Phase 1/2 Study of Mirdametinib + Vinblastine for Newly Diagnosed/Previously Untreated PLGG + Activation of MAPK

NCT06666348 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: MIRV
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 5

Brief Summary

This is a 3-part open-label study (feasibility phase, treatment phase and follow-up phase) of orally administered mirdametinib in combination with intravenous vinblastine chemotherapy in patients with PLGG with activation of MAPK pathway. Feasibility Phase: The maximum tolerated/recommended phase 2 dose (MTD/RP2D) of the mirdametinib plus vinblastine combination will be assessed using a modified Rolling-6 design. Treatment Phase: Patients will receive mirdametinib twice daily (continuously) at a fixed dose (2mg/m2 po BID up to 4 mg BID) for a total of 13 cycles (28 days cycle). Weekly intravenous vinblastine at MTD will be given for a total of 17 cycles. If adverse events occur, two dose reductions are allowed. Follow-up Phase: Following the end of treatment, patients will be scheduled for a follow-up visit every 6 months for 36 months to evaluate PFS, TTP and OS.

Conditions

Pediatric Low-grade Glioma

Keywords

PLGG; Pediatric PLGG; Pediatric; MAPK; NF1; KIAA1549-BRAF; pediatric low-grade glioma

Outcome Measures

Primary Outcomes (2)

• Determine maximum tolerated dose of Mirdametinib plus Vinblastine.

  The maximum tolerated/recommended phase 2 dose (MTD/RP2D) of the mirdametinib plus vinblastine combination using a modified Rolling-6 design.

  3 years

• Determine the objective response rate of mirdametinib plus vinblastine for PLGG with Mitogen-activated Protein Kinase (MAPK) pathway activation in treatment naïve patients.

  The proportion of patients with complete (CR), major (MaR), partial (PR) and minor response (MiR) as the best response on study based on RAPNO criteria. Response = MiR+PR+MaR+CR

  5 years

Secondary Outcomes (7)

• Efficacy outcome measures: Overall Survival.

  Up to 3 years following completion of treatment.

• Efficacy outcome measures: Progression-Free Survival.

  Up to 3 years following completion of treatment.

• Efficacy outcome measures: Time to Progression.

  Up to 3 years following completion of treatment.

• Efficacy outcome measures: Objective Response Rate.

  Up to 3 years following completion of treatment.

• Determine the safety and tolerability of the combination of mirdametinib plus vinblastine.

  5 years

Other Outcomes (2)

• Evaluate the response rate based on the tumor volume.

  5 years

• To investigate and correlate biological features to tumor response.

  5 years

Study Arms (1)

Mirdametinib + IV Vinblastine

EXPERIMENTAL

Patients will receive oral mirdametinib twice daily (continuous) at a fixed dose (2mg/m2 PO BID, rounded to the nearest 1mg, up to a maximum of 4 mg BID) for a total of 13 cycles. Each cycle will last 28 days.

Drug: Mirdametinib

Interventions

Mirdametinib DRUG

Participants will receive orally administered mirdametinib in combination with intravenous vinblastine chemotherapy

Also known as: Vinblastine

Mirdametinib + IV Vinblastine

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• St. Justine's Hospital: lead

Study Sites (5)

Stollery Children's Hospital

Edmonton, Alberta, T6G 2E1, Canada

RECRUITING

Childrens and Womens Health Centre of British Columbia - British Columbia Childrens Hospital

Vancouver, British Columbia, V6H 3V4, Canada

RECRUITING

Children's Hospital, London Health Sciences Centre

London, Ontario, N6A5W9, Canada

RECRUITING

The Hospital for Sick Children

Toronto, Ontario, M5G 1E8, Canada

RECRUITING

CHU Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

RECRUITING

Related Publications (10)

• Robinson GW, Vinitsky A, Bag AK, et al. LGG-53. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA. Neuro Oncol. 2024; 26(Suppl 4):0

  RESULT

• Gross AM MC, Warren KE, Widemann BC. Plasma and cerebrospinal fluid pharmacokinetics of selumetinib in non-human primates (NHP). Journal of Clinical Oncology. 2017; 35((15_suppl)):e14070-e14070

  RESULT

• Lassaletta A, Scheinemann K, Zelcer SM, Hukin J, Wilson BA, Jabado N, Carret AS, Lafay-Cousin L, Larouche V, Hawkins CE, Pond GR, Poskitt K, Keene D, Johnston DL, Eisenstat DD, Krishnatry R, Mistry M, Arnoldo A, Ramaswamy V, Huang A, Bartels U, Tabori U, Bouffet E. Phase II Weekly Vinblastine for Chemotherapy-Naive Children With Progressive Low-Grade Glioma: A Canadian Pediatric Brain Tumor Consortium Study. J Clin Oncol. 2016 Oct 10;34(29):3537-3543. doi: 10.1200/JCO.2016.68.1585.

