Selumetinib for Pediatric Brain Cancer

Recruiting at 17 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticancer agents, MEK inhibitors

Disqualifiers: Uncontrolled seizures, Significant organ dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

220 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on other anticancer or investigational agents, and certain medications that prolong the QT interval are not allowed. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Selumetinib for pediatric brain cancer?

Selumetinib has shown promising results in treating pediatric low-grade gliomas, a type of brain tumor, by targeting specific proteins involved in tumor growth. It is also approved for use in children with neurofibromatosis 1, a condition that can lead to tumors, and has demonstrated activity in various cancers, suggesting its potential effectiveness in pediatric brain cancer. ^{1 2 3 4 5}

Is Selumetinib safe for children with brain cancer?

Selumetinib has been studied in children for various conditions, including neurofibromatosis type 1, and is generally considered safe with common side effects like skin issues, stomach problems, and tiredness. More serious but less common side effects can affect the heart and eyes, so close monitoring is needed. Overall, it has a favorable safety profile in both children and adults. ^{2 6 7 8 9}

How is the drug Selumetinib unique for treating pediatric brain cancer?

Selumetinib is unique because it is an oral drug that specifically targets and inhibits MEK1/2, a part of the MAP kinase pathway, which is often involved in tumor growth. This targeted approach is different from traditional chemotherapy, which affects both cancerous and healthy cells. ^{1 4 7 8 10}

Research Team

Jason R Fangusaro

Principal Investigator

Pediatric Brain Tumor Consortium

Eligibility Criteria

This trial is for young patients aged 3-21 with recurrent or refractory low grade glioma, including various types of brain tumors like astrocytoma. Participants must have specific tumor characteristics confirmed by recent tests and be willing to provide tissue samples for genetic testing.

Inclusion Criteria

Absolute neutrophil count >= 1,000/uL (unsupported) (within 14 days of registration and within 7 days of the start of treatment)

Platelets >= 100,000/L (unsupported) (within 14 days of registration and within 7 days of the start of treatment)

I haven't taken any growth factor medications for at least 1 or 2 weeks.

Exclusion Criteria

I have seizures that are not controlled by medication.

I have been treated with a BRAF inhibitor before, but not sorafenib.

I do not have any serious illnesses that could affect the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive selumetinib orally twice daily on days 1-28. Cycles repeat every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

24 months

Re-treatment

Patients who experience a sustained objective response and have completed 2 years of treatment may be enrolled on the re-treatment study after progression/recurrence. Treatment continues indefinitely in the absence of disease progression or unacceptable toxicities.

Indefinite

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

4 weeks

Treatment Details

Interventions

• Selumetinib

Trial Overview The trial is examining the effects and optimal dosage of Selumetinib, a drug intended to inhibit tumor growth by blocking enzymes necessary for cell proliferation. It's designed as a phase I/II study to determine side effects and effectiveness in children and young adults.

Participant Groups

Group I: Treatment (selumetinib) Experimental Treatment 2 Interventions

Patients receive selumetinib PO BID on days 1-28. Cycles repeat every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience a sustained objective response from selumetinib on the phase I or phase II portions of the trial, and who have completed 2 years of treatment and stopped study drug may be enrolled on the re-treatment study after progression/recurrence. Patients in the re-treatment study may continue treatment indefinitely in the absence of disease progression or unacceptable toxicities. Patients undergo blood sample collection on study.

Selumetinib is already approved in United States, European Union for the following indications:

Approved in United States as Koselugo for:

• Neurofibromatosis type 1 (NF1) in pediatric patients 2 years of age and older with symptomatic, inoperable plexiform neurofibromas (PN)

Approved in European Union as Koselugo for:

• Neurofibromatosis type 1 (NF1) in pediatric patients 2 years of age and older with symptomatic, inoperable plexiform neurofibromas (PN)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Selumetinib, a MEK 1/2 inhibitor, shows promise in treating pediatric low-grade gliomas, with ADC histogram metrics correlating with treatment response and progression-free survival in children with specific tumor types.

In particular, responders to selumetinib treatment exhibited significant decreases in ADC metrics over time, suggesting that these imaging biomarkers could help predict which patients are likely to benefit from the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ADC Histogram Analysis of Pediatric Low-Grade Glioma Treated with Selumetinib: A Report from the Pediatric Brain Tumor Consortium. Vajapeyam, S., Brown, D., Ziaei, A., et al.[2023]

In a study using the BT-40 low-grade childhood astrocytoma xenograft model, resistance to the MEK inhibitor selumetinib was found to be unstable, with tumors reverting to sensitivity when not treated, indicating potential for effective treatment strategies.

Combining selumetinib with a STAT3 inhibitor (LLL12) led to complete tumor regressions in selumetinib-resistant xenografts, suggesting that targeting both BRAF(V600E) and STAT3 pathways could be a promising approach to overcome drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development, characterization, and reversal of acquired resistance to the MEK1 inhibitor selumetinib (AZD6244) in an in vivo model of childhood astrocytoma. Bid, HK., Kibler, A., Phelps, DA., et al.[2021]

In a multicenter phase 2 study involving 50 patients with recurrent or progressive pediatric low-grade glioma, selumetinib demonstrated significant activity, with 36% of patients in the BRAF aberration group and 40% in the NF1-associated group achieving a sustained partial response.

Selumetinib was well-tolerated, with no treatment-related deaths reported, and the most common serious side effects were manageable, suggesting it could serve as a safer alternative to standard chemotherapy for these specific patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Fangusaro, J., Onar-Thomas, A., Young Poussaint, T., et al.[2020]

Selumetinib (KOSELUGO) was approved by the FDA for treating pediatric patients aged 2 and older with inoperable plexiform neurofibromas, showing a 66% overall response rate in a trial of 50 patients, with many experiencing significant symptom relief for at least 12 months.

While selumetinib is effective, it carries risks typical of MEK inhibitors, including potential ocular, cardiac, and gastrointestinal side effects, but the overall benefit-risk assessment is considered favorable for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma. Casey, D., Demko, S., Sinha, A., et al.[2022]

In a phase I/II study involving 139 pediatric patients with relapsed/refractory malignancies, trametinib was found to have a recommended dose of 0.032 mg/kg for children under 6 years and 0.025 mg/kg for those 6 years and older, with manageable safety profiles and no dose-limiting toxicities when combined with dabrafenib.

Among 49 patients with BRAF V600-mutant low-grade gliomas, the combination therapy of dabrafenib and trametinib showed a higher objective response rate of 25% compared to 15% for trametinib alone, indicating improved efficacy with the combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. Bouffet, E., Geoerger, B., Moertel, C., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

ADC Histogram Analysis of Pediatric Low-Grade Glioma Treated with Selumetinib: A Report from the Pediatric Brain Tumor Consortium. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics and Pharmacodynamics of Selumetinib. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Phase II Study of Selumetinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic Alterations: Arm E of the NCI-COG Pediatric MATCH Trial. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Development, characterization, and reversal of acquired resistance to the MEK1 inhibitor selumetinib (AZD6244) in an in vivo model of childhood astrocytoma. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of the MEK inhibitor selumetinib and its active N-desmethyl metabolite: data from 10 phase I trials. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Comparison of the Pharmacokinetics of the Phase II and Phase III Capsule Formulations of Selumetinib and the Effects of Food on Exposure: Results From Two Randomized Crossover Trials in Healthy Male Subjects. [2022]