* Corrected QT interval (QTc) \<480 ms according to the Fridericia method (QTcF)
• •5. Women of childbearing potential must have a negative serum pregnancy test before the start of therapy.
• •6. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• •7. Patients previously treated with radiotherapy must have recovered from acute toxicities associated with such treatment. Toxicities of investigational therapies should have recovered to grade 1 or less before start of the trial medication.
• •Subjects must meet all of the following criteria to be enrolled in the Neurohistiocytosis cohort of this study:
• •1. Have documented MAPK pathway mutation, or mutation not identified by tumor sequencing.: Patients with completed but negative tumor sequencing, or patients without sequencing performed but without safe disease sites for biopsy, are eligible for this study owing to the high likelihood of MAPK pathway mutation.
• •2. Have documentation of disease: Patients must have a histologically confirmed histiocytic neoplasm or a constellation of histologic, radiologic, clinical, and/or molecular findings consistent with histiocytic neoplasm. This qualification is made because it is well known that biopsies of histiocytic neoplasms are variable and do not always demonstrate "typical" morphologic appearance with all of the classically described elements.\[54\] As a result, histiocytic neoplasms are not exclusively pathologic diagnoses-rather, they are interpretations of histologic findings in a clinical and radiologic context.
• •3. Have measurable neurohistiocytic disease: Patients must have measurable radiologic or functional neurologic disease as defined by any of the following below. The presence of systemic disease is allowed however there must be at least one eligible manifestation of neurologic disease as defined below:
• •* Measurable disease according to modified PERCIST (mPERCIST) involving neurologic structures, i.e. meninges, brain or spinal cord parenchyma, or ocular structures (see sections below for these criteria) OR
• •* Measurable disease according to RECIST 1.1 involving neurologic structures OR
• •* Any of the below neurologic deficits referable to neurohistiocytosis amenable to longitudinal quantified assessment. The following are the allowable deficits, deemed referable to disease, with their corresponding assessments and minimum required abnormalities:
• •* Dysarthria as defined Speech Intelligibility of B or worse as measured by the Frenchay Dysarthria Scale
• •* Ataxia as defined by a score of 3 or higher on the Scale for assessment and rating of ataxia (SARA)
• •* Diplopia as defined by Prism Diopter of 5 or higher
• •* Loss of visual acuity defined as best corrected visual acuity (BCVA) 20/40 (0.3 LogMAR) or worse in either eye
• •* Diminished visual field, defined as 20% or higher deficit in Humphrey Visual Field 24-2 pattern deviation.
• •Subjects must meet all of the following criteria to be enrolled in the glioma cohort of this study:
• •1. Have: somatic NF1 mutation as per next-generation sequencing (such as MSK Impact) --or- germline NF1 as per NIH clinical criteria
• •2. Have a histologically confirmed glioma (per the 2021 WHO Classification of Tumors of the central nervous system)
• •3. Have measurable, MRI-evaluable, unequivocal contrast enhancing disease as determined by radiologist on T1 post-contrast weighted images. Per RANO criteria, measurable lesion is defined as at least 1 enhancing lesion measuring \> 1 cm x \> 1 cm
• •4. Have recurrent or progressive disease and received prior treatment with chemotherapy, radiation, or both
• •5. Surgical resection is indicated for treatment, but surgery is not urgently indicated (e.g. for whom surgery within the next 4-6 weeks is appropriate)
• •6. Have expected survival of \> 3 months