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Phase II study of multidisciplinary therapy of pediatric intracranial ependymoma with risk classification by postoperative residual tumor size and histological malignancy. (JCCG EPN1501)

Pediatric intracranial ependymoma clinical trial (JCCG EPN1501)

32

Patient Background Age: 3 years 0 months-19 years 6 months (Average age 8.75+/-4.38 years old) Sex: Male: 20, Female: 12 Specific Symptoms: Symptoms increased intracranial pressure due to hydrocephalus: 7, Gait disturbance: 3, Impaired consciousness: 3,Seizures: 7,Speech impairment: 2, Developmental delay: 1,Cerebellar ataxia: 2, Hyperactivity: 1,Dizziness: 1,Bilateral lower left quadrant hemianopia: 1 (With specific symptoms: 19, without:13) Tumor Location:Supratentorial: 20, Infratentorial: 12 Extent of Resection at the time of the initial surgery: GTR1:22(68.8%), GTR2:2(6.2%),NTR: 3(9.4%),STR:5(156%).If the total removal of the tumor is considered to be one of the two groups of GTR1 and GTR2, the complete removal rate was 24 out of 32 cases (75.0%) in all patients. Definitions: GTR1: No residual tumor on microscopy or postoperative imaging NTR: Residual tumor <=5 mm on imaging STR: Residual tumor > 5 mm or biopsy Symptoms: Headache: 10, Vomiting: 12,Dizziness: 1,Seizures:1,Neurological deficits: 1,Mild dysphagia: 1 (With symptoms: 18, Without: 14) Pathology: Anaplastic ependymoma WHO Grade III: 24(75.0%), Anaplastic ependymoma with focal ependymosarcoma: 1(3.1%), Ependymoma WHO Grade II: 7(21.9%) Group Classification: Group A: GTR1 with supratentorial tumor and WHO Grade II Group B: GTR1 with supratentorial tumor and WHO Grade III, GTR1 with infratentorial tumor, or GTR2/NTR (any location or histology); radiation within 3 weeks of registration preferred, followed by observation Group C: STR (any location or histology), subdivided into C-1 and C-2 based on postchemotherapy resectability Breakdown of group classification: Group A: 4 cases (12.5%), Group B: 23 cases (71.9%), Group C: 5 cases (15.6%).

Patient Enrollment Status This study began in October 2016 with a target enrollment of 40 patients. The initial planned completion date was October 2020; however, as the target number of patients was not reached, the enrollment period was extended until April 3, 2022. Ultimately, a total of 33 patients were enrolled, falling short of the target. The progress of patient enrollment is as follows: In 2017, 6 patients were enrolled: 1 in February