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

Plexiform Neurofibroma Clinical Trial

— ReNeu  

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03962543
• Other study ID #: MEK-NF-201
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 29, 2019
• Est. completion date: May 23, 2025

Study information

• Verified date: March 2024
• Source: SpringWorks Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 114
• Est. completion date: May 23, 2025
• Est. primary completion date: September 20, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Neurofibroma
• Neurofibroma, Plexiform
• Neurofibromatoses
• Neurofibromatosis 1
• Neurofibromatosis Type 1 (NF1)
• Plexiform Neurofibroma

Intervention

Drug:
• Mirdametinib (PD-0325901) oral capsule or dispersible tablet
Mirdametinib (PD-0325901) capsule or dispersible tablet

Locations

Country	Name	City	State
United States	Albany Medical Center	Albany	New York
United States	University of Michigan CS Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Center for Advanced Pediatrics	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	University of Alabama at Birmingham/Children's of Alabama	Birmingham	Alabama
United States	Children's Hospital at Montefiore	Bronx	New York
United States	UNC Medical Center	Chapel Hill	North Carolina
United States	UVA Health, Division of Neuro-Oncology	Charlottesville	Virginia
United States	University of Chicago Medical Centers	Chicago	Illinois
United States	University of Illinois Hospital and Health Systems	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Children's Medical Center	Dallas	Texas
United States	Henry Ford Hospital	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Clinical Research Center	Gainesville	Florida
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	IU Health Brain Tumor Infusion Clinic	Indianapolis	Indiana
United States	University of Iowa Hospitals & Clinics	Iowa City	Iowa
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	Kosair Charities Pediatric Clinical Research Unit	Louisville	Kentucky
United States	Nicklaus Children's Hospital	Miami	Florida
United States	MACC Fund Research Center	Milwaukee	Wisconsin
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Henry-Joyce Cancer Clinic	Nashville	Tennessee
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	University of Oklahoma Health Sciences Center, Jimmy Everest Center for Cancer and Blood Disorders in Children	Oklahoma City	Oklahoma
United States	Children's Hospital of Orange County	Orange	California
United States	University of California - Irvine Health	Orange	California
United States	AdventHealth Pediatric Oncology Hematology at Orlando	Orlando	Florida
United States	Orlando Health, Inc.	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford	Palo Alto	California
United States	St. Joseph's Univeristy Medical Center	Paterson	New Jersey
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California - Davis Comprehensive Cancer Center	Sacramento	California
United States	Washington University School of Medicine-Siteman Cancer Center	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	University of Utah, Center for Clinical and Translational Sciences	Salt Lake City	Utah
United States	Swedish Medical Center - Cherry Hill Campus	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	Nemours A. I. duPont Hospital for Children	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
SpringWorks Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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