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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Plexiform Neurofibroma; Neurofibromatosis Type 1 (NF1)
• Intervention / Treatment: Drug: Mirdametinib (PD-0325901) oral capsule or dispersible tablet

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).

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham/Children's of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90095
      • UCLA Oncology Center
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Orange, California, United States, 92868-3201
      • University of California - Irvine Health
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford
    • Sacramento, California, United States, 95817
      • University of California - Davis Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours A. I. duPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Clinical Research Center
    • Miami, Florida, United States, 33155
      • Nicklaus Children's Hospital
    • Orlando, Florida, United States, 32806
      • Orlando Health, Inc.
    • Orlando, Florida, United States, 32804
      • AdventHealth Pediatric Oncology Hematology at Orlando
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta - Center for Advanced Pediatrics
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Hospital and Health Systems
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Centers
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • IU Health Brain Tumor Infusion Clinic
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Charities Pediatric Clinical Research Unit
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan CS Mott Children's Hospital
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine-Siteman Cancer Center
  • New Jersey
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Univeristy Medical Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Bronx, New York, United States, 10467
      • Children's Hospital at Montefiore
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center, Jimmy Everest Center for Cancer and Blood Disorders in Children
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh UPMC
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Henry-Joyce Cancer Clinic
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah, Center for Clinical and Translational Sciences
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • UVA Health, Division of Neuro-Oncology
    • Norfolk, Virginia, United States, 23510
      • Children's Hospital of The King's Daughters
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center - Cherry Hill Campus
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • MACC Fund Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mirdametinib (PD-0325901); 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; Mirdametinib (PD-0325901) capsule or dispersible tablet; Other Names: PD-0325901; Mirdametinib

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in physical function status as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS): physical function/mobility/upper extremity short forms (8a and 8b).	PROMIS measures capability of physical functioning, with questions related to daily activities. Participants ≥ 18 years of age complete a self-report of physical function. Participants 8-17 years of age complete a self-report of physical function in the upper extremity or lower extremity (mobility), depending on location of the PN. Parents/guardians of children ages 2-17 complete a parent proxy report corresponding to the pediatric version. The recall period is 7 days.	Up to 24 months
Change from Baseline in localized strength.	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.	Up to 24 months
Change from Baseline in range of motion of PN-associated functional impairment.	If motor dysfunction or weakness is evident, range of motion of the affected areas and/or joints will be measured by a goniometer.	Up to 24 months
Change from Baseline in endurance.	If airway or lower extremity motor dysfunction is evident, endurance will be measured by completion of a 6-minute walking test.	Up to 24 months
Time to Response defined as the time between first dose and the first date of objective response.	Response will be determined by a blinded centralized review of volumetric MRI.	Up to 24 months
Time to progression, from the first dose to the date of a ≥ 20% increase in tumor volume.	Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.	Up to 24 months
Progression Free Survival, defined as the time in months from the first dose to the date of a ≥ 20% increase in tumor volume or death.	Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.	Up to 24 months
Change from Baseline in PN-associated disfigurement using standardized photography, centrally reviewed.	For participants with a PN that is visible and amenable to photography, changes in visible tumor aspects will be evaluated by a centralized reviewer.	Up to 24 months
Comparison of tumor response to levels of pERK and biomarkers indicative of inhibition of downstream targets of MEK (eg, ERK phosphorylation).	Measured in tumor biopsies in participants ≥ 18 years of age.	Up to 24 months
Acceptability of the dispersible tablet formulation as measured by the Pediatric Oral Medicine Acceptability Questionnaire (P-OMAQ)	The 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 . The recall period is 7 days.	up to 7 days

Collaborators and Investigators

• Sponsor: SpringWorks Therapeutics, Inc.
• Investigators: Principal Investigator: Christopher L Moertel, MD, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2019
• Primary Completion (Actual): September 20, 2023
• Study Completion (Estimated): May 23, 2025

Study Registration Dates

• First Submitted: April 12, 2019
• First Submitted That Met QC Criteria: May 22, 2019
• First Posted (Actual): May 24, 2019

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: PD-0325901; Neurofibromatosis 1; MEK Inhibitor; Neurofibroma; Plexiform Neurofibroma; Neurofibromatoses; Mirdametinib
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Nerve Sheath Neoplasms; Neurocutaneous Syndromes; Peripheral Nervous System Neoplasms; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform
• Other Study ID Numbers: MEK-NF-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: SpringWorks Therapeutics is committed to data transparency and sharing data to further research while maintaining the privacy and confidentiality of research participants. Pertinent patient-level data from completed registrational clinical trials will be made available by SpringWorks to qualified researchers upon approval of reasonable requests following de-identification/anonymization pursuant to applicable law.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No