• Incidence of treatment-emergent adverse events. [ Time Frame: Up to 24 months ]
  Adverse events will be assessed according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
• Duration of response (DOR) for participants who meet criteria for objective response rate. [ Time Frame: Up to 24 months ]
  Response will be determined by a blinded centralized review of volumetric MRI.
• Change from Baseline on quality of life (QOL) as measured by the Pediatric Quality of Life Inventory (PedsQL), Acute version. [ Time Frame: Up to 24 months ]
  The PedsQL consists of a 23-item core measure of global QOL that can be completed in approximately 5 minutes. There are four subscales: physical functioning, emotional functioning, social functioning and school/work functioning. Participants ≥ 5 years of age complete an age-appropriate self-report; and parents/guardians of children ages 2-17 complete a parent proxy report of the age-specific QOL. The recall period is 7 days.
• Change from Baseline in pain as measured by the Numeric Rating Scale-11 (NRS-11). [ Time Frame: Up to 24 months ]
  The NRS-11 is a self-reported 11-point numerical scale that assesses pain severity. Participants ≥ 8 years of age are asked to select a number from 0 (no pain) to 10 (worst pain you can imagine) that best describes their worst pain. The recall period is 24 hours.
• Change from Baseline in pain as measured by the Pain Interference Index (PII). [ Time Frame: Up to 24 months ]
  The PII assesses relevant aspects of one's life, including pain interference with activities, spending time with family/friends, mood, sleep and attention. Participants ≥ 6 years of age complete a self-report, and parents/guardians of children age 6-17 complete a parent proxy report. The recall period is 24 hours.

• Incidence of treatment-emergent adverse events [ Time Frame: Up to 24 months ]
  Adverse events will be assessed according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
• Duration of response (DOR) for participants who meet criteria for objective response rate. [ Time Frame: Up to 24 months ]
  Response will be determined by a blinded centralized review of volumetric MRI.
• Change from Baseline on quality of life as measured by the Pediatric Quality of Life Inventory (PedsQL), Acute version. [ Time Frame: Up to 24 months ]
  The PedsQL consists of a 23-item core measure of global QOL that can be completed in approximately 5 minutes. There are four subscales: physical functioning, emotional functioning, social functioning and school/work functioning. Participants ≥ 5 years of age complete an age-appropriate self-report; and parents/guardians of children ages 2-17 complete a parent proxy report of the age-specific QOL. The recall period is 7 days.
• Change from Baseline in pain as measured by the Numeric Rating Scale-11 (NRS-11). [ Time Frame: Up to 24 months ]
  The NRS-11 is a self-reported 11-point numerical scale that assesses pain severity. Participants ≥ 8 years of age are asked to select a number from 0 (no pain) to 10 (worst pain you can imagine) that best describes their worst pain. The recall period is 24 hours.
• Change from Baseline in pain as measured by the Pain Interference Index (PII). [ Time Frame: Up to 24 months ]
  The PII assesses relevant aspects of one's life, including pain interference with activities, spending time with family/friends, mood, sleep and attention. Participants ≥ 6 years of age complete a self-report, and parents/guardians of children age 6-17 complete a parent proxy report. The recall period is 24 hours.

• Change from Baseline in physical function status as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS): physical function/mobility/upper extremity short forms (8a and 8b). [ Time Frame: Up to 24 months ]
  PROMIS measures capability of physical functioning, with questions related to daily activities. Participants ≥ 18 years of age complete a self-report of physical function. Participants 8-17 years of age complete a self-report of physical function in the upper extremity or lower extremity (mobility), depending on location of the PN. Parents/guardians of children ages 2-17 complete a parent proxy report corresponding to the pediatric version. The recall period is 7 days.
• Change from Baseline in localized strength. [ Time Frame: Up to 24 months ]
• Change from Baseline in range of motion of PN-associated functional impairment. [ Time Frame: Up to 24 months ]
• Change from Baseline in endurance. [ Time Frame: Up to 24 months ]
• Time to Response defined as the time between first dose and the first date of objective response. [ Time Frame: Up to 24 months ]
  Response will be determined by a blinded centralized review of volumetric MRI.
• Time to progression, from the first dose to the date of a ≥ 20% increase in tumor volume. [ Time Frame: Up to 24 months ]
  Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.
• Progression Free Survival, defined as the time in months from the first dose to the date of a ≥ 20% increase in tumor volume or death. [ Time Frame: Up to 24 months ]
  Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.
• Change from Baseline in PN-associated disfigurement using standardized photography, centrally reviewed. [ Time Frame: Up to 24 months ]
  For participants with a PN that is visible and amenable to photography, changes in visible tumor aspects will be evaluated by a centralized reviewer.
• Comparison of tumor response to levels of pERK and biomarkers indicative of inhibition of downstream targets of MEK (eg, ERK phosphorylation). [ Time Frame: Up to 24 months ]
  Measured in tumor biopsies in participants ≥ 18 years of age.

Neurofibromas are benign peripheral nerve sheath tumors, which are classified as plexiform neurofibromas (PNs) if they extend longitudinally along a nerve and involve multiple fascicles. PNs are a major cause of morbidity and disfigurement in individuals with NF1, and as the tumor growth progresses, can cause a multitude of clinical deficits including pain and impaired physical function. PNs have the potential to undergo malignant transformation to Malignant Peripheral Nerve Sheet Tumors (MPNST).

Mirdametinib (PD-0325901) is an orally delivered, highly selective small-molecule inhibitor of the dual specificity kinases, MEK1 and MEK2 (MAPK/ERK Kinase) which prevents the phosphorylation and subsequent activation of mitogen-activated protein kinase (MAPK).

Previous studies of mirdametinib (PD-0325901) demonstrated PN shrinkage and sustained inhibition of pERK. Reduced tumor volume indicated that cell proliferation or cell death may be altered in PNs with administration of mirdametinib (PD-0325901).

• Plexiform Neurofibroma
• Neurofibromatosis Type 1 (NF1)

Key Inclusion Criteria:

• Participant has documented NF1 mutation or a diagnosis of neurofibromatosis type 1 (NF1) using National Institute of Health (NIH) Consensus Conference criteria inclusive of the presence of a plexiform neurofibroma (PN).
• Participant has a PN that is causing significant morbidity.
• Participant has a PN that cannot be completely surgically removed.
• Participant has a target tumor that is amenable to volumetric MRI analysis.
• Participant is willing to undergo a tumor biopsy pre and post treatment if ≥ 18 years of age.
• Participant has adequate organ and bone marrow function.

Key Exclusion Criteria:

• Participant has abnormal liver function or history of liver disease.
• Participant has lymphoma, leukemia or any malignancy within the past 5 years (except for resected basal/squamous skin carcinomas without metastases within 3 years).
• Participant has breast cancer within 10 years.
• Participant has active optic glioma or other low-grade glioma requiring treatment.
• Participant has abnormal QT interval corrected or other heart disease within 6 months.
• Participant has a history of retinal pathology, risk factors for retinal vein occlusion or has a history of glaucoma.
• Participant has known malabsorption syndrome or gastrointestinal conditions that would impair absorption of mirdametinib (PD-0325901).
• Participant has received NF1 PN-targeted therapy within 45 days.
• Participant previously received or is currently receiving therapy with mirdametinib (PD-0325901) or any other MEK1/2 inhibitor.
• Participant has received radiation therapy within 6 months or has received radiation to the orbit at any time.
• Participant is unable to undergo or tolerate MRI.
• Participant has active bacterial, fungal or viral infection.
• Participant has experienced other severe acute or chronic medical or psychiatric conditions within 1 year.