Selumetinib vs Carboplatin/Vincristine for Brain Cancer

Not currently recruiting at 144 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents, Vitamin E

Disqualifiers: Concurrent malignancy, Serious illness, Pregnancy, 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: 18

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the drug selumetinib is as effective as or better than standard chemotherapy (carboplatin and vincristine) for treating low-grade glioma, a type of brain tumor associated with NF1, a genetic condition. The study examines whether selumetinib can improve vision for patients with tumors affecting the optic pathway (vision nerves). Participants should have NF1-related low-grade glioma, potentially affecting their vision or causing neurological symptoms, and should not have received other treatments besides surgery. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering patients a chance to contribute to groundbreaking research.

Do I need to stop my current medications to join the trial?

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 vitamin E supplements above the recommended daily dose. It's best to discuss your current medications with the trial team.

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

Research has shown that selumetinib is generally safe for people with certain conditions. In past studies, many patients' conditions remained stable or improved without major safety issues. For example, one study found that 68% of patients responded positively, and no new safety problems emerged. Selumetinib is also approved in the EU for a similar condition, which supports its safety.

Carboplatin and vincristine, standard chemotherapy drugs, have long been used to treat various cancers, including brain tumors. While they can cause side effects, these are usually well-understood and managed in medical settings.

Overall, both treatments have demonstrated some level of safety in previous research, but monitoring for any side effects during trials remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatment options for brain cancer, such as carboplatin and vincristine, selumetinib offers a novel approach by targeting the MEK pathway. This pathway plays a crucial role in cell growth and survival, and by inhibiting it, selumetinib aims to directly disrupt cancer cell proliferation. Researchers are excited about selumetinib because it represents a targeted therapy that could offer more precise and potentially less toxic treatment compared to traditional chemotherapy, which affects both cancerous and healthy cells. Additionally, selumetinib is administered orally, providing a more convenient option compared to intravenous treatments.

What evidence suggests that this trial's treatments could be effective for NF1-associated low-grade glioma?

Research has shown that selumetinib, one of the treatments studied in this trial, may effectively treat low-grade glioma, a type of brain tumor in children, particularly those with NF1, a genetic disorder. In one study, 84% of children who took selumetinib experienced either a reduction in tumor size or no further tumor growth, indicating that the drug helped prevent tumor progression in most cases. Another study found that selumetinib worked well specifically for low-grade glioma linked to NF1, highlighting its potential for this condition. In this trial, selumetinib will be compared to the usual treatment, chemotherapy with carboplatin and vincristine, which kills tumor cells. However, selumetinib might offer a more targeted approach by blocking the enzymes tumors need to grow. ^{1 6 7 8 9}

Who Is on the Research Team?

Jason R Fangusaro

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 Neurofibromatosis type 1 (NF1) and low-grade glioma (LGG), including tumors of the optic pathway. They must have measurable tumors, no prior tumor-directed therapy except surgery, stable blood pressure, adequate organ function, and not be pregnant or breastfeeding. Participants need to agree to use effective contraception during the study.

Inclusion Criteria

I have an untreated NF-1 associated low-grade glioma, except for surgery.

I can swallow whole capsules.

I have been diagnosed with neurofibromatosis type 1.

Exclusion Criteria

Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible

Patients may not be receiving any other investigational agents

I haven't had surgery in the last 2 weeks and don't take high doses of vitamin E.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Treatment

Patients receive carboplatin and vincristine intravenously on a specific schedule over 64 days

9 weeks

10 visits (in-person)

Maintenance Treatment

Patients continue receiving carboplatin and vincristine every 6 weeks for 8 cycles

48 weeks

4 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion with MRIs and physical exams

Up to 10 years

Every 3 months for 1 year, every 6 months for 2 years, then annually

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin; Vincristine
• Selumetinib

Trial Overview The trial compares Selumetinib—a drug that blocks enzymes needed by tumor cells—with standard chemotherapy drugs Carboplatin/Vincristine in treating NF1-associated LGG. It aims to determine if Selumetinib is as effective or better than standard treatment in improving vision for those with optic pathway tumors.

How Is the Trial Designed?

Group I: Arm II (selumetinib sulfate) Experimental Treatment 4 Interventions

Patients receive selumetinib sulfate PO BID on days 1-28 of each cycle. Treatment is continuous and cycles repeat every 28 days for 27 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.

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

INDUCTION: Patients receive carboplatin IV over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 and vincristine IV or IV push over 1 minute on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial. MAINTENANCE: Patients receive carboplatin IV over 60 minutes on days 1, 8, 15, and 22 of each cycle and vincristine IV or IV push over 1 minute on days 1, 8, and 15 of each cycle. Cycles repeat every 6 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.

Carboplatin; Vincristine is already approved in United States, European Union for the following indications:

Approved in United States as Carboplatin for:

• Ovarian cancer
• Lung cancer
• Testicular cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in United States as Vincristine for:

• Acute lymphoblastic leukemia
• Hodgkin's lymphoma
• Non-Hodgkin's lymphoma
• Rhabdomyosarcoma
• Neuroblastoma
• Wilms' tumor

Approved in European Union as Vincristine for:

• Acute lymphoblastic leukemia
• Hodgkin's lymphoma
• Non-Hodgkin's lymphoma

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 Phase II study involving 117 children with drug-resistant solid tumors, carboplatin showed some effectiveness, particularly against Wilms' tumor, Ewing's sarcoma, neuroblastoma, soft tissue sarcoma, and endodermal sinus tumor of the testis.

