Chemotherapy + Stem Cell Transplant for Brain Cancer

No longer recruiting at 219 trial locations

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Must not be taking: Anticonvulsants, Azole antifungals

Disqualifiers: Radiation therapy, Chemotherapy, 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: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the most effective chemotherapy combinations for treating specific aggressive brain tumors in children, specifically supratentorial primitive neuroectodermal tumors and high-risk medulloblastoma. Researchers aim to determine which combination of chemotherapy drugs works best before a stem cell transplant (autologous hematopoietic stem cell transplantation). Participants will receive one of two different chemotherapy regimens, followed by a stem cell rescue, to identify which approach better combats these challenging cancers. This trial suits young patients recently diagnosed with these cancers who have not yet received radiation or chemotherapy. As a Phase 3 trial, it represents the final step before FDA approval, offering participants access to potentially effective treatments.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications, such as trimethoprim/sulfamethoxazole (Bactrim), probenecid, penicillins, cephalosporins, aspirin, proton pump inhibitors, NSAIDs, IV contrast media, urinary acidifiers, phenytoin, fosphenytoin, and certain enzyme-inducing anticonvulsants. You should avoid these on the day of methotrexate treatment and until methotrexate levels are low enough. Check with the trial team for specific guidance on your medications.

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

Research has shown that the treatments in this trial have been used in other studies, providing some information about their safety.

In Arm I, the treatment includes drugs such as vincristine, etoposide, cyclophosphamide, and cisplatin, followed by carboplatin and thiotepa with stem cell support. Some safety data is available for this combination. Previous patients demonstrated that it can be well-tolerated, although risks exist. Common side effects include low blood counts, which might lead to infections or tiredness. However, stem cell support aids the body in recovering from these strong treatments.

In Arm II, vincristine and cisplatin are also used, with the addition of methotrexate. Methotrexate is carefully monitored with supportive care to manage possible side effects. This treatment also involves high-dose chemotherapy followed by stem cell support, which aids recovery. Again, side effects like low blood counts and risk of infection may occur, but these are closely monitored.

Both treatment plans have been used in other clinical settings, providing some reassurance about their safety. While side effects can occur, the medical team takes steps to manage them. If considering joining a trial, these are important points to discuss with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for brain cancer because they combine high-dose chemotherapy with an innovative approach using stem cell transplants. Unlike standard treatments that often rely on surgery, radiation, or lower-dose chemotherapy, this method uses high doses of drugs like methotrexate and thiotepa, which are more powerful but typically too toxic in high amounts. The unique twist here is the use of autologous peripheral blood stem cell (PBSC) transplants to help patients recover faster and tolerate the high-dose chemo better. This combination could potentially lead to better outcomes by aggressively targeting cancer cells while supporting the body's recovery.

What evidence suggests that this trial's treatments could be effective for brain cancer?

Research has shown that high-dose chemotherapy combined with autologous peripheral blood stem cell (PBSC) rescue may help treat brain tumors in children, such as medulloblastoma. In this trial, participants in Arm I will receive vincristine, etoposide, cyclophosphamide, and cisplatin, followed by consolidation therapy with carboplatin, etoposide, and thiotepa. Participants in Arm II will receive high-dose methotrexate along with vincristine, etoposide, cyclophosphamide, and cisplatin, followed by the same consolidation therapy. Studies have found that these drugs can improve outcomes for patients with serious brain tumors. These findings suggest that these chemotherapy treatments could be effective for young patients with certain brain tumors. ^{2 6 7 8 9}

Who Is on the Research Team?

Claire M Mazewski

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for young patients with newly diagnosed brain tumors, specifically supratentorial primitive neuroectodermal tumors or high-risk medulloblastoma. They should have undergone recent surgery and meet specific health criteria like normal heart and lung function, adequate blood counts, and no prior chemo or radiation therapy.

Inclusion Criteria

I haven't had radiation or chemotherapy, only corticosteroids.

My breathing and oxygen levels are stable.

My blood counts meet the required levels.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive combination chemotherapy with or without methotrexate, repeated every 3 weeks for 3 courses

9 weeks

Multiple visits for chemotherapy administration

Consolidation Therapy

Patients receive carboplatin and thiotepa with autologous peripheral blood stem cell rescue, repeated every 4 weeks for 3 courses

12 weeks

Multiple visits for chemotherapy and stem cell administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Periodic visits for monitoring

What Are the Treatments Tested in This Trial?

