Selumetinib vs. Chemotherapy for Brain Cancer

Recruiting at 136 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents, Vitamin E

Disqualifiers: Pregnancy, Concurrent malignancy, Heart disease, 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

Compensation: Varies

Number of Visits: 17

170 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for low-grade glioma, a type of brain cancer, to determine its effectiveness compared to standard chemotherapy. Participants will receive either selumetinib, which may halt tumor growth by blocking certain enzymes, or the standard chemotherapy drugs carboplatin and vincristine, which kill cancer cells or prevent their division. The trial also seeks to determine if selumetinib improves quality of life compared to the usual treatment. Eligible participants are those aged 2 to 21 with untreated low-grade glioma and without the BRAFV600E genetic mutation. As a Phase 3 trial, this study 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 need to stop taking your current medications. However, you cannot be on any investigational agents or receive any prior tumor-directed therapy like chemotherapy or radiation. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.

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

Research has shown that selumetinib was well-tolerated in past studies. No new safety concerns emerged, and patients responded well to the treatment. The FDA approved selumetinib for use in children with certain tumors, indicating its general safety for these conditions.

Carboplatin and vincristine, used in standard chemotherapy, have been in use for a long time. Carboplatin is usually easier on patients than some other cancer drugs, like cisplatin. Vincristine is effective but can cause side effects such as nerve damage. Both drugs have well-known safety records due to their extensive history of use.

In summary, both selumetinib and the chemotherapy drugs have evidence supporting their safety, but each has its own considerations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about selumetinib sulfate for brain cancer because it offers a different approach than standard chemotherapy options like carboplatin and vincristine sulfate. Unlike traditional chemotherapy, which generally targets rapidly dividing cells, selumetinib is a MEK inhibitor that specifically interferes with a pathway often involved in cancer cell growth and survival. This targeted approach not only has the potential to be more effective against certain types of brain tumors but also might result in fewer overall side effects. Additionally, selumetinib is taken orally, offering a more convenient and potentially less invasive treatment option for patients.

What evidence suggests that this trial's treatments could be effective for low-grade glioma?

This trial will compare selumetinib with a chemotherapy regimen of carboplatin and vincristine for brain cancer. Studies have shown that selumetinib can effectively treat low-grade gliomas (LGG) in children. In previous trials, about 84% of participants experienced prolonged disease stability, meaning their tumors did not grow or spread further. Another study found that selumetinib helped shrink tumors in 16% of patients. Participants in one arm of this trial will receive selumetinib, which targets specific enzymes that cancer needs to grow. Meanwhile, the standard treatment with carboplatin and vincristine, given to participants in another arm, attacks cancer cells and has been used successfully in similar conditions. Both treatments show promise. ^{6 7 8 9 10}

Who Is on the Research Team?

Peter M de Blank

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 2 to 21 with low-grade glioma brain tumors without certain genetic mutations or neurofibromatosis. They should not have had previous tumor treatments except surgery, must be able to swallow capsules, and meet specific health criteria like normal organ function tests.

Inclusion Criteria

My kidney function is within the required range for my age and gender.

My low-grade glioma does not have the BRAFV600E mutation and has only been treated with surgery.

My blood pressure is 130/80 mmHg or lower, with or without medication.

Exclusion Criteria

I have had issues with my retina, like detachment or vein blockage.

I have a genetic disorder linked to higher risk of heart disease.

I am not pregnant and have taken a pregnancy test if capable of becoming pregnant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive vincristine sulfate and carboplatin intravenously, with blood collection and MRI at baseline and end of induction

9 weeks

10 visits (in-person)

Maintenance

Patients continue receiving vincristine sulfate and carboplatin intravenously, with blood collection and MRI throughout the trial

Up to 48 weeks

4 visits per cycle (in-person), up to 8 cycles

Treatment with Selumetinib

Patients receive selumetinib sulfate orally twice daily, with blood collection and MRI throughout the trial

Up to 27 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Every 3 months for year 1, every 6 months for years 2-3, annually for years 4-10

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin; Vincristine Sulfate
• Selumetinib

Trial Overview The study compares the new drug Selumetinib against the standard chemotherapy drugs Carboplatin and Vincristine in treating low-grade gliomas. It aims to determine if Selumetinib is as effective as or better than standard treatment while also assessing its impact on quality of life.

