Mirdametinib plus vinblastine for newly diagnosed pediatric low-grade glioma with MAPK activation

A Phase 1/2 Study of Mirdametinib and Vinblastine for Newly Diagnosed or Previously Untreated Patients With Pediatric Low-grade Glioma and Activation of the MAPK Pathway

This trial will test whether giving oral mirdametinib together with weekly vinblastine helps children and young adults (ages 2–25) with newly diagnosed low-grade glioma that shows MAPK pathway activation.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 2 Years to 25 Years
• Sex: All
• Sponsor: St. Justine's Hospital (other)
• Drugs / interventions: mirdametinib, chemotherapy
• Locations: 5 sites (Edmonton, Alberta and 4 other locations)
• Trial ID: NCT06666348 on ClinicalTrials.gov

What this trial studies

This is an open-label Phase 1/2 study combining the MEK inhibitor mirdametinib with weekly intravenous vinblastine in patients with newly diagnosed pediatric low-grade glioma that has MAPK pathway activation. A feasibility lead-in using a modified Rolling-6 design will determine the maximum tolerated/recommended Phase 2 dose of the combination, with mirdametinib given continuously (2 mg/m2 twice daily up to 4 mg BID) and vinblastine given weekly. In the treatment phase patients receive 13 cycles of continuous mirdametinib (28-day cycles) and up to 17 weekly vinblastine cycles, with up to two dose reductions allowed for toxicity. After treatment, patients are followed every six months for 36 months to document progression-free survival, time to progression, and overall survival.

Who should consider this trial

Good fit: Children and young adults aged 2 to 25 years with newly diagnosed, previously untreated PLGG that shows MAPK pathway activation (including NF1 or KIAA1549-BRAF fusion but excluding tumors with BRAF V600E), a BSA ≥ 0.40 m2, and available tumor tissue (or clinical NF1 diagnosis) are ideal candidates.

Not a fit: Patients with PLGG harboring BRAF V600E, those who have received prior definitive therapy for their tumor, or patients unable to tolerate oral therapy or frequent hospital visits are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the combination could improve tumor control and lengthen progression-free survival compared with historical outcomes for newly diagnosed PLGG while potentially reducing the need for more toxic therapies.

How similar studies have performed: Single-agent MEK inhibitors (for example selumetinib) have shown activity in PLGG and vinblastine is an established chemotherapy for this disease, so the combination builds on prior positive single-agent experience though the specific combo is relatively novel.

Eligibility criteria

Inclusion Criteria:

* Signed written informed consent prior to study participation.
* Study activities compliance: must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by contrast enhanced MRI.
* Aged ≥ 2 years to ≤ 25 years when starting mirdametinib.
* BSA ≥ 0,40m2
* Diagnosis:

Participants must have PLGG with NF1 gene mutation (based on clinical NIH criteria, germline NF1 mutation or molecular analysis of the tumor) or PLGG with KIAA1549-BRAF fusion (based on molecular analysis of the tumor) or PLGG with evidence of MAPK pathway alteration with the exception of patients with BRAF V600E mutation (based on molecular analysis of the tumor).

* Tumor tissue is required (at minimum, paraffin-embedded tissue block and additionally fresh frozen tissue \[if available\]). Patients with NF1 and Low Grade Glioma (LGG) can still be enrolled without tissue if no surgery or biopsy was conducted.
* Baseline MRI.
* Life expectancy greater than 6 months.
* Lansky/Karnofsky score ≥ 50.
* Normal organ and marrow function (see study protocol for specifics).
* Female and male patients of fertile age must agree to use highly effective contraceptive measures.
* Must be able to ingest by mouth and retain entirely the administered medication. Mirdametinib can not be administered via nasogastric tube or gastrostomy tube.

Exclusion Criteria:

* Patients who are receiving other investigational agents.
* Cardiac: QTcB ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 49%.
* Patients who have any other malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
* Tumor with BRAF V600E mutation.
* Patients who received previous systemic or radiotherapy treatment.
* Other severe and uncontrollable medical disease
* Blood pressure higher than 95th percentile for patient's age, height and gender.
* Increased risk of serious retinopathy and retinal vein occlusion.
* Known diagnosis of human immunodeficiency virus infection, hepatitis B or C.
* Previous major surgery within 2 weeks.
* History of allergic reactions to compounds of similar chemical or biological composition to mirdametinib.
* Pregnant or breastfeeding.

Where this trial is running

Edmonton, Alberta and 4 other locations

• Stollery Children's Hospital — Edmonton, Alberta, Canada (RECRUITING)
• Childrens and Womens Health Centre of British Columbia - British Columbia Childrens Hospital — Vancouver, British Columbia, Canada (RECRUITING)
• Children's Hospital, London Health Sciences Centre — London, Ontario, Canada (RECRUITING)
• The Hospital for Sick Children — Toronto, Ontario, Canada (RECRUITING)
• CHU Sainte-Justine — Montreal, Quebec, Canada (RECRUITING)

Study contacts

• Study coordinator: Sébastien Perreault, M.D, FRCPC

Conditions: Pediatric Low-grade Glioma, PLGG, Pediatric PLGG, Pediatric, MAPK, NF1, KIAA1549-BRAF, pediatric low-grade glioma