Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: St. Jude Children's Research Hospital
Must not be taking: MEK inhibitors
Disqualifiers: Retinal pathology, Malabsorption, Liver disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial tests mirdametinib, a drug that blocks cancer growth signals, in children and young adults with specific types of brain tumors. It aims to see if the drug is safe and effective in slowing down or stopping tumor growth. Mirdametinib has been tested in studies for neurofibromatosis type 1-related plexiform neurofibromas.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, if you are taking P-gp and BCRP inhibitors, you must stop them at least a week or 5 half-lives before starting the trial medication. Also, if you are on corticosteroids, your dose must be stable or decreasing for at least a week before enrollment.
What makes the drug Mirdametinib unique for treating brain tumors?
Mirdametinib is a MEK inhibitor, which means it targets a specific part of the cell signaling pathway involved in tumor growth, making it potentially effective for brain tumors with certain genetic mutations. This approach is different from traditional chemotherapy, which targets all rapidly dividing cells, and may offer a more targeted treatment option for patients with specific tumor profiles.
12345Eligibility Criteria
This trial is for children, adolescents, and young adults up to 25 years old with a specific type of brain tumor called low-grade glioma. They must have relapsed or progressed after previous treatments but can't have had any MEK inhibitors before (except in certain cases). Participants need proper organ function and no history of liver disease or other serious medical conditions that could affect the study.Inclusion Criteria
Participant and/or guardian can understand and is willing to sign a written informed consent document according to institutional guidelines
I am between 2 and 25 years old at the time of joining the study.
I have recovered from my previous cancer treatments.
+16 more
Exclusion Criteria
I have a known liver disease or liver-related condition.
I have glaucoma that is not well-managed.
I have a condition that affects how my body absorbs medication.
+8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase 1 Treatment
Participants receive mirdametinib to determine safety, tolerability, and maximum tolerated dose. Treatment is administered in cycles of 28 days.
Up to 25 months
Monthly visits for dose adjustments and monitoring
Phase 2 Treatment
Participants receive mirdametinib at the recommended phase 2 dose to evaluate efficacy and safety. Treatment is administered in cycles of 28 days.
Up to 24 months
Monthly visits for efficacy and safety assessments
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 5 years
Periodic visits for long-term monitoring
Participant Groups
The trial is testing Mirdametinib, a drug designed to penetrate the brain and target tumors by inhibiting a protein called MEK. It's an open-label Phase 1/2 study, meaning both researchers and participants know what treatment is being given, aimed at seeing how well this drug works in pediatric patients with low-grade glioma.
5Treatment groups
Experimental Treatment
Group I: Phase I: Recurrent and/or progressive low-grade glioma without prior exposure to MEK inhibitorsExperimental Treatment1 Intervention
Participants will receive mirdametinib at one of the dose levels twice daily days 1-28. For the first cycle of treatment, participants will take mirdametinib tablets dissolved in water. After the first cycle of treatment, participants may receive the medicine the same way (dissolved in water) or may receive capsules. Treatment repeats every 28 days for up to 26 cycles of treatment (24 months) in the absence of disease progression or unacceptable toxicity.
Group II: Phase 2, Cohort 3b:Experimental Treatment1 Intervention
Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
Group III: Phase 2, Cohort 3a:Experimental Treatment1 Intervention
Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants with previous exposure to mirdametinib may receive a starting dose lower than the RP2D, depending on the dose they tolerated during their previous exposure. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
Group IV: Phase 2, Cohort 2: Recurrent and/or Progressive without prior exposure to MEK inhibitorsExperimental Treatment1 Intervention
Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
Group V: Phase 2, Cohort 1: Newly diagnosed and/or previously untreated (except surgery)Experimental Treatment1 Intervention
Participants will receive the RP2D of mirdametinib. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
St. Jude Children's Research HospitalMemphis, TN
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Who Is Running the Clinical Trial?
St. Jude Children's Research HospitalLead Sponsor
SpringWorks Therapeutics, Inc.Industry Sponsor
References
Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. [2023]Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT.
FDA Approval Summary: Dabrafenib in combination with trametinib for BRAF V600E mutation-positive low-grade glioma. [2023]On March 16, 2023, the U.S. Food and Drug Administration (FDA) approved dabrafenib in combination with trametinib (Tafinlar®, Mekinist®, Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from Study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAF V600E mutation were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on RANO LGG (2017) criteria was assessed in 110 patients randomized to D+T (n=73) or C+V (n=37). ORR was 47% (95% CI: 35, 59) in the D+T arm and 11% (95% CI: 3.0, 25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI: 14.5, NE) in the D+T arm and not estimable (95% CI: 6.6, NE) in the C+V arm. Progression-free-survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI: 3.6, 11.8) (HR=0.31 [95% CI: 0.17, 0.55]; p= 20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAF V600E mutation.
BRAF inhibitors in BRAF-V600 mutated primary neuroepithelial brain tumors. [2016]Primary neuroepithelial brain tumors encompass a wide variety of glial and glioneuronal neoplasms. Malignant tumors, tumors located in surgically inaccessible locations (e.g., eloquent brain areas, deep structures, brain stem) and recurrent or progressive tumors pose considerable treatment challenges and are candidates for novel therapeutics based on molecular insights. Small kinase inhibitors of v-RAF murine sarcoma viral oncogene homologue B1 (BRAF) have shown considerable antineoplastic activity in some tumor types harboring activating BRAF-V600 mutations (e.g., melanoma) and promising data are emerging on BRAF inhibitor therapy of mutation-bearing primary brain tumors.
Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. [2022]Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.
Targeted therapy for BRAFV600E malignant astrocytoma. [2022]Malignant astrocytomas (MA) are aggressive central nervous system tumors with poor prognosis. Activating mutation of BRAF (BRAF(V600E)) has been reported in a subset of these tumors, especially in children. We have investigated the incidence of BRAF(V600E) in additional pediatric patient cohorts and examined the effects of BRAF blockade in preclinical models of BRAF(V600E) and wild-type BRAF MA.