While myelosuppression (low blood cell counts) was common, carboplatin exhibited low rates of nonhematologic toxicity, such as ototoxicity and nephrotoxicity, making it a potentially safer option compared to its parent compound, cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of carboplatin in children with recurrent or progressive solid tumors. A report from the Childrens Cancer Group. Ettinger, LJ., Gaynon, PS., Krailo, MD., et al.[2019]

In a Phase II trial involving 95 children with recurrent brain tumors, carboplatin showed some efficacy, particularly in medulloblastoma and central nervous system PNET, with a notable response rate in patients who had not previously been treated with cisplatin.

The treatment was associated with significant side effects, including low neutrophil and platelet counts in a substantial number of patients, but it did not cause nephrotoxicity, indicating a relatively safer profile in that regard.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial. Gaynon, PS., Ettinger, LJ., Baum, ES., et al.[2019]

Cisplatin and carboplatin are both effective platinum-based chemotherapy agents, but they differ significantly in their side effects; cisplatin can cause severe kidney damage and neurotoxicity, while carboplatin is safer for renal function and has less neurotoxicity.

Carboplatin's toxicity profile allows for dose adjustments based on renal function, making it a more manageable option for patients, whereas cisplatin requires hydration protocols to mitigate its harmful effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative adverse effect profiles of platinum drugs. McKeage, MJ.[2018]

In a study involving 14 children with various brain tumors, the combination of carboplatin and etoposide (JET regimen) showed promising efficacy, particularly in medulloblastoma, with a response rate of 83% (3 complete responses and 2 partial responses).

The treatment was generally well tolerated, with myelosuppression being the main side effect, but mild gastrointestinal toxicity and no significant nephro- or neurotoxicity were observed, indicating a favorable safety profile for this regimen in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose carboplatin in combination with etoposide (JET regimen) for childhood brain tumors. Castello, MA., Clerico, A., Deb, G., et al.[2019]

In a study of 30 patients with newly diagnosed brain metastases from non-small cell lung cancer (NSCLC), the combination of carboplatin and pemetrexed resulted in a 40% objective cerebral response rate, indicating a significant improvement in brain tumor control compared to the standard care of whole brain radiotherapy.

The treatment also showed promising overall survival outcomes, with a median overall survival of 39 weeks and event-free survival of 31 weeks, suggesting that this combination therapy may effectively address both cerebral and systemic disease in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Bailon, O., Chouahnia, K., Augier, A., et al.[2022]

Carboplatin, administered as a radiosensitizer during craniospinal radiation therapy, showed promising outcomes for patients with metastatic medulloblastomas, with a 5-year overall survival rate of 82% for those treated at the recommended phase II dose.

Myelosuppression was identified as a dose-limiting side effect, leading to the determination of 35 mg/m²/dose as the optimal dose for carboplatin, highlighting the importance of monitoring side effects in treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study. Jakacki, RI., Burger, PC., Zhou, T., et al.[2022]

In a study involving 44 patients with recurrent childhood brain tumors, carboplatin was found to have a disease-specific response rate of 43% in medulloblastoma, indicating its potential effectiveness in treating this type of cancer.

Carboplatin demonstrated a favorable safety profile with mild side effects, such as low emetic effects and no significant auditory or renal toxicity, making it a promising candidate for further studies in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and recurrent childhood brain tumors. Allen, JC., Walker, R., Luks, E., et al.[2017]

Carboplatin is a safer alternative to cisplatin for treating small cell lung cancer (SCLC) due to its lower risk of renal, neuro, and ototoxicity, and shows similar effectiveness in combination regimens, although more randomized trials are needed to confirm this.

In non-small cell lung cancer (NSCLC), carboplatin has an overall response rate of nearly 10% and can be as effective as other treatment combinations, making it a suitable option for patients with existing health issues related to kidney or nerve function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of therapeutic trials of carboplatin in lung cancer. Bunn, PA.[2018]

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 real-world study of 54 patients with advanced non-squamous non-small cell lung cancer, the combination of carboplatin, pemetrexed, and pembrolizumab showed a higher disease control rate (86.7%) compared to carboplatin and pemetrexed alone (54%).

Patients with brain metastases treated with the combination therapy had a significantly lower progression rate (33.3%) compared to those receiving only carboplatin and pemetrexed (91.7%), indicating that this regimen may be particularly effective for this challenging patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A tertiary care cancer center experience with carboplatin and pemetrexed in combination with pembrolizumab in comparison with carboplatin and pemetrexed alone in non-squamous non-small cell lung cancer. Afzal, MZ., Dragnev, K., Shirai, K.[2023]

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]

Citations

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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/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 ...

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

A phase II prospective study of selumetinib in children with ... Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01386450

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 ...

7. onclive.com onclive.com/view/selumetinib-nets-eu-approval-for-adult-nf1-associated-plexiform-neurofibromas

Selumetinib Nets EU Approval for Adult NF1-Associated ... No new safety concerns were identified with selumetinib for the treatment of patients with NF1-associated PNs. The most common any-grade ...

8. nejm.org nejm.org/doi/full/10.1056/NEJMoa1912735

Selumetinib in Children with Inoperable Plexiform ... A total of 34 patients (68%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10547508/

Long-term safety and efficacy of selumetinib in children with ... To maintain tumor response, treatment with selumetinib often lasts many years and long-term safety and efficacy data have not previously been described. This ...