Efficacy of Mirdametinib Alone or Combination With Radiotherapy for Germline and Sporadic NF1-Altered High-Grade Glioma

NCT07521657 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: IRB-300016184
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase 2, open label, parallel multi-arm study of mirdametinib in combination with radiation in participants with recurrent sporadic glioblastoma (GBM) harboring NF1 alterations (Cohort 1); participants with NF1 with a newly diagnosed GBM (Cohort 2); mirdametinib alone in other NF1-associated High-Grade Gliomas (Cohort 3).

Conditions

Neurofibromatosis 1 (NF1)

Keywords

Neurofibromatosis 1; NF1; gliomas; glioblastoma; High-Grade Gliomas (HHG); High-Grade Astrocytoma with Piloid Features (HGAP)

Outcome Measures

Primary Outcomes (3)

• Cohort 1

  Estimate overall survival at 12 months in participants with recurrent sporadic GBM harboring an NF1 alteration treated with repeat irradiation in combination with mirdametinib.

  From treatment to 12 months

• Cohort 2

  Estimate overall survival at 18 months in participants with a newly-diagnosed NF1-associated GBM treated with irradiation in combination with mirdametinib in Cohort 2.

  From treatment to 18 months

• Cohort 3

  Estimate response rate at six months in participants with germline NF1 and HGAP or a non-GBM high grade glioma. Tumor response is based on MRI imaging per RANO 2.0 guidelines.

  From treatment to 6 months

Study Arms (3)

Cohort 1: Recurrent, sporadic glioblastoma (not NF1)

EXPERIMENTAL

Participants with recurrent sporadic glioblastoma (GBM) harboring NF1 alterations will receive mirdametinib and radiation.

Combination Product: mirdametinib with radiation

Cohort 2: New diagnosed glioblastoma with no prior therapy (NF1 participants only)

EXPERIMENTAL

NF1 participants with new glioblastoma (GBM) will receive mirdametinib and radiation.

Combination Product: mirdametinib with radiation

Cohort 3: HGAP or HGG not meeting criteria for Cohort 2 (NF1 participants only)

EXPERIMENTAL

NF1 participants with High-Grade Astrocytoma with Piloid Features (HGAP) or other NF1-associated HGG not meeting criteria for Cohort 2 will receive mirdametinib alone.

Drug: mirdametinib

Interventions

mirdametinib with radiation COMBINATION_PRODUCT

Participants in Cohorts 1 and 2 will receive mirdametinib in combination with radiation therapy followed by mirdametinib alone.

Cohort 1: Recurrent, sporadic glioblastoma (not NF1); Cohort 2: New diagnosed glioblastoma with no prior therapy (NF1 participants only)

mirdametinib DRUG

Participants in Cohort 3 will receive mirdametinib alone.

Cohort 3: HGAP or HGG not meeting criteria for Cohort 2 (NF1 participants only)

Eligibility Criteria

• Age: 12 Years - 89 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Tumor diagnosis:
• Cohort 1 (applies to non-NF1 related GBM): GBM, IDH-wildtype grade 4 of brain or spinal cord by WHO 2021 central nervous system tumor diagnostic criteria52 that is recurrent after irradiation and first-line chemotherapy (if appropriate). Any number of prior recurrences is acceptable. Tumor Next Generation Sequencing (NGS) must demonstrate at least one pathogenic/likely pathogenic NF1 alteration (known or suspected to confer loss of function) at time of first or recurrent surgery that could putatively confer loss-of-function.
• Cohort 2 (applies to participants with NF1): Pathology consistent with GBM, IDH-wildtype grade 4 by WHO 2021 CNS tumor diagnostic criteria or HGG with somatic TP53 mutation (brain or spinal cord). Participants may not have received any therapy beyond surgical resection for the target HGG.
• Cohort 3 (applies to participants with NF1): HGAP (including low-grade glioma classified as HGAP by methylation profiling) or other HGG not meeting criteria for Cohort 2. Participants may not have received prior therapy for the HGG.
• Neurofibromatosis 1:
• Cohort 1: Participants may not have a diagnosis of NF1.
• Cohort 2/3: All participants must have a diagnosis of NF1 based on the 2021 revised consensus criteria.
• Age: Cohort 1: Participants must be ≥ 18 years of age at the time of enrollment. Cohorts 2/3: Participants must be ≥ 12 years of age at the time of enrollment.
• Performance Level: Participants must have performance status of \>= 60 using Karnofsky for participants aged \>= 16 years, and Lansky for participants \< 16 years of age.
• Cohort 3: Participants must have measurable disease by RANO 2.0 HGG or LGG criteria on baseline MRI.
• Participants must have available archival tissue from the HGG or GBM of interest. Tissue blocks strongly preferred and will be returned to sending site at end of study. Exceptions may be made following discussion with study team if tissue has been exhausted and methylation profiling already performed.
• Organ Function Requirements:
• Adequate bone marrow function defined as:
• Absolute neutrophil count \> 1,000/mcL
• Platelets \> 100,000/mcL

You may not qualify if:

• Tumor positive for pathogenic IDH-mutation, H3.1 or H3.3 mutation, or BRAF alteration.
• Participant has not recovered to ≤ Grade 1 non-hematologic toxic effects of prior therapy before starting study treatment. Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and may enroll.
• Prior MEK inhibitor therapy:
• Cohort 1: Prior MEK inhibitor therapy contraindicated
• Cohorts 2/3: Prior MEK inhibitor therapy to target glioma contraindicated (even if the target tumor was previously suspected or biopsy-proven low-grade glioma). No oral MEK inhibitor therapy in the past 12 months for other manifestations of NF1 (including non-target glioma).
• Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, any of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) ≤ 180 days prior to start date;
• Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
• Left ventricular ejection fraction (LVEF) \< 50% as determined by MUGA or ECHO;
• Baseline QTc interval \> 450 msec;
• History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia).
• Impairment of gastrointestinal function or disease which may significantly alter the absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal absorption), or recent (≤ 90 days) history of a partial or complete bowel obstruction, or other conditions that will interfere significantly with the absorption of oral drugs.
• History of recent (≤ 90 days) thromboembolic or cerebrovascular event such as transient ischemic attack, cerebrovascular accident, or hemodynamically significant (massive or sub-massive) deep vein thrombosis or pulmonary emboli (DVT/PE). Note: Participants with DVT/PE that does not result in hemodynamic instability may enroll as long as they are anticoagulated for at least 4 weeks.
• Other Malignancies:
• Cohort 1: Participants must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Participants with other malignancies must be disease-free for \> 2 years.

Sponsors & Collaborators

• Children's Hospital of Philadelphia: collaborator
• University of Alabama at Birmingham: lead
• Congressionally Directed Medical Research Programs: collaborator

Study Sites (1)

Childrens of Alabama

Birmingham, Alabama, 34294, United States

Location

MeSH Terms

Conditions

Neurofibromatosis 1; Glioma; Glioblastoma

Interventions

mirdametinib; Radiation

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Astrocytoma

Intervention Hierarchy (Ancestors)

Physical Phenomena

Study Officials

• Girish Dhall, MD

  University of Alabama at Birmingham

  STUDY DIRECTOR

Central Study Contacts

Juliette Southworth, BS

CONTACT

2055298967; jsouthworth@uab.edu

Karen Cole-Plourde, BA

CONTACT

2055141317; kplourde@uab.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chair of NFCTC

Study Record Dates

• First Submitted: April 3, 2026
• First Posted: April 13, 2026
• Study Start: August 1, 2026
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): August 1, 2031
• Last Updated: April 13, 2026

Record last verified: 2026-01

Locations

US (1)