Clinical Trials /

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

NCT03962543

Description:

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.

Related Conditions:
  • Neurofibromatosis Type 1
  • Plexiform Neurofibroma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: MEK Inhibitor PD-0325901 in Patients With Neurofibromatosis Type 1 (NF1)-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

Clinical Trial IDs

  • ORG STUDY ID: MEK-NF-201
  • NCT ID: NCT03962543

Conditions

  • Plexiform Neurofibroma
  • Neurofibromatosis Type 1 (NF1)

Interventions

DrugSynonymsArms
PD-0325901 oral capsulePD-0325901PD-0325901

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
PD-0325901ExperimentalPD-0325901 capsule 2 mg/m^2 (maximum dose of 4 mg) by mouth twice daily
  • PD-0325901 oral capsule

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.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Response will be determined by a blinded centralized review of volumetric MRI.

Secondary Outcome Measures

Measure:Incidence of treatment-emergent adverse events
Time Frame:Up to 24 months
Safety Issue:
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.
Measure:Duration of response (DOR) for participants who meet criteria for objective response rate.
Time Frame:Up to 24 months
Safety Issue:
Description:Response will be determined by a blinded centralized review of volumetric MRI.
Measure: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
Safety Issue:
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.
Measure:Change from Baseline in pain as measured by the Numeric Rating Scale-11 (NRS-11).
Time Frame:Up to 24 months
Safety Issue:
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.
Measure:Change from Baseline in pain as measured by the Pain Interference Index (PII).
Time Frame:Up to 24 months
Safety Issue:
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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:SpringWorks Therapeutics, Inc.

Trial Keywords

  • Neurofibromatoses
  • Neurofibromatosis 1
  • Plexiform Neurofibroma
  • PD-0325901
  • MEK Inhibitor
  • Neurofibroma

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