Selumetinib + Vinblastine for Low-Grade Glioma

Recruiting at 91 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 agents

Disqualifiers: Concurrent malignancy, Diffuse intrinsic pontine tumors, Serious medical conditions, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

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: 3

Duration: up to 27 months

300 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial investigates the best dose of vinblastine in combination with selumetinib and the benefit of adding vinblastine to selumetinib compared to selumetinib alone in treating children and young adults with low-grade glioma (a common type of brain cancer) that has come back after prior treatment (recurrent) or does not respond to therapy (progressive). Selumetinib is a drug that works by blocking a protein that lets tumor cells grow without stopping. Vinblastine blocks cell growth by stopping cell division and may kill cancer cells. Giving selumetinib in combination with vinblastine may work better than selumetinib alone in treating recurrent or progressive low-grade glioma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have taken certain drugs like fluconazole or strong CYP3A4 inducers or inhibitors within 7 days before enrolling, and any multivitamin containing vitamin E must be stopped before enrollment.

Is the combination of Selumetinib and Vinblastine safe for treating low-grade glioma?

Selumetinib has been studied in children with low-grade gliomas, and researchers have identified the recommended dose and potential side effects. While specific safety data for the combination with Vinblastine is not provided, Selumetinib alone has been evaluated for safety in pediatric patients. ^{1 2 3 4 5}

What makes the drug Selumetinib unique for treating low-grade glioma?

Selumetinib is unique because it targets the MEK1/2 proteins in the MAPK pathway, which is often active in low-grade gliomas, offering a targeted approach compared to standard chemotherapy. This drug is particularly promising for patients with specific genetic mutations like BRAF, which are common in these tumors. ^{1 2 3 4 6}

What data supports the effectiveness of the drug Selumetinib for treating low-grade glioma?

Research shows that Selumetinib, a drug targeting the MAPK pathway, has shown promise in treating pediatric low-grade gliomas, with some patients responding well to the treatment. However, there are cases where resistance develops, indicating that while it can be effective, it may not work for everyone. ^{1 2 3 4 6}

Research Team

Daniel C Bowers

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for children and young adults aged 2-21 (up to 25 in some phases) with low-grade glioma that's recurrent or progressive after treatment. Participants must have had prior therapy, a body surface area of at least 0.5 m^2, stable organ function, no severe allergies to the drugs being tested, controlled blood pressure, and the ability to swallow capsules.

Inclusion Criteria

HYPERTENSION:

You must be between 2 and 21 years old to participate in the study's feasibility phase.

Patients must have eligibility confirmed by rapid central pathology and central molecular screening reviews performed on APEC14B1

Exclusion Criteria

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

You are allergic to selumetinib, vinblastine, or similar drugs.

You have existing eye problems.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive selumetinib and vinblastine for 17 cycles, followed by 10 additional cycles of selumetinib alone, or selumetinib alone for up to 27 cycles.

up to 27 months

Monthly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for year 1, every 6 months for years 2-3, annually for years 4-5

Treatment Details

Interventions

• Selumetinib Sulfate
• Vinblastine Sulfate

Trial Overview The study compares two treatments: Selumetinib alone versus a combination of Selumetinib and Vinblastine. It aims to find out if adding Vinblastine improves outcomes for patients with low-grade glioma that has returned or isn't responding well to other treatments.

Participant Groups

Group I: Feasibility & Efficacy Phase Arm I (selumetinib, vinblastine) Experimental Treatment 6 Interventions

Patients receive vinblastine sulfate IV over 1 minute or IV infusion on days 1, 8, 15, and 22 and selumetinib sulfate PO BID on days 1-28. Treatment repeats every 28 days. Patients receive selumetinib and vinblastine for a total duration of 17 cycles followed by 10 additional cycles of selumetinib alone in the absence of disease progression or unacceptable toxicity. Patients undergo MRI throughout the trial. Patients also undergo blood sample collection during screening and on study.

Group II: Efficacy Phase Arm II (selumetinib) Active Control 5 Interventions

Patients receive selumetinib sulfate PO BID on days 1-28. Treatment repeats every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI throughout the trial. Patients also undergo blood sample collection during screening and on study.

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

Approved in United States as Koselugo for:

• Neurofibromatosis type 1

Approved in European Union as Koselugo for:

• Neurofibromatosis type 1

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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 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]

The MEK inhibitor Selumetinib shows varying efficacy against pediatric low-grade glioma cell lines, with Res186 cells being resistant and Res259 cells being sensitive, indicating the need for personalized treatment approaches.

Selumetinib induces cell cycle arrest in sensitive cells by altering key regulatory proteins, and combining it with a specific cAMP-dependent protein kinase A inhibitor can help overcome resistance in previously resistant cell lines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the mitogen‑activated protein kinase kinase and protein kinase A pathways overcomes acquired resistance to Selumetinib in low‑grade glioma cells. Melotti, L., Meco, D., Battaglia, A., et al.[2021]

A patient with disseminated low-grade glioma (LGG) and the BRAFV600E mutation showed resistance to the MEK inhibitor selumetinib but responded well to the BRAF inhibitor dabrafenib, indicating potential treatment options within the same pathway.

The patient's response to dabrafenib lasted for 9 months before clinical progression, suggesting that different agents targeting the MAPK pathway can be effective even after resistance to another agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dramatic clinical and radiographic response to BRAF inhibition in a patient with progressive disseminated optic pathway glioma refractory to MEK inhibition. Bavle, A., Jones, J., Lin, FY., et al.[2018]

The MEK inhibitor selumetinib was found to have promising antitumor activity in children with progressive low-grade gliomas (LGGs), with a recommended phase II dose (RP2D) established at 25 mg/m2/dose twice daily, where 20% of subjects showed sustained partial responses.

Common dose-limiting toxicities (DLTs) included rash and mucositis, but at the RP2D, only 3 out of 24 subjects experienced DLTs, indicating a better safety profile at this dosage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Banerjee, A., Jakacki, RI., Onar-Thomas, A., et al.[2022]

References

1. 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]

2. 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]

3. 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]

4. Greece pubmed.ncbi.nlm.nih.gov

Targeting the mitogen‑activated protein kinase kinase and protein kinase A pathways overcomes acquired resistance to Selumetinib in low‑grade glioma cells. [2021]

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

Dramatic clinical and radiographic response to BRAF inhibition in a patient with progressive disseminated optic pathway glioma refractory to MEK inhibition. [2018]

6. England pubmed.ncbi.nlm.nih.gov

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. [2022]