Interventions

• Autologous Hematopoietic Stem Cell Transplantation
• Carboplatin
• Cisplatin
• Cyclophosphamide
• Etoposide
• Filgrastim
• Leucovorin Calcium
• Methotrexate
• Thiotepa
• Vincristine Sulfate

Trial Overview

The study compares two chemotherapy regimens before intense chemotherapy followed by stem cell transplant to see which works better for treating these brain tumors. It includes drugs like Cisplatin, Methotrexate, Thiotepa, Carboplatin, Cyclophosphamide and others.

How Is the Trial Designed?

Group I: Arm II (induction+consolidation chemotherapy, autologous PBSC) Experimental Treatment 12 Interventions

Patients receive vincristine IV over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or PO every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (induction+consolidation chemotherapy, autologous PBSC) Active Control 10 Interventions

Patients receive vincristine IV over 1 minute on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3. Treatment repeats every 3 weeks for 3 courses. Within 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

A case of a malignant childhood glioma showed tumor progression despite surgery and radiotherapy during chemotherapy with cisplatinum, vincristine, and CCNU.

The tumor temporarily responded to oral treatment with VP16 and trofosfamide, suggesting that a Phase II study with this combination could be beneficial for similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second temporal remission in a malignant glioma with trofosfamide and etoposide: a case report. Wolff, JE., Boos, J., Krähling, KH., et al.[2016]

In a study involving 91 children with meningeal leukemia, both two-agent (methotrexate and hydrocortisone) and three-agent (adding cytosine arabinoside) intrathecal chemotherapy regimens achieved high rates of complete CNS remission (100% and 96%, respectively).

While the three-agent therapy resulted in a longer median CNS remission duration (64.6 weeks) compared to the two-agent therapy (47.2 weeks), the difference was not statistically significant, and both regimens showed reduced toxicity compared to methotrexate alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination intrathecal therapy for meningeal leukemia: two versus three drugs. Sullivan, MP., Moon, TE., Trueworthy, R., et al.[2021]

Cis-dichlorodiammineplatinum(II) can cause serious side effects such as nephrotoxicity, gastrointestinal issues (like nausea and vomiting), and myelosuppression, highlighting the need for careful monitoring during treatment.

Other potential side effects include ototoxicity (which can lead to hearing loss), anaphylactic reactions, and peripheral neuropathies, indicating that while the drug may be effective, its safety profile requires close attention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic effects of cis-dichlorodiammineplatinum(II) in man. Von Hoff, DD., Schilsky, R., Reichert, CM., et al.[2022]

In a study involving four pediatric patients with malignant brain tumors, treatment with very high-dose etoposide and cyclophosphamide followed by autologous bone marrow rescue showed promising results, particularly in two patients with brain stem gliomas who experienced clinical improvement and tumor size reduction.

The treatment led to a response duration of three to nine months, and detectable levels of the drugs were found in cerebrospinal fluid, suggesting that further research into this chemotherapy regimen for pediatric brain tumors is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of high-dose cyclophosphamide plus high-dose etoposide in malignant brain tumors of children followed by autologous bone marrow rescue]. Hanada, R., Inaba, T., Yaginuma, A., et al.[2013]

Chemotherapy for pediatric brain tumor patients is generally well-tolerated and can be more effective after major surgical resection, especially with agents like cisplatin and cyclophosphamide that require hydration.

New supportive care measures, such as mesna and antiemetics like ondansetron, have significantly improved the tolerance of chemotherapy, reducing side effects like hemorrhagic cystitis and neutropenia, which enhances overall treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications of chemotherapy in patients with brain and spinal cord tumors. Allen, JC.[2018]

Cisplatin is a widely used cancer treatment but can cause serious dose-dependent toxicities, including nausea, renal insufficiency, and myelosuppression, especially in cases of overdose.

There are currently no specific antidotes for cisplatin overdose, but management strategies include aggressive hydration, monitoring, and supportive therapies, with some experimental treatments showing limited effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin overdose: toxicities and management. Tsang, RY., Al-Fayea, T., Au, HJ.[2022]

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