Neoplasms

All Conditions

Rare Diseases

Ependymoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Anaplastic Ependymoma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Dermatologic Agents

Carboplatin

Etoposide

Cyclophosphamide

Vincristine

Cisplatin

Lenograstim

Etoposide phosphate

Podophyllotoxin

Mesna

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

Adjuvants, Immunologic

Tubulin Modulators

Antimitotic Agents

Protective Agents

Keratolytic Agents

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.

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.

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.

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

3-Dimensional Conformal Radiation Therapy

Clinical Observation

Filgrastim

Laboratory Biomarker Analysis

Amy A Smith

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.

PRIMARY OBJECTIVE:

I. To determine the event free survival (EFS) and overall survival (OS) of children with completely resected ependymoma treated with post-operative conformal radiation therapy (cRT) and then randomized to receive or not receive four cycles of post radiation maintenance chemotherapy (vincristine, cisplatin, etoposide and cyclophosphamide \[VCEC\]).

EXPLORATORY OBJECTIVES:

I. To estimate the EFS and OS of children with incompletely resected ependymoma who are unable to achieve a complete response (CR) by post-operative induction chemotherapy or by second surgery who will then be non-randomly assigned to cRT followed by four cycles of maintenance chemotherapy (VCEC).

II. To further evaluate the EFS and OS of children with supratentorial classic ependymoma who achieve a complete resection at first or second resection OR children who achieve a CR to short course induction chemotherapy following first surgery.

III. To evaluate whether the addition of maintenance chemotherapy post-radiation therapy contributes to neurobehavioral morbidity and reduced functional outcomes over time, compared to patients treated with radiation therapy followed by observation alone.

IV. To examine differences in neurobehavioral outcomes and quality of life of children treated with proton beam radiation therapy compared to children treated with conventional radiation delivery techniques.

V. To evaluate biologic prognostic factors in childhood ependymoma by studying molecular groups as defined by deoxyribonucleic acid (DNA) methylation profiling and immunohistochemistry, copy number variants to identify 1q gain in posterior fossa ependymomas, CDKN2A loss (homozygous deletion) in supratentorial ependymomas and specific genetic alterations such as RELA fusions, YAP1 fusions and the H3 K27M mutation on initial tumor samples and correlating these data with clinical outcome.

Va. To explore prognostic molecular signatures and genomic alterations in ependymomas by building upon the data derived from ACNS0121 to correlate biomarkers listed above with World Health Organization (WHO) grade, location, extent of resection, treatment, EFS and OS.

OUTLINE: This is a multicenter study partially randomized phase III study. Patients are randomized or non-randomly treated according to tumor location and extent of surgical resection or post-surgery induction chemotherapy response.

Arm I: 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.

ARM II: 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.

ARM III: 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.

ARM IV: Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are non-randomly assigned to Arm II treatment.

After completion of study therapy, patients are followed up every 4 months for 5 years, and then annually thereafter.

Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma

Phase III Randomized Trial of Post-Radiation Chemotherapy in Patients With Newly Diagnosed Ependymoma Ages 1 to 21 Years

Kaplan-Meier estimates of EFS are calculated from randomization date to first occurrence of disease progression, disease recurrence, second malignant neoplasm, or death from any cause. The comparison between randomized arms (post-radiation maintenance chemotherapy versus post-radiation observation only) for this stratum is conveyed by the hazard ratio and 95% Wald confidence interval.

Kaplan-Meier estimates of OS are calculated from randomization date to death from any cause. The comparison between randomized arms (post-radiation maintenance chemotherapy versus post-radiation observation only) for this stratum is conveyed by the hazard ratio and 95% Wald confidence interval.

The Kaplan-Meier estimate of EFS is calculated from enrollment date to first occurrence of disease progression, disease recurrence, second malignant neoplasm, or death from any cause.

The Kaplan-Meier estimate of OS is calculated from enrollment date to death from any cause.

Kaplan-Meier estimates of EFS are calculated from randomization date to first occurrence of disease progression, disease recurrence, second malignant neoplasm, or death from any cause. The comparison between randomized arms (post-radiation maintenance chemotherapy versus post-radiation observation only) is conveyed by the hazard ratio and 90.46% stagewise adjusted Wald confidence interval.

Kaplan-Meier estimates of OS are calculated from randomization date to death from any cause. The comparison between randomized arms (post-radiation maintenance chemotherapy versus post-radiation observation only) is conveyed by the hazard ratio and 90.46% stagewise adjusted Wald confidence interval.

National Cancer Institute (NCI)

Children's Oncology Group

Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.

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.

Arm I: Observation

Arm II: Randomized to Radiation With Maintenance Chemotherapy

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.

Arm III: Randomized to Radiation Only

Arm IV: Nonrandomly Assigned to Arm II Treatment

Patients with tumor other than ependymoma or withdrew before protocol-specified radiotherapy administered

Not Ependymoma or Withdrew Before Radiation

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Canada

Australia

New Zealand

Region of Enrollment

Results Reporting Coordinator

The study was designed to test the superiority of RT+maintenance vs. RT alone as measured by EFS using the hazard ratio via a 1-sided log-rank test. The planned sample size was 160 subjects per arm. 85 EFS events were needed, which were expected after 8 years of accrual and 2 years of follow-up. At 5% type 1 error, the study had 93% power to detect an increase in 2-year EFS from 75% (RT alone) to 87% (RT+maintenance). The design also incorporated interim analyses for futility and efficacy.

