Maintenance Chemotherapy vs Observation for Ependymoma

Recruiting at 212 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Disqualifiers: Metastatic disease, Spinal cord ependymoma, 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: 25

479 Participants Needed

Trial Summary

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

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that no prior treatment other than surgery and corticosteroids is allowed, which might imply that other medications should be stopped. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination including cisplatin and cyclophosphamide for ependymoma?

There is some evidence that a combination of cisplatin and cyclophosphamide can lead to prolonged responses in cases of anaplastic ependymoma that are resistant to surgery and radiotherapy, although chemotherapy generally has modest effects for this condition. ^{1 2 3 4 5}

Is maintenance chemotherapy safe for ependymoma treatment?

Conformal radiation therapy (CRT) for ependymoma has been studied to reduce side effects on the central nervous system (CNS), and carboplatin is known to cause nausea and vomiting, which can be managed with antiemetic drugs. Cisplatin has shown some efficacy in ependymoma treatment, but chemotherapy for this condition is generally considered challenging due to resistance. ^{4 6 7 8 9}

How does the treatment of 3D-CRT with chemotherapy differ from other treatments for ependymoma?

This treatment combines 3D-CRT (a precise form of radiation therapy) with a mix of chemotherapy drugs like carboplatin, cisplatin, cyclophosphamide, etoposide, and vincristine, which is unique because it targets the tumor with both radiation and multiple drugs. Unlike standard treatments that often rely on surgery and radiation alone, this approach aims to enhance effectiveness by using a combination of therapies, although the role of chemotherapy in ependymoma is still under investigation. ^{10 11 12 13 14}

What is the purpose of this trial?

The primary aim of this randomized phase III trial was to study whether the addition of maintenance chemotherapy delivered after surgical resection and focal radiation would be better than surgery and focal radiation alone. The trial also studied if patients who received induction chemotherapy and then either achieved a complete response or went on to have a complete resection would also benefit from maintenance chemotherapy. Children ages 1-21 years with newly diagnosed intracranial ependymoma were included. There were 2 arms that were not randomized. One arm studied patients with Grade II tumors located in the supratentorial compartment that were completely resected. One arm studied patients with residual tumor and those patients all received maintenance chemotherapy after focal radiation. Chemotherapy drugs, such as vincristine sulfate, carboplatin, cyclophosphamide, etoposide, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving chemotherapy in combination with radiation therapy may kill more tumor cells and allow doctors to save the part of the body where the cancer started.

Research Team

Amy A Smith

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for children and young adults aged 1-21 with newly diagnosed brain ependymoma, who've had surgery but no other treatment. It's not for those with spinal cord ependymoma or certain other types, pregnant or breastfeeding individuals, or patients with metastatic disease.

Inclusion Criteria

My child has ependymoma but can still participate in the study despite any neurological issues.

I have been newly diagnosed with a specific type of brain tumor called ependymoma.

REGULATORY: All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

I have only had surgery or used corticosteroids for my condition.

I do not have cancer spread beyond the primary site as confirmed by MRIs and CSF tests.

Pregnant female patients are not eligible for this study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Patients receive induction chemotherapy with vincristine, carboplatin, cyclophosphamide, and etoposide to achieve complete response or prepare for further treatment

7 weeks

Multiple visits for chemotherapy administration

Radiation Therapy

Patients undergo conformal radiotherapy over 6-7 weeks

6-7 weeks

Daily visits for radiation therapy

Maintenance Chemotherapy

Patients receive maintenance chemotherapy with vincristine, etoposide, cisplatin, and cyclophosphamide

12 weeks

Every 21 days for 4 courses

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 4 months for 5 years, then annually

Treatment Details

Interventions

• 3-Dimensional Conformal Radiation Therapy
• Carboplatin
• Cisplatin
• Clinical Observation
• Cyclophosphamide
• Etoposide
• Laboratory Biomarker Analysis
• Vincristine

Trial Overview The study tests if maintenance chemotherapy after surgery and radiation helps more than just surgery and radiation alone in treating brain ependymoma. Some will receive combination chemotherapy drugs plus specialized radiation therapy aimed at killing tumor cells while sparing healthy tissue.

Participant Groups

Group I: Arm II (radiotherapy, chemotherapy) Experimental Treatment 8 Interventions

Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.

Group II: Arm I (chemotherapy, observation) Experimental Treatment 7 Interventions

Patients with classic histology(WHO Grade II) supratentorial ependymoma who have undergone microscopic gross total resection (GTR1) or achieved CR either after first or second resection or after post-operative induction chemotherapy are assigned to observation. For patients without GTR1, induction chemotherapy is comprised of vincristine intravenously (IV) over 1 minute on days 1 and 8 of cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks and cycle 2 continues for 4 weeks in the absence of disease progression or unacceptable toxicity.