  PMID: 27573663 RESULT

• Fangusaro J, Onar-Thomas A, Young Poussaint T, Lensing S, Ligon AH, Lindeman N, Banerjee A, Kilburn LB, Lenzen A, Pillay-Smiley N, Pollack IF, Robison NJ, Partap S, Qaddoumi I, Landi D, Jones DTW, Stewart CF, Fouladi M, Dunkel IJ. A phase 2 PBTC study of selumetinib for recurrent/progressive pediatric low-grade glioma: Strata 2, 5, and 6 with long-term outcomes on strata 1, 3, and 4. Neuro Oncol. 2025 Oct 14;27(9):2415-2428. doi: 10.1093/neuonc/noaf065.

  PMID: 40241281 RESULT

• Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, Banerjee A, Packer RJ, Kilburn LB, Goldman S, Pollack IF, Qaddoumi I, Jakacki RI, Fisher PG, Dhall G, Baxter P, Kreissman SG, Stewart CF, Jones DTW, Pfister SM, Vezina G, Stern JS, Panigrahy A, Patay Z, Tamrazi B, Jones JY, Haque SS, Enterline DS, Cha S, Fisher MJ, Doyle LA, Smith M, Dunkel IJ, Fouladi M. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019 Jul;20(7):1011-1022. doi: 10.1016/S1470-2045(19)30277-3. Epub 2019 May 28.

  PMID: 31151904 RESULT

• Weiss BD, Wolters PL, Plotkin SR, Widemann BC, Tonsgard JH, Blakeley J, Allen JC, Schorry E, Korf B, Robison NJ, Goldman S, Vinks AA, Emoto C, Fukuda T, Robinson CT, Cutter G, Edwards L, Dombi E, Ratner N, Packer R, Fisher MJ. NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. J Clin Oncol. 2021 Mar 1;39(7):797-806. doi: 10.1200/JCO.20.02220. Epub 2021 Jan 28.

  PMID: 33507822 RESULT

• Jones DT, Gronych J, Lichter P, Witt O, Pfister SM. MAPK pathway activation in pilocytic astrocytoma. Cell Mol Life Sci. 2012 Jun;69(11):1799-811. doi: 10.1007/s00018-011-0898-9. Epub 2011 Dec 13.

  PMID: 22159586 RESULT

• Packer RJ, Lange B, Ater J, Nicholson HS, Allen J, Walker R, Prados M, Jakacki R, Reaman G, Needles MN, et al. Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol. 1993 May;11(5):850-6. doi: 10.1200/JCO.1993.11.5.850.

  PMID: 8487049 RESULT

• Sievert AJ, Fisher MJ. Pediatric low-grade gliomas. J Child Neurol. 2009 Nov;24(11):1397-408. doi: 10.1177/0883073809342005.

  PMID: 19841428 RESULT

• Fangusaro J, Witt O, Hernaiz Driever P, Bag AK, de Blank P, Kadom N, Kilburn L, Lober RM, Robison NJ, Fisher MJ, Packer RJ, Young Poussaint T, Papusha L, Avula S, Brandes AA, Bouffet E, Bowers D, Artemov A, Chintagumpala M, Zurakowski D, van den Bent M, Bison B, Yeom KW, Taal W, Warren KE. Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group. Lancet Oncol. 2020 Jun;21(6):e305-e316. doi: 10.1016/S1470-2045(20)30064-4.

  PMID: 32502457 RESULT

MeSH Terms

Interventions

mirdametinib; Vinblastine

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Officials

• Sébastien Perreault, M.D, FRCPC

  CHU Sainte Justine, URCHOI Department

  STUDY CHAIR

Central Study Contacts

Sébastien Perreault, M.D, FRCPC

CONTACT

514-345-4931; s.perreault@umontreal.ca

MIRV Study Team

CONTACT

mirv.study.hsj@ssss.gouv.qc.ca

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is a 3-part open-label study (feasibility phase, treatment phase and follow-up phase) of orally administered mirdametinib in combination with intravenous vinblastine chemotherapy in patients with PLGG with activation of MAPK pathway. Feasibility Phase: The maximum tolerated/recommended phase 2 dose (MTD/RP2D) of the mirdametinib plus vinblastine combination will be assessed using a modified Rolling-6 design. Treatment Phase: Patients will receive mirdametinib twice daily (continuously) at a fixed dose (2mg/m2 po BID up to 4 mg BID) for a total of 13 cycles (28 days cycle). Weekly intravenous vinblastine at MTD will be given for a total of 17 cycles. If adverse events occur, two dose reductions are allowed. Follow-up Phase: Following the end of treatment, patients will be scheduled for a follow-up visit every 6 months for 36 months to evaluate PFS, TTP and OS.

Study Record Dates

• First Submitted: October 9, 2024
• First Posted: October 30, 2024
• Study Start: January 12, 2026
• Primary Completion (Estimated): April 1, 2030
• Study Completion (Estimated): April 1, 2033
• Last Updated: February 19, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• Time Frame: 2030-2040
• Access Criteria: Upon request to the sponsor and study chair

Locations

CA (5)