Description:
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).
Title
- Brief Title: MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
MEK-NF-201
- NCT ID:
NCT03962543
Conditions
- Plexiform Neurofibroma
- Neurofibromatosis Type 1 (NF1)
Interventions
| Drug | Synonyms | Arms |
|---|
| Mirdametinib (PD-0325901) oral capsule or dispersible tablet | PD-0325901, Mirdametinib | Mirdametinib (PD-0325901) |
Purpose
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).
Detailed Description
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).
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Mirdametinib (PD-0325901) | Experimental | Mirdametinib (PD-0325901) capsule or dispersible tablet 2 mg/m^2 (maximum dose of 4 mg) by mouth twice daily | - Mirdametinib (PD-0325901) oral capsule or dispersible tablet
|
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 2 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Complete or partial response rate compared to baseline. Partial response is defined as a ≥ 20% reduction in target tumor volume. |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | Response will be determined by a blinded centralized review of volumetric MRI. |
Secondary Outcome Measures
| Measure: | Incidence of treatment-emergent adverse events. |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | Adverse events will be assessed according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. |
| Measure: | Duration of response (DOR) for participants who meet criteria for objective response rate. |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | Response will be determined by a blinded centralized review of volumetric MRI. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Change from Baseline in pain as measured by the Numeric Rating Scale-11 (NRS-11). |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Change from Baseline in pain as measured by the Pain Interference Index (PII). |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | 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. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | SpringWorks Therapeutics, Inc. |
Trial Keywords
- Neurofibromatoses
- Neurofibromatosis 1
- Plexiform Neurofibroma
- PD-0325901
- MEK Inhibitor
- Neurofibroma
- Mirdametinib
Last Updated
August 9, 2021
