MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas

A Phase 2b Trial of the MEK 1/2 Inhibitor (MEKi) PD-0325901 in Adult and Pediatric Patients With Neurofibromatosis Type 1 (NF1)-Associated Inoperable Plexiform Neurofibromas (PNs) That Are Causing Significant Morbidity

This study evaluates mirdametinib (PD-0325901) in the treatment of symptomatic inoperable neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PNs). All participants will receive mirdametinib (PD-0325901). Eligible participants may continue in a long-term follow-up phase.

Neurofibromas are non-malignant 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 problems 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).

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.