MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas
- Conditions
- Plexiform NeurofibromaNeurofibromatosis Type 1 (NF1)
- Interventions
- Registration Number
- NCT03962543
- Lead Sponsor
- SpringWorks Therapeutics, Inc.
- Brief 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.
- Detailed Description
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).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 114
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Mirdametinib (PD-0325901) Mirdametinib (PD-0325901) oral capsule or dispersible tablet Mirdametinib (PD-0325901) capsule or dispersible tablet 2 mg/m\^2 (maximum dose of 4 mg) by mouth twice daily
- Primary Outcome Measures
Name Time Method Confirmed Objective Response Rate at the End of the Treatment Phase. Up to 24 months Response will be determined by a blinded centralized review of volumetric MRI. The confirmed objective response rate (complete or partial response) by the end of Treatment Phase (i.e., Cycle 24) is defined as the proportion of participants who have a confirmed ≥ 20% reduction in target tumor volume as compared to baseline as assessed by a BICR, and the response needs to be confirmed by BICR in a consecutive tumor assessment within 2 - 6 months. Partial response is defined as a ≥ 20% reduction in target tumor volume from baseline. Complete response is defined as the complete resolution of the target tumor.
- Secondary Outcome Measures
Name Time Method Percentage of Patients With Treatment-Emergent Adverse Events. All SAEs and AEs were collected from the time of signing ICF until 30 days after the last dose of study treatment, an average of 1 year and 10 months and up to 3 years and 10 months. All adverse events were coded using MedDRA Version 24.0. 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 Confirmed Objective Response. Starting on the onset of confirmed objective response in the Treatment Phase and afterwards on the 15th day of every 4 cycles (each cycle is 28 days) until disease progression or death, whichever comes first, assessed up to approximately 3 years Duration of response is defined as the time in months between the first instance of response that is subsequently confirmed, until the date of radiographic disease progression or death, whichever occurs first. For participants who enter the LTFU Phase, all MRI assessments in both the Treatment Phase and LTFU Phase will be used to determine duration of response. Participants without radiographic disease progression or death while on study will have their results censored to their most recent adequate (i.e. evaluable) tumor assessment date.
Change From Baseline on Quality of Life (QOL) as Measured by the Pediatric Quality of Life Inventory (PedsQL) at Cycle 13, Acute Version. Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months The PedsQL consists of a 23-item core measure of global QOL that can be completed in approximately 5 minutes. There is a total score and 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. PedsQL items are answered on a Likert scale with responses ranging from 0 to 4 (where 0 means it is never a problem and 4 means it is almost always a problem). These items are then reverse scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. On this scale, higher scores indicate better outcomes. Overall scale scores are calculated as the mean of the scores for the questions in said scale (or of all questions for the total score). The change from baseline is modelled using a mixed-model for repeated measures.
Change From Baseline in Pain as Measured by the Numeric Rating Scale-11 (NRS-11) at Cycle 13. Baseline and Cycle 13 (1 cycle = 28 days), up to 12 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. The change from baseline is modelled using a mixed-model for repeated measures.
Change From Baseline in Pain as Measured by the Pain Interference Index (PII) at Cycle 13. Baseline and Cycle 13 (1 cycle = 28 days), up to 12 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 aged 6-17 complete a parent proxy report. The recall period is 24 hours. The PII consists of 6 questions, each asking the responder to select one number from 0 to 6 that best describes how their/their proxy's pain has impacted various items over the past 24 hours with 0 representing "Not at all" and 6 representing "Completely". The mean of the completed items is taken as the PII score for a single assessment. The PII score presented each visit will be taken as the average of the PII scores over the 7 consecutive days up to and including visit day, with no transformation applied. The change from baseline is modelled using a mixed-model for repeated measures.
Trial Locations
- Locations (50)
University of Alabama at Birmingham/Children's of Alabama
🇺🇸Birmingham, Alabama, United States
Mayo Clinic Hospital
🇺🇸Phoenix, Arizona, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
UCLA Oncology Center
🇺🇸Los Angeles, California, United States
University of California - Irvine Health
🇺🇸Orange, California, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
Lucile Packard Children's Hospital Stanford
🇺🇸Palo Alto, California, United States
University of California - Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Scroll for more (40 remaining)University of Alabama at Birmingham/Children's of Alabama🇺🇸Birmingham, Alabama, United States