Clinical trial NCT03962543: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Plexiform Neurofibroma
Neurofibromatosis Type 1 (NF1)
Keywords: Neurofibromatoses
Neurofibromatosis 1
Plexiform Neurofibroma
PD-0325901
MEK Inhibitor
Neurofibroma
Mirdametinib
Lead sponsor: SpringWorks Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2019-05-24
Enrollment: 114
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
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.
Primary purpose: TREATMENT

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 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).

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.

Primary outcomes:
measure: 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.
timeFrame: Up to 24 months
Secondary outcomes:
measure: Incidence of treatment-emergent adverse events.
timeFrame: Up to 24 months
measure: Duration of response (DOR) for participants who meet criteria for objective response rate.
timeFrame: Up to 24 months
measure: Change from Baseline on quality of life (QOL) as measured by the Pediatric Quality of Life Inventory (PedsQL), Acute version.
timeFrame: Up to 24 months
measure: Change from Baseline in pain as measured by the Numeric Rating Scale-11 (NRS-11).
timeFrame: Up to 24 months
measure: Change from Baseline in pain as measured by the Pain Interference Index (PII).
timeFrame: Up to 24 months
Other outcomes:
measure: 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).
timeFrame: Up to 24 months
measure: Change from Baseline in localized strength.
timeFrame: Up to 24 months
measure: Change from Baseline in range of motion of PN-associated functional impairment.
timeFrame: Up to 24 months
measure: Change from Baseline in endurance.
timeFrame: Up to 24 months
measure: Time to Response defined as the time between first dose and the first date of objective response.
timeFrame: Up to 24 months
measure: Time to progression, from the first dose to the date of a ≥ 20% increase in tumor volume.
timeFrame: Up to 24 months
measure: 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.
timeFrame: Up to 24 months
measure: Change from Baseline in PN-associated disfigurement using standardized photography, centrally reviewed.
timeFrame: Up to 24 months
measure: Comparison of tumor response to levels of pERK and biomarkers indicative of inhibition of downstream targets of MEK (eg, ERK phosphorylation).
timeFrame: Up to 24 months
measure: Acceptability of the dispersible tablet formulation as measured by the Pediatric Oral Medicine Acceptability Questionnaire (P-OMAQ)
timeFrame: up to 7 days
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham/Children's of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: UCLA Oncology Center
state: California
city: Orange
country: United States
facility: University of California - Irvine Health
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford
state: California
city: Sacramento
country: United States
facility: University of California - Davis Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Wilmington
country: United States
facility: Nemours A. I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Clinical Research Center
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Orlando
country: United States
facility: AdventHealth Pediatric Oncology Hematology at Orlando
state: Florida
city: Orlando
country: United States
facility: Orlando Health, Inc.
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Center for Advanced Pediatrics
state: Georgia
city: Chicago
country: United States
facility: University of Illinois Hospital and Health Systems
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Centers
state: Illinois
city: Indianapolis
country: United States
facility: IU Health Brain Tumor Infusion Clinic
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Louisville
country: United States
facility: Kosair Charities Pediatric Clinical Research Unit
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan CS Mott Children's Hospital
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine-Siteman Cancer Center
state: Missouri
city: Paterson
country: United States
facility: St. Joseph's Univeristy Medical Center
state: New Jersey
city: Albany
country: United States
facility: Albany Medical Center
state: New York
city: Bronx
country: United States
facility: Children's Hospital at Montefiore
state: New York
city: Chapel Hill
country: United States
facility: UNC Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center, Jimmy Everest Center for Cancer and Blood Disorders in Children
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh UPMC
state: Pennsylvania
city: Nashville
country: United States
facility: Henry-Joyce Cancer Clinic
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Center for Clinical and Translational Sciences
state: Utah
city: Charlottesville
country: United States
facility: UVA Health, Division of Neuro-Oncology
state: Virginia
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center - Cherry Hill Campus
state: Washington
city: Milwaukee
country: United States
facility: MACC Fund Research Center
state: Wisconsin
Study officials:
affiliation: University of Minnesota
name: Christopher L Moertel, MD
role: PRINCIPAL_INVESTIGATOR
References: