mek inhibitor mirdametinib (pd-0325901) in patients with neurofibromatosis type 1 associated plexiform neurofibromas

Conditions: Plexiform Neurofibroma; Neurofibromatosis Type 1 (NF1)

Summary: 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 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).

Eligibility criteria:
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.

Keywords: neurofibromatoses neurofibromatosis 1 plexiform neurofibroma pd-0325901 mek inhibitor neurofibroma mirdametinib