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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03962543
Recruitment Status : Recruiting
First Posted : May 24, 2019
Last Update Posted : January 13, 2020
Information provided by (Responsible Party):
SpringWorks Therapeutics, Inc.

Brief Summary:
This study evaluates PD-0325901 in the treatment of symptomatic inoperable neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PNs). All participants will receive PD-0325901.

Condition or disease Intervention/treatment Phase
Plexiform Neurofibroma Neurofibromatosis Type 1 (NF1) Drug: PD-0325901 oral capsule Phase 2

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).

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 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 PD-0325901.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Intervention Model Description: All participants will receive 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)
Primary Purpose: Treatment
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
Actual Study Start Date : September 6, 2019
Estimated Primary Completion Date : July 31, 2022
Estimated Study Completion Date : July 31, 2022

Arm Intervention/treatment
Experimental: PD-0325901
PD-0325901 capsule 2 mg/m^2 (maximum dose of 4 mg) by mouth twice daily
Drug: PD-0325901 oral capsule
PD-0325901 capsule
Other Name: PD-0325901

Primary Outcome Measures :
  1. Complete or partial response rate compared to baseline. Partial response is defined as a ≥ 20% reduction in target tumor volume. [ Time Frame: Up to 24 months ]
    Response will be determined by a blinded centralized review of volumetric MRI.

Secondary Outcome Measures :
  1. Incidence of treatment-emergent adverse events [ Time Frame: Up to 24 months ]
    Adverse events will be assessed according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

  2. Duration of response (DOR) for participants who meet criteria for objective response rate. [ Time Frame: Up to 24 months ]
    Response will be determined by a blinded centralized review of volumetric MRI.

  3. Change from Baseline on quality of life as measured by the Pediatric Quality of Life Inventory (PedsQL), Acute version. [ Time Frame: Up to 24 months ]
    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.

  4. Change from Baseline in pain as measured by the Numeric Rating Scale-11 (NRS-11). [ Time Frame: Up to 24 months ]
    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.

  5. Change from Baseline in pain as measured by the Pain Interference Index (PII). [ Time Frame: Up to 24 months ]
    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.

Other Outcome Measures:
  1. 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). [ Time Frame: Up to 24 months ]
    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.

  2. Change from Baseline in localized strength. [ Time Frame: Up to 24 months ]
  3. Change from Baseline in range of motion of PN-associated functional impairment. [ Time Frame: Up to 24 months ]
  4. Change from Baseline in endurance. [ Time Frame: Up to 24 months ]
  5. Time to Response defined as the time between first dose and the first date of objective response. [ Time Frame: Up to 24 months ]
    Response will be determined by a blinded centralized review of volumetric MRI.

  6. Time to progression, from the first dose to the date of a ≥ 20% increase in tumor volume. [ Time Frame: Up to 24 months ]
    Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.

  7. 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. [ Time Frame: Up to 24 months ]
    Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.

  8. Change from Baseline in PN-associated disfigurement using standardized photography, centrally reviewed. [ Time Frame: Up to 24 months ]
    For participants with a PN that is visible and amenable to photography, changes in visible tumor aspects will be evaluated by a centralized reviewer.

  9. 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 ]
    Measured in tumor biopsies in participants ≥ 18 years of age.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   2 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.
  • Participant can swallow capsules whole.

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 PD-0325901
  • Participant has received NF1 PN-targeted therapy within 28 days.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03962543

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Contact: Nicole H Leedom 984-204-8065

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Sponsors and Collaborators
SpringWorks Therapeutics, Inc.

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Responsible Party: SpringWorks Therapeutics, Inc. Identifier: NCT03962543    
Other Study ID Numbers: MEK-NF-201
First Posted: May 24, 2019    Key Record Dates
Last Update Posted: January 13, 2020
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by SpringWorks Therapeutics, Inc.:
Neurofibromatosis 1
Plexiform Neurofibroma
MEK Inhibitor
Additional relevant MeSH terms:
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Neurofibromatosis 1
Neurofibroma, Plexiform
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms