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

Primary Purpose

Plexiform Neurofibroma, Neurofibromatosis Type 1 (NF1)

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Mirdametinib (PD-0325901) oral capsule or dispersible tablet
Sponsored by
SpringWorks Therapeutics, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Plexiform Neurofibroma focused on measuring Neurofibromatoses, Neurofibromatosis 1, Plexiform Neurofibroma, PD-0325901, MEK Inhibitor, Neurofibroma, Mirdametinib

Eligibility Criteria

2 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Alabama at Birmingham/Children's of Alabama
  • Mayo Clinic Hospital
  • Arkansas Children's Hospital
  • Children's Hospital Los Angeles
  • UCLA Oncology Center
  • University of California - Irvine Health
  • Children's Hospital of Orange County
  • Lucile Packard Children's Hospital Stanford
  • University of California - Davis Comprehensive Cancer Center
  • Children's Hospital Colorado
  • Nemours A. I. duPont Hospital for Children
  • Children's National Medical Center
  • University of Florida Clinical Research Center
  • Nicklaus Children's Hospital
  • AdventHealth Pediatric Oncology Hematology at Orlando
  • Orlando Health, Inc.
  • Johns Hopkins All Children's Hospital
  • Moffitt Cancer Center
  • Children's Healthcare of Atlanta - Center for Advanced Pediatrics
  • University of Illinois Hospital and Health Systems
  • University of Chicago Medical Centers
  • IU Health Brain Tumor Infusion Clinic
  • University of Iowa Hospitals & Clinics
  • Kosair Charities Pediatric Clinical Research Unit
  • University of Michigan CS Mott Children's Hospital
  • Henry Ford Hospital
  • University of Minnesota/Masonic Cancer Center
  • Mayo Clinic
  • Washington University School of Medicine-Siteman Cancer Center
  • St. Joseph's Univeristy Medical Center
  • Albany Medical Center
  • Children's Hospital at Montefiore
  • UNC Medical Center
  • Duke University Medical Center
  • University of Cincinnati Medical Center
  • Cincinnati Children's Hospital Medical Center
  • Cleveland Clinic Foundation
  • Nationwide Children's Hospital
  • University of Oklahoma Health Sciences Center, Jimmy Everest Center for Cancer and Blood Disorders in Children
  • Oregon Health and Science University
  • Children's Hospital of Pittsburgh UPMC
  • Henry-Joyce Cancer Clinic
  • Children's Medical Center
  • Cook Children's Medical Center
  • The University of Texas MD Anderson Cancer Center
  • University of Utah, Center for Clinical and Translational Sciences
  • UVA Health, Division of Neuro-Oncology
  • Children's Hospital of The King's Daughters
  • Swedish Medical Center - Cherry Hill Campus
  • MACC Fund Research Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Mirdametinib (PD-0325901)

Arm Description

Mirdametinib (PD-0325901) capsule or dispersible tablet 2 mg/m^2 (maximum dose of 4 mg) by mouth twice daily

