TriangleNCT03962543 · CITED IN SOURCE DOCUMENTS
MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE2
- Status at capture
- ACTIVE NOT RECRUITING
- Registry last update
- 2026-07-10
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.
Open the original ClinicalTrials.gov record → · Download preserved record
What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Confirmed Objective Response Rate at the End of the Treatment Phase.
Percentage of Patients With Treatment-Emergent Adverse Events.
Duration of Response (DOR) for Participants Who Meet Criteria for Confirmed Objective Response.
Change From Baseline on Quality of Life (QOL) as Measured by the Pediatric Quality of Life Inventory (PedsQL) at Cycle 13, Acute Version.
Change From Baseline in Pain as Measured by the Numeric Rating Scale-11 (NRS-11) at Cycle 13.
Change From Baseline in Pain as Measured by the Pain Interference Index (PII) at Cycle 13.
Change From Baseline in Localized Strength (Dynamometer) at Cycle 13.
Change From Baseline in Range of Motion of PN-Associated Functional Impairment at Cycle 13.
Change From Baseline in Endurance at Cycle 13.
Time to Response Defined as the Time Between First Dose and the First Date of Objective Response That is Subsequently Confirmed.
Time to Progression, From the First Dose to the First Date of a ≥ 20% Increase in Tumor Volume From Baseline.
Progression Free Survival, Defined as the Time in Months From the First Dose to the Date of the First ≥ 20% Increase in Tumor Volume From Baseline or Death.
Change From Baseline in PN-Associated Disfigurement Using Standardized Photography, Centrally Reviewed.
Comparison of Tumor Response to Levels of pERK and Biomarkers Indicative of Inhibition of Downstream Targets of MEK (eg, ERK Phosphorylation).
Acceptability of the Dispersible Tablet Formulation as Measured by the Pediatric Oral Medicine Acceptability Questionnaire (P-OMAQ)
Change From Baseline in Localized Strength (Medical Research Council (MRC) Scale Grading) at Cycle 13.
Change From Baseline in Physical Function Status as Measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) at Cycle 13: Pediatric v2.0 Mobility 8a.
Change From Baseline in Physical Function Status as Measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) at Cycle 13: Pediatric v2.0 Upper Extremities 8a.
Change From Baseline in Physical Function Status as Measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) at Cycle 13: Adult v2.0 Physical Function 8b.
Adverse events
Limitations, agreements, and source contact
Who could take part
- 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.
- healthy Volunteers
- false
- minimum Age
- 2 Years
- sex
- ALL
- std Ages
- CHILD
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- Mirdametinib (PD-0325901) capsule or dispersible tablet 2 mg/m\^2 (maximum dose of 4 mg) by mouth twice daily
- intervention Names
- Drug: Mirdametinib (PD-0325901) oral capsule or dispersible tablet
- label
- Mirdametinib (PD-0325901)
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- Mirdametinib (PD-0325901)
- description
- Mirdametinib (PD-0325901) capsule or dispersible tablet
- name
- Mirdametinib (PD-0325901) oral capsule or dispersible tablet
- other Names
- PD-0325901
- Mirdametinib
- type
- DRUG
Study design
- allocation
- NA
- intervention Model
- SINGLE_GROUP
- intervention 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 Info
- masking
- NONE
- primary Purpose
- TREATMENT
Enrollment
- count
- 114
- type
- ACTUAL
Registered outcome plans (not posted results)
- other Outcomes
- description
- Assessment of strength will be conducted only in the area affected by the target tumor. Measurements will be obtained using Medical Research Council (MRC) grading followed by quantitative assessments using the sponsor provided MicroFET2 dynamometer. Dynamometer assessment (in lbs) must be conducted in accordance with the study reference manual. For each participant, the sum of the dynamometer scores for the muscle groups tested will be taken as an overall score for each visit with higher scores indicating better localized strength. To assess the change from baseline at a visit, a participant will need assessments in which all the following categories, as assessed at baseline, match at that visit: side affected, position during assessment (sitting/supine/lateral decubitus), muscle group assessed. The change from baseline in localized strength measured by the sum of the dynamometer scores for the muscle groups tested will be assessed at Cycle 13.
- measure
- Change From Baseline in Localized Strength (Dynamometer) at Cycle 13.