Group III: ARM IV (radiotherapy, chemotherapy) Active Control 8 Interventions

Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are nonrandomly assigned to Arm II treatment.

Group IV: Arm III (radiotherapy, observation) Active Control 3 Interventions

Patients with supratentorial ependymoma (Grade II without GTR1 or ST Grade III) or any infratentorial ependymoma (Grade II or III) who have undergone gross or near total resection or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks and then undergo observation. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.

3-Dimensional Conformal Radiation Therapy is already approved in United States, European Union, Canada, Japan, China, Switzerland for the following indications:

Approved in United States as 3D-CRT for:

• Various types of cancer, including gynecologic cancers

Approved in European Union as 3D-CRT for:

• Various types of cancer, including gynecologic cancers

Approved in Canada as 3D-CRT for:

• Various types of cancer, including gynecologic cancers

Approved in Japan as 3D-CRT for:

• Various types of cancer, including gynecologic cancers

Approved in China as 3D-CRT for:

• Various types of cancer, including gynecologic cancers

Approved in Switzerland as 3D-CRT for:

• Various types of cancer, including gynecologic cancers

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

Childhood intracranial ependymoma has a poor prognosis, particularly in young children and those who cannot undergo complete surgical resection, with about two-thirds experiencing recurrence even without visible tumor remnants.

Cisplatin is the only chemotherapy agent that has shown some effectiveness in treating ependymoma, but overall, these tumors are generally resistant to chemotherapy, highlighting the need for new treatment strategies and well-designed clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Childhood ependymoma: a systematic review of treatment options and strategies. Grill, J., Pascal, C., Chantal, K.[2022]

In a multicenter study of lung cancer patients undergoing carboplatin-based chemotherapy, a one-day dexamethasone (DEX) regimen combined with 5-HT3RA and aprepitant (APR) resulted in significantly higher rates of delayed nausea compared to a multiple-day DEX regimen.

The findings suggest that while a DEX-sparing strategy may be considered, it should be approached with caution due to the increased risk of nausea, indicating the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of one-day versus multiple-day dexamethasone for chemotherapy-induced nausea and vomiting in lung cancer patients receiving carboplatin-based chemotherapy: a propensity score-matched analysis. Hayashi, T., Shimokawa, M., Mizuki, F., et al.[2021]

In a study of 69 patients undergoing cisplatin chemotherapy for testicular cancer, aprepitant significantly improved the complete response rate to 42% compared to only 13% with placebo, indicating its efficacy in preventing nausea and vomiting.

Patients overwhelmingly preferred the aprepitant treatment cycle, with no reported toxicity, suggesting that aprepitant is a safe and effective addition to standard antiemetic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier oncology group study. Albany, C., Brames, MJ., Fausel, C., et al.[2022]

Complete surgical resection of ependymomas significantly improves patient survival, making it crucial to evaluate the extent of disease through cerebrospinal fluid cytology and MRI before deciding on treatment.

For patients with residual disease who cannot undergo further surgery, limited-field radiotherapy is typically used, but the effectiveness of craniospinal irradiation remains debated due to the tendency for local recurrences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ependymomas. Chowdhary, S., Green, MR., Chamberlain, M.[2022]

In adults with intra-cranial ependymal tumors, there is a lack of universally accepted prognostic factors and treatment guidelines due to the rarity of these tumors and limited data.

Current evidence from a phase III trial in children shows that adding chemotherapy (lomustine, vincristine, and prednisone) to cranio-spinal irradiation does not improve survival compared to radiation therapy alone, suggesting that chemotherapy should only be used in controlled clinical trials for adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidelines for the treatment of adult intra-cranial grade II-III ependymal tumours. Reni, M.[2004]

References

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

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2. Greece pubmed.ncbi.nlm.nih.gov

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Safety and efficacy of concurrent carboplatin during full-dose craniospinal irradiation for high-risk/metastatic medulloblastoma in a resource-limited setting. [2021]

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Childhood ependymoma: a systematic review of treatment options and strategies. [2022]

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Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. [2022]

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Efficacy of Single-dose First-generation 5-HT3 Receptor Antagonist and Dexamethasone for Preventing Nausea and Vomiting Induced by Low-dose Carboplatin-based Chemotherapy. [2017]

8. Germany pubmed.ncbi.nlm.nih.gov

Efficacy of one-day versus multiple-day dexamethasone for chemotherapy-induced nausea and vomiting in lung cancer patients receiving carboplatin-based chemotherapy: a propensity score-matched analysis. [2021]

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

Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier oncology group study. [2022]

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11. Germany pubmed.ncbi.nlm.nih.gov

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

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13. Italy pubmed.ncbi.nlm.nih.gov

Guidelines for the treatment of adult intra-cranial grade II-III ependymal tumours. [2004]

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

Current Clinical Challenges in Childhood Ependymoma: A Focused Review. [2022]