Selumetinib + Vinblastine for Low-Grade Glioma

Not currently recruiting at 113 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks the best treatment for low-grade glioma, a common brain cancer in children and young adults whose cancer has returned or isn't responding to current treatments. It tests two approaches: using selumetinib (a targeted therapy) alone to stop tumor growth, and combining it with vinblastine, which may kill cancer cells. The aim is to determine if the combination is more effective than selumetinib alone. This trial may suit those with low-grade glioma that has returned or worsened after previous treatment. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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 there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that selumetinib has been tested in young patients with low-grade glioma and is generally well-tolerated. Studies have found that while some patients experience side effects, they are often mild or manageable. Common side effects include skin rash and upset stomach.

Currently, specific safety information for using selumetinib and vinblastine together to treat low-grade glioma is unavailable. However, both drugs have been studied separately. Vinblastine, often used in chemotherapy, can cause side effects like low blood cell counts and hair loss. These side effects are typical for chemotherapy drugs and are usually closely monitored by doctors.

The fact that selumetinib is being studied in a phase 3 trial indicates that earlier research has shown it to be reasonably safe. Phase 3 trials are usually conducted when a treatment is considered safe enough based on previous testing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of selumetinib and vinblastine for treating low-grade glioma because this approach targets the MEK pathway, which is crucial for tumor growth, offering a new mechanism of action compared to standard therapies like surgery and radiation. Unlike traditional treatments, selumetinib is an oral medication that can be taken at home, making it more convenient for patients. Furthermore, combining it with vinblastine, which is administered intravenously, may enhance effectiveness by attacking the cancer from multiple angles. This dual approach holds promise for improving outcomes in a condition where current options are limited.

What evidence suggests that the combination of selumetinib and vinblastine could be effective for low-grade glioma?

Studies have shown that selumetinib effectively treats pediatric low-grade glioma, a common brain tumor in children. In one study, 32% of patients experienced partial tumor shrinkage, and about 66% had stable disease for two years. In this trial, some participants will receive selumetinib alone, while others will receive a combination of selumetinib and vinblastine, a drug that stops cancer cells from dividing. Research suggests that combining selumetinib with vinblastine might improve these results. Early findings indicate that this combination could be more effective than selumetinib alone for managing tumors that recur or worsen. These findings offer hope for better outcomes in children and young adults with this condition. ^{1 2 6 7 8}

Who Is on the Research Team?

Daniel C Bowers

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8485450/

A phase II trial of selumetinib in children with recurrent optic ... In the current trial, selumetinib treatment led to 4 centrally confirmed, sustained PRs (16%) and prolonged stability (PR or SD) in 21/25 (84%) of children with ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01089101

Study Details | NCT01089101 | Selumetinib in Treating ... 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 ...

3. academic.oup.com academic.oup.com/neuro-oncology/article-abstract/27/9/2415/8114838

Strata 2, 5, and 6 with long-term outcomes on strata 1, 3, and 4 Selumetinib provided stability and responses across many pLGG subgroups, and some patients achieved prolonged disease control without ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5570236/

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in ... Long-term outcome of 4040 children diagnosed with pediatric low-grade gliomas: an analysis of the surveillance epidemiology and end results (SEER) database.

5. healio.com healio.com/news/hematology-oncology/20170604/selumetinib-effective-for-pediatric-lowgrade-glioma

Selumetinib effective for pediatric low-grade glioma Eight of these patients (32%) achieved a partial response and 66% (+/–11%) achieved 2-year PFS. Two of seven patients with a BRAF V600E mutation ...

6. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT01089101

Selumetinib in Treating Young Patients With Recurrent or ... 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 ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.10504

A phase II prospective study of selumetinib in children with ... A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium ...

8. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D134BC00001

Efficacy and Safety of Selumetinib in Adults with NF1 who ... A global study to demonstrate the effectiveness of selumetinib in participants with NF1 who have symptomatic, inoperable plexiform neurofibromas.