Chemotherapy + Stem Cell Transplant for Brain Cancer

Recruiting at 208 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

91 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase III trial is studying two different combination chemotherapy regimens to compare how well they work in treating young patients with newly diagnosed supratentorial primitive neuroectodermal tumors or high-risk medulloblastoma when given before additional intense chemotherapy followed by peripheral blood stem cell rescue. It is not yet known which combination chemotherapy regimen is more effective when given before a peripheral stem cell transplant in treating supratentorial primitive neuroectodermal tumors or medulloblastoma.

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.

What data supports the effectiveness of the chemotherapy and stem cell transplant treatment for brain cancer?

Research shows that chemotherapy can prolong life in patients with recurrent brain tumors and contribute to curative therapy in newly diagnosed patients. Additionally, a study found that chemotherapy produced response rates of 32% with cisplatin and 59% with cyclophosphamide, especially when used in combination with other drugs. ^{1 2 3 4 5}

Is the chemotherapy and stem cell transplant treatment generally safe for humans?

The treatment can have serious side effects, including hearing loss, kidney problems, nerve damage, and blood-related issues. These effects are often related to specific drugs like cisplatin and may require careful monitoring and supportive care to manage. Some side effects can be long-lasting or permanent, so it's important to discuss potential risks with your healthcare provider. ^{1 6 7 8 9}

What makes the chemotherapy and stem cell transplant treatment for brain cancer unique?

This treatment combines multiple chemotherapy drugs with a stem cell transplant, which is not a standard approach for brain cancer. The use of high-dose chemotherapy drugs like cyclophosphamide, etoposide, and thiotepa, followed by stem cell rescue, aims to enhance effectiveness against aggressive brain tumors, offering hope for cases where traditional treatments have limited success. ^{2 10 11 12 13}

Research Team

Claire M Mazewski

Principal Investigator

Children's Oncology Group

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

Chemotherapy for mycosis fungoides and the Sézary syndrome. [2006]

3. Germany pubmed.ncbi.nlm.nih.gov

[Chemotherapy of brain tumors in childhood. Review of the literature and pilot protocol]. [2007]

4. Germany pubmed.ncbi.nlm.nih.gov

Second temporal remission in a malignant glioma with trofosfamide and etoposide: a case report. [2016]

5. United States pubmed.ncbi.nlm.nih.gov

Combination intrathecal therapy for meningeal leukemia: two versus three drugs. [2021]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Cisplatin overdose: toxicities and management. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Successful rechallenge with cisplatin following cisplatin induced ischemic cerebrovascular accident in a patient with small cell lung cancer. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Acute cerebrovascular accident after treatment with cis-platinum and methylprednisolone. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Toxic effects of cis-dichlorodiammineplatinum(II) in man. [2022]

10. Italy pubmed.ncbi.nlm.nih.gov

Cisplatin and etoposide combination therapy for primary glial tumors: preliminary results. [2020]

11. France pubmed.ncbi.nlm.nih.gov

Basis and results of chemotherapeutic treatment of gliomas. [2009]

12. Japan 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]. [2013]

13. United States pubmed.ncbi.nlm.nih.gov

High-dose thiotepa and etoposide in children with poor-prognosis brain tumors. [2013]