Eligible, randomized participants (intent-to-treat)

Event-free Survival (EFS) in Children Who Have Completely Resected Ependymoma or Achieved CR and Are Treated With Post-radiation Maintenance Chemotherapy or Post-radiation Observation Only

It was planned to test the superiority of RT+maintenance vs. RT alone as measured by OS using the hazard ratio via a 1-sided log-rank test using the planned sample size of 160 subjects per arm which was optimized for the EFS outcome. A one-sided significance threshold of 5% was planned for this comparison as well.

Overall Survival (OS) in Children Who Have Completely Resected Ependymoma or Achieved CR and Are Treated With Post-radiation Maintenance Chemotherapy or Post-radiation Observation Only

In stratum 1, it was also planned to test the superiority of RT+maintenance vs. RT alone as measured by EFS using the hazard ratio via a 2-sided log-rank test. A two-sided significance threshold of 5% was planned for this comparison.

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) after initial surgery (stratum 1) are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy.

Arm II: Randomized to Radiation With Maintenance Chemotherapy in Stratum 1

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 after initial surgery (stratum 1) are randomized to undergo conformal radiotherapy over 6-7 weeks and then undergo observation.

Arm III: Randomized to Radiation Only in Stratum 1

Eligible, randomized participants (intent-to-treat) in stratum 1 (completely resected ependymom at initial surgery)

EFS in Children Who Have Completely Resected Ependymoma at Initial Surgery and Are Treated With Post-radiation Maintenance Chemotherapy or Post-radiation Observation Only

In stratum 2, it was also planned to test the superiority of RT+maintenance vs. RT alone as measured by EFS using the hazard ratio via a 2-sided log-rank test. A two-sided significance threshold of 5% was planned for this comparison.

Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma with incomplete resection after initial surgery and then CR after induction chemotherapy, or patients with GTR/NTR after second surgery (stratum 2) are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy.

Arm II: Randomized to Radiation With Maintenance Chemotherapy in Stratum 2

Patients with supratentorial ependymoma (Grade II without GTR1 or ST Grade III) or any infratentorial ependymoma (Grade II or III) with incomplete resection after initial surgery and then CR after induction chemotherapy, or patients with GTR/NTR after second surgery (stratum 2) are randomized to undergo conformal radiotherapy over 6-7 weeks and then undergo observation.

Arm III: Randomized to Radiation Only in Stratum 2

Eligible, randomized participants (intent-to-treat) in stratum 2 (completely resected ependymom at initial surgery)

EFS With Incomplete Resection After Initial Surgery, Then Achieved CR After Induction Chemotherapy or GTR/NTR After Second Surgery and Treated With Post-radiation Maintenance Chemotherapy or Post-radiation Observation Only

In stratum 1, it was also planned to test the superiority of RT+maintenance vs. RT alone as measured by OS using the hazard ratio via a 2-sided log-rank test. A two-sided significance threshold of 5% was planned for this comparison.

OS in Children Who Have Completely Resected Ependymoma at Initial Surgery and Are Treated With Post-radiation Maintenance Chemotherapy or Post-radiation Observation Only.

In stratum 2, it was also planned to test the superiority of RT+maintenance vs. RT alone as measured by OS using the hazard ratio via a 2-sided log-rank test. A two-sided significance threshold of 5% was planned for this comparison.

Eligible, randomized participants (intent-to-treat) in stratum 2 (induction chemotherapy or second surgery required)

OS in Children With Incomplete Resection After Initial Surgery Who Then Achieved CR After Induction Chemotherapy or GTR/NTR After Second Surgery and Are Treated With Post-radiation Maintenance Chemotherapy or Post-radiation Observation Only

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

Eligible participants in Arm IV (intent-to-treat)

EFS of Children With Incompletely Resected Ependymoma Who Are Unable to Achieve a Complete Response (CR) by Post-operative Induction Chemotherapy or by Second Surgery and Who Are Non-randomly Assigned to Receive Maintenance Chemotherapy

OS of Children With Incompletely Resected Ependymoma Who Are Unable to Achieve a Complete Response (CR) by Post-operative Induction Chemotherapy or by Second Surgery and Who Are Non-randomly Assigned to Receive Maintenance Chemotherapy

EFS of Children With Supratentorial Classic Ependymoma Who Achieve Complete Resection at First or Second Surgery or Children Who Achieve Complete Response (CR) After Induction Chemo and Who Are Non-randomly Assigned to Observation

OS of Children With Supratentorial Classic Ependymoma Who Achieve Complete Resection at First or Second Surgery or Children Who Achieve Complete Response (CR) After Induction Chemo and Who Are Non-randomly Assigned to Observation

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma	NCT01096368	Anaplastic Epen... Brain Ependymom... Cellular Ependy... Clear Cell Epen... Ependymoma Papillary Epend...	3-Dimensional C... Carboplatin Cisplatin Clinical Observ... Cyclophosphamid... Etoposide Filgrastim Laboratory Biom... Mesna Vincristine	12 Months - 21 Years	Children's Oncology Group
Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma	NCT01096368	Anaplastic Epen... Brain Ependymom... Cellular Ependy... Clear Cell Epen... Ependymoma Papillary Epend...	3-Dimensional C... Carboplatin Cisplatin Clinical Observ... Cyclophosphamid... Etoposide Filgrastim Laboratory Biom... Mesna Vincristine	12 Months - 21 Years	Children's Oncology Group

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