How Is the Trial Designed?

Group I: Arm II (selumetinib sulfate) Experimental Treatment 5 Interventions

Patients receive selumetinib sulfate PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at baseline and undergo collection of blood and MRI throughout the trial.

Group II: Arm I (vincristine sulfate, carboplatin) Active Control 5 Interventions

INDUCTION: Patients receive vincristine sulfate IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64, and carboplatin IV over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and MRI throughout the trial. MAINTENANCE: Patients receive vincristine sulfate IV on days 1, 8, and 15, and carboplatin IV over 60 minutes on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 42 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and MRI throughout the trial.

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

In a study of 50 low-grade glioma patients treated with carboplatin and vincristine, 40% experienced carboplatin hypersensitivity reactions (CHR), with most being mild (grade I).

Management strategies like premedication and desensitization allowed for a high continuation success rate of 75% for carboplatin therapy, indicating that timely intervention can help many patients continue their treatment despite CHR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical features and management of carboplatin-related hypersensitivity reactions in pediatric low-grade glioma. Genc, DB., Canpolat, C., Berrak, SG.[2021]

In a multicenter phase II trial involving 129 patients with bronchogenic carcinoma, carboplatin showed an overall response rate of 17.8%, with a notably higher response rate of 28.4% in patients with small-cell lung cancer.

The treatment was associated with significant toxic effects, particularly thrombocytopenia and leukopenia, affecting nearly half of the patients, but it did not result in renal, aural, or neurotoxicities, indicating a relatively safe profile compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of carboplatin in patients with nonresected lung cancer. Japan Cooperative Oncology Group on Lung Cancer. [2019]

In a study of 42 patients with brain metastases from non-small cell lung cancer, adding carboplatin chemotherapy to whole brain radiotherapy did not improve median survival, which was 4.4 months for radiotherapy alone compared to 3.7 months for the combined treatment.

The objective response rates were 10% for radiotherapy alone and 29% for the combined treatment, but these differences were not statistically significant, indicating limited efficacy of the combined approach in improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lung. Guerrieri, M., Wong, K., Ryan, G., et al.[2013]

A phase 1 trial involving 26 children with low-grade gliomas tested two schedules of carboplatin and vinblastine, revealing that Schedule A was not feasible due to high rates of neutropenia, while Schedule B showed a more tolerable safety profile at a carboplatin dose of 400 mg/m².

The combination treatment on Schedule B resulted in 1 partial response and 6 minor responses among evaluable patients, with notable improvements in vision for 7 out of 9 patients with visual pathway tumors, suggesting potential efficacy and warranting further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of vinblastine in combination with carboplatin for children with low-grade gliomas: a Children's Oncology Group phase 1 consortium study. Jakacki, RI., Bouffet, E., Adamson, PC., et al.[2021]

A Phase I clinical trial involving 10 patients with recurrent high-grade gliomas demonstrated that intracerebral convection-enhanced delivery (CED) of carboplatin is feasible and safe at doses up to 4μg over 72 hours, with only one possible adverse event reported.

The median progression-free survival (PFS) and overall survival (OS) after treatment were 2.1 months and 9.6 months, respectively, indicating that while the treatment is safe, further studies are needed to assess its efficacy in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of intracerebral convection-enhanced delivery of carboplatin for treatment of recurrent high-grade gliomas. Wang, JL., Barth, RF., Cavaliere, R., et al.[2021]

In a Phase I study involving 15 patients with various brain tumors, intracarotid carboplatin showed some efficacy, with one patient experiencing partial remission and others showing stable disease, although the median survival was only 9 weeks.

The treatment was associated with mild to moderate nausea and some hematological side effects, but severe complications occurred in patients with pre-existing vascular issues, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of intracarotid administration of carboplatin. Stewart, DJ., Belanger, JM., Grahovac, Z., et al.[2019]

Platinum-based chemotherapy shows a response rate of 23% to 50% in treating brain metastases, indicating its effectiveness despite the challenges posed by the brain blood barrier.