- time Frame
- Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months
- description
- If motor dysfunction or weakness is evident, range of motion of the affected areas and/or joints will be measured by a goniometer.
- measure
- Change From Baseline in Range of Motion of PN-Associated Functional Impairment at Cycle 13.
- time Frame
- Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months
- description
- If airway or lower extremity motor dysfunction is evident, endurance will be measured by completion of a 6-minute walking test.
- measure
- Change From Baseline in Endurance at Cycle 13.
- time Frame
- Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months
- description
- Response will be determined by a blinded centralized review of volumetric MRI. Time to response is defined as the time in months from the start of treatment to the date of first response that was subsequently confirmed.
- measure
- Time to Response Defined as the Time Between First Dose and the First Date of Objective Response That is Subsequently Confirmed.
- time Frame
- Up to 24 months
- description
- Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI. Time to progression is defined as the time in months between the first treatment date until the date of radiographic disease progression. For participants who enter the LTFU Phase, all MRI assessments in both the Treatment Phase and LTFU Phase will be used to determine time to progression. Participants without radiographic disease progression will have their results censored to their most recent adequate (i.e. evaluable) tumor assessment date.
- measure
- Time to Progression, From the First Dose to the First Date of a ≥ 20% Increase in Tumor Volume From Baseline.
- time Frame
- On the 15th day of every 4 cycles (each cycle is 28 days) until disease progression is observed, assessed up to approximately 3.5 years
- description
- Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI. Progression free survival is defined as the time in months between the first treatment date, 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 progression free survival. 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.
- measure
- Progression Free Survival, Defined as the Time in Months From the First Dose to the Date of the First ≥ 20% Increase in Tumor Volume From Baseline or Death.
- time Frame
- On the 15th day of every 4 cycles (each cycle is 28 days) until disease progression is observed or death, whichever comes first, assessed up to approximately 3.5 years
- description
- For participants with a PN that is visible and amenable to photography, changes in visible tumor aspects will be evaluated by a centralized reviewer.
- measure
- Change From Baseline in PN-Associated Disfigurement Using Standardized Photography, Centrally Reviewed.
- time Frame
- Up to 24 months
- description
- Measured in tumor biopsies in participants ≥ 18 years of age.
- measure
- Comparison of Tumor Response to Levels of pERK and Biomarkers Indicative of Inhibition of Downstream Targets of MEK (eg, ERK Phosphorylation).
- time Frame
- Up to 24 months
- description
- The Pediatric Oral Medicine Acceptability Questionnaire (P-OMAQ) uses a 5-point numerical rate scale to measure acceptability of use of the tablet formulation with questions related to taste, smell and administration of study medication. Participants ≥ 8 years of age complete a 12-item self-report; adult parents/caregivers responsible for oversight of study drug administration for participants ages 6 months to 17 years complete a 19-item caregiver report. Each questionnaire is provided with a "past 7 days" recall with all items using a 5-point Numerical Rate Scale (1 to 5) with higher item-scores reflecting greater oral treatment acceptability. The overall P-OMAQ-P (pediatric self-report) and P-OMAQ-C (adult caregiver) scores for a participant in the study will be taken as the mean of all answered questions on the respective questionnaire.
- measure
- Acceptability of the Dispersible Tablet Formulation as Measured by the Pediatric Oral Medicine Acceptability Questionnaire (P-OMAQ)
- time Frame
- Completed only once through study completion
- description
- If motor dysfunction or weakness is evident, strength of the affected muscle groups will be measured by dynamometer and assessed by a muscle grading scale. Medical Research Council (MRC) Scale grading (0-5) must be conducted in accordance with the study reference manual. MRC Grading is assessed on a scale of 0 to 5, with 0 representing no movement being observed, and 5 representing the muscle contracting normally against full resistance. To assess the change from baseline at a visit, a participant will need assessments in which all the following categories, as assessed at baseline, match at that visit: side affected, position during assessment (sitting/supine/lateral decubitus), muscle group assessed. The MRC Grade visit score is calculated for each participant separately, and these scores are then averaged.
- measure
- Change From Baseline in Localized Strength (Medical Research Council (MRC) Scale Grading) at Cycle 13.
