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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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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

Conditions
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Plexiform Neurofibroma, Neurofibromatosis Type 1 (NF1)

Intervention / Treatment
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* Drug: Mirdametinib (PD-0325901) oral capsule or dispersible tablet


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: All participants will receive mirdametinib (PD-0325901) at a dose of 2 mg/m^2 twice daily (maximum dose of 4 mg twice daily), calculated based on body surface area. Dose will be administered in a 3-week on, 1-week off schedule.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mirdametinib (PD-0325901)<br>Mirdametinib (PD-0325901) capsule or dispersible tablet 2 mg/m^2 (maximum dose of 4 mg) by mouth twice daily | Drug: Mirdametinib (PD-0325901) oral capsule or dispersible tablet<br>* Mirdametinib (PD-0325901) capsule or dispersible tablet<br>* Other names: Mirdametinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete or partial response rate at the end of the Treatment Phase compared to baseline. Partial response is defined as a ≥ 20% reduction in target tumor volume. | Response will be determined by a blinded centralized review of volumetric MRI. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events. | Adverse events will be assessed according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. | Up to 24 months | 
| Duration of response (DOR) for participants who meet criteria for objective response rate. | Response will be determined by a blinded centralized review of volumetric MRI. | Up to 24 months | 
| Change from Baseline on quality of life (QOL) as measured by the Pediatric Quality of Life Inventory (PedsQL), Acute version. | 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. | Up to 24 months | 
| Change from Baseline in pain as measured by the Numeric Rating Scale-11 (NRS-11). | 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. | Up to 24 months | 
| Change from Baseline in pain as measured by the Pain Interference Index (PII). | 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. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neurofibromatoses, Neurofibromatosis 1, Plexiform Neurofibroma, PD-0325901, MEK Inhibitor, Neurofibroma, Mirdametinib