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
April 12, 2019
Last Updated
October 18, 2023
Sponsor
SpringWorks Therapeutics, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03962543
Brief Title
MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
September 29, 2019 (Actual)
Primary Completion Date
November 23, 2023 (Anticipated)
Study Completion Date
May 23, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
SpringWorks Therapeutics, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Plexiform Neurofibroma, Neurofibromatosis Type 1 (NF1)
Keywords
Neurofibromatoses, Neurofibromatosis 1, Plexiform Neurofibroma, PD-0325901, MEK Inhibitor, Neurofibroma, Mirdametinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
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
None (Open Label)
Allocation
N/A
Enrollment
114 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Mirdametinib (PD-0325901)
Arm Type
Experimental
Arm Description
Mirdametinib (PD-0325901) capsule or dispersible tablet 2 mg/m^2 (maximum dose of 4 mg) by mouth twice daily
Intervention Type
Drug
Intervention Name(s)
Mirdametinib (PD-0325901) oral capsule or dispersible tablet
Other Intervention Name(s)
PD-0325901, Mirdametinib
Intervention Description
Mirdametinib (PD-0325901) capsule or dispersible tablet
Primary Outcome Measure Information:
Title
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.
Description
Response will be determined by a blinded centralized review of volumetric MRI.
Time Frame
Up to 24 months
Secondary Outcome Measure Information:
Title
Incidence of treatment-emergent adverse events.
Description
Adverse events will be assessed according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Time Frame
Up to 24 months
Title
Duration of response (DOR) for participants who meet criteria for objective response rate.
Description
Response will be determined by a blinded centralized review of volumetric MRI.
Time Frame
Up to 24 months
Title
Change from Baseline on quality of life (QOL) as measured by the Pediatric Quality of Life Inventory (PedsQL), Acute version.
Description
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.
Time Frame
Up to 24 months
Title
Change from Baseline in pain as measured by the Numeric Rating Scale-11 (NRS-11).
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.
Time Frame
Up to 24 months
Title
Change from Baseline in pain as measured by the Pain Interference Index (PII).
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 age 6-17 complete a parent proxy report. The recall period is 24 hours.
Time Frame
Up to 24 months
Other Pre-specified Outcome Measures:
Title
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).
Description
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.
Time Frame
Up to 24 months
Title
Change from Baseline in localized strength.
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.
Time Frame
Up to 24 months
Title
Change from Baseline in range of motion of PN-associated functional impairment.
Description
If motor dysfunction or weakness is evident, range of motion of the affected areas and/or joints will be measured by a goniometer.
Time Frame
Up to 24 months
Title
Change from Baseline in endurance.
Description
If airway or lower extremity motor dysfunction is evident, endurance will be measured by completion of a 6-minute walking test.
Time Frame
Up to 24 months
Title
Time to Response defined as the time between first dose and the first date of objective response.
Description
Response will be determined by a blinded centralized review of volumetric MRI.
Time Frame
Up to 24 months
Title
Time to progression, from the first dose to the date of a ≥ 20% increase in tumor volume.
Description
Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.
Time Frame
Up to 24 months
Title
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.
Description
Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.
Time Frame
Up to 24 months
Title
Change from Baseline in PN-associated disfigurement using standardized photography, centrally reviewed.
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.
Time Frame
Up to 24 months
Title
Comparison of tumor response to levels of pERK and biomarkers indicative of inhibition of downstream targets of MEK (eg, ERK phosphorylation).
Description
Measured in tumor biopsies in participants ≥ 18 years of age.
Time Frame
Up to 24 months
Title
Acceptability of the dispersible tablet formulation as measured by the Pediatric Oral Medicine Acceptability Questionnaire (P-OMAQ)
Description
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.
Time Frame
up to 7 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
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.
Facility Information:
Facility Name
University of Alabama at Birmingham/Children's of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
Mayo Clinic Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
Arkansas Children's Hospital
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72202
Country
United States
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
UCLA Oncology Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of California - Irvine Health
City
Orange
State/Province
California
ZIP/Postal Code
92868-3201
Country
United States
Facility Name
Children's Hospital of Orange County
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Lucile Packard Children's Hospital Stanford
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
University of California - Davis Comprehensive Cancer Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Nemours A. I. duPont Hospital for Children
City
Wilmington
State/Province
Delaware
ZIP/Postal Code
19803
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
University of Florida Clinical Research Center
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Nicklaus Children's Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33155
Country
United States
Facility Name
AdventHealth Pediatric Oncology Hematology at Orlando
City
Orlando
State/Province
Florida
ZIP/Postal Code
32804
Country
United States
Facility Name
Orlando Health, Inc.
City
Orlando
State/Province
Florida
ZIP/Postal Code
32806
Country
United States
Facility Name
Johns Hopkins All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Children's Healthcare of Atlanta - Center for Advanced Pediatrics
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30329
Country
United States
Facility Name
University of Illinois Hospital and Health Systems
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
University of Chicago Medical Centers
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
IU Health Brain Tumor Infusion Clinic
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
University of Iowa Hospitals & Clinics
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Kosair Charities Pediatric Clinical Research Unit
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
University of Michigan CS Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
University of Minnesota/Masonic Cancer Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Washington University School of Medicine-Siteman Cancer Center
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
St. Joseph's Univeristy Medical Center
City
Paterson
State/Province
New Jersey
ZIP/Postal Code
07503
Country
United States
Facility Name
Albany Medical Center
City
Albany
State/Province
New York
ZIP/Postal Code
12208
Country
United States
Facility Name
Children's Hospital at Montefiore
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
UNC Medical Center
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
University of Cincinnati Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
University of Oklahoma Health Sciences Center, Jimmy Everest Center for Cancer and Blood Disorders in Children
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Children's Hospital of Pittsburgh UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Henry-Joyce Cancer Clinic
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Children's Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
Cook Children's Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
The University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Utah, Center for Clinical and Translational Sciences
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84108
Country
United States
Facility Name
UVA Health, Division of Neuro-Oncology
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22903
Country
United States
Facility Name
Children's Hospital of The King's Daughters
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23510
Country
United States
Facility Name
Swedish Medical Center - Cherry Hill Campus
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122
Country
United States
Facility Name
MACC Fund Research Center
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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