- time Frame
- Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months
- description
- PROMIS measures capability of physical functioning, with questions related to daily activities. Participants 8-17 years complete a self-report of physical function in the upper extremity or lower extremity (mobility), depending on the location of the PN. The recall period is 7 days. All PROMIS items are answered on a Likert scale with responses ranging from 1 to 5, with higher scores representing higher reported mobility. The total raw score will be calculated as the sum of the individual item responses at a given visit (total raw scale range 8-40). The total raw scores for the measure will be converted to T-scores using the applicable score conversion table in the user manual and scoring instructions (PROMIS, 2023) ranging from 14 to 59 for self-report, and 14 to 56 for parent proxy with higher scores representing higher reported mobility and better outcomes. A T-score of 50 indicates the population mean with a standard deviation of 10.
- measure
- Change From Baseline in Physical Function Status as Measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) at Cycle 13: Pediatric v2.0 Mobility 8a.
- time Frame
- Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months
- description
- PROMIS measures capability of physical functioning, with questions related to daily activities. Participants 8-17 years complete a self-report of physical function in the upper extremity or lower extremity (mobility), depending on the location of the PN. The recall period is 7 days. All PROMIS items are answered on a Likert scale with responses ranging from 1 to 5, with higher scores representing higher physical functioning in the upper extremities. The total raw score will be calculated as the sum of the individual item responses at a given visit (total raw scale range 8-40). The total raw scores for the measure will be converted to T-scores using the applicable score conversion table in the user manual and scoring instructions (PROMIS, 2023) ranging from 10 to 57 for self-report, and 13 to 55 for parent proxy with higher scores representing higher reported physical functioning and better outcomes. A T-score of 50 indicates the population mean with a standard deviation of 10.
- measure
- Change From Baseline in Physical Function Status as Measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) at Cycle 13: Pediatric v2.0 Upper Extremities 8a.
- time Frame
- Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months
- primary Outcomes
- description
- 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.
- measure
- Confirmed Objective Response Rate at the End of the Treatment Phase.
- time Frame
- Up to 24 months
- secondary Outcomes
- description
- 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.
- measure
- Percentage of Patients With Treatment-Emergent Adverse Events.
- time Frame
- 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.
- description
- 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.
- measure
- Duration of Response (DOR) for Participants Who Meet Criteria for Confirmed Objective Response.
- time Frame
- 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
- description
- 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.
- measure
- Change From Baseline on Quality of Life (QOL) as Measured by the Pediatric Quality of Life Inventory (PedsQL) at Cycle 13, Acute Version.
- time Frame
- Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months
- 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. The change from baseline is modelled using a mixed-model for repeated measures.
- measure
- Change From Baseline in Pain as Measured by the Numeric Rating Scale-11 (NRS-11) at Cycle 13.
- time Frame
- Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months
- 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 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.
- measure
- Change From Baseline in Pain as Measured by the Pain Interference Index (PII) at Cycle 13.
- time Frame
- Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months
Full study description
- 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).
Source references
- references
- citation
- Moertel CL, Hirbe AC, Shuhaiber HH, Bielamowicz K, Sidhu A, Viskochil D, Weber MD, Lokku A, Smith LM, Foreman NK, Hajjar FM, McNall-Knapp RY, Weintraub L, Antony R, Franson AT, Meade J, Schiff D, Walbert T, Ambady P, Bota DA, Campen CJ, Kaur G, Klesse LJ, Maraka S, Moots PL, Nevel K, Bornhorst M, Aguilar-Bonilla A, Chagnon S, Dalvi N, Gupta P, Khatib Z, Metrock LK, Nghiemphu PL, Roberts RD, Robison NJ, Sadighi Z, Stapleton S, Babovic-Vuksanovic D, Gershon TR; ReNeu Trial Investigators; ReNeu Study Investigators. ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma. J Clin Oncol. 2025 Feb 20;43(6):716-729. doi: 10.1200/JCO.24.01034. Epub 2024 Nov 8.
- pmid
- 39514826
- type
- DERIVED
Source notices and limitations
Discovery and provenance
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- nbsp;<a href="https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm">Drugs@FDA</a>.</p><h2>Efficacy and Safety</h2><p>Efficacy was evaluated in ReNeu (NCT03962543), a multicenter, single-arm trial in 114 patients ≥2 years of age (58 adults, 56 pediatric patients) with symptomatic, inoperable NF1-associated PN causing sig
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- 2025-02-11
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- source title
- FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection
Preserved source evidence · Not medical advice