Anti-EGFR therapies can achieve response rates between 38% and 69.6% in specific populations, such as those with EGFR mutations or certain demographics, while bevacizumab is now approved for use in non-small cell lung cancer patients with brain metastases, suggesting a growing acceptance of systemic treatments for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Brain metastases of non small cell lung cancers: systemic treatments]. Chaubet-Houdu, M., Besse, B.[2018]

In a study of 26 patients with intracerebral tumors, a combination of intraarterial and systemic chemotherapy resulted in a 46% overall response rate, with glioma patients showing a 50% response rate, indicating potential efficacy in treating these tumors.

While the treatment was associated with some reversible neurological toxicity and dose-limiting myelosuppression, the overall regimen did not demonstrate increased activity compared to previous treatments, suggesting the need for further research into more effective combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined intraarterial and systemic chemotherapy for intracerebral tumors. Stewart, DJ., Grahovac, Z., Hugenholtz, H., et al.[2019]

In a study of 127 patients with resected non-small cell lung cancer, adjuvant chemotherapy with carboplatin showed comparable overall survival and progression-free survival to cisplatin, indicating it can be a valid alternative when cisplatin is not tolerated.

Both chemotherapy regimens resulted in similar rates of high-grade hematologic toxicity, suggesting that carboplatin can be used safely without increasing the risk of severe side effects compared to cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of adjuvant carboplatin-based chemotherapy compared to cisplatin in non-small cell lung cancer. Couillard-Montminy, V., Gagnon, PY., Fortin, S., et al.[2019]

Cisplatin, carboplatin, and oxaliplatin show limited penetration into the cerebrospinal fluid (CSF) and brain extracellular fluid (ECF), with less than 5% of plasma drug exposure reaching these areas, which may affect their efficacy in treating brain tumors.

Microdialysis revealed that while CSF concentrations of oxaliplatin were lower than those in brain ECF, the overall differences in CNS penetration among the three platinum analogs were not clinically significant, suggesting that CSF measurements can be used to estimate brain drug exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates. Jacobs, S., McCully, CL., Murphy, RF., et al.[2021]

In a study of 158 patients with intrinsic brain tumors, several chemotherapeutic agents showed notable efficacy, with carmustine (BCNU) having a response rate of 47% and a median duration of response of nine months.

When patients who initially responded to one drug were given a second drug, only 15% showed a response, indicating limited effectiveness of switching treatments after initial therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-agent chemotherapy of brain tumors. A five-year review. Wilson, CB., Gutin, P., Boldrey, EB., et al.[2019]

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. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33631016/

A phase II trial of selumetinib in children with recurrent optic ... Conclusions: Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based ...

3. 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 ...

4. academic.oup.com academic.oup.com/neuro-oncology/article-abstract/27/9/2429/8126772

Consortium trial demonstrates efficacy of selumetinib in ... Consortium trial demonstrates efficacy of selumetinib in pediatric low-grade glioma · Neuro-Oncology Unit, Division of Haematology Oncology, The ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04576117

NCT04576117 | A Study to Compare Treatment With the ... Giving selumetinib in combination with vinblastine may work better than selumetinib alone in treating recurrent or progressive low-grade glioma. Detailed ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40473450/

Efficacy and safety of selumetinib in adults with ... - PubMed Selumetinib led to a rapid response (median 3·7 months), with an objective response rate of 20% (n=14/71; 95% CI 11·2 to 30·9) by cycle 16 ...

7. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(25)00986-9/abstract

Efficacy and safety of selumetinib in adults with ... No new safety concerns were identified. The observations of reduction in tumour volume by cycle 16, reduction in chronic and spike pain, ...

8. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(25)00986-9/fulltext?rss=yes

Efficacy and safety of selumetinib in adults with ... Data from the primary analysis of KOMET indicate that selumetinib treatment achieved a significant objective response rate versus placebo by ...

9. onclive.com onclive.com/view/fda-approves-selumetinib-for-symptomatic-pediatric-nf-1-associated-inoperable-plexiform-neurofibromas

FDA Approves Selumetinib for Symptomatic Pediatric NF-1 ... Selumetinib is approved for pediatric patients with NF1 with inoperable plexiform neurofibromas, based on bioavailability and efficacy studies.

10. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37115514/

Long-term safety and efficacy of selumetinib in children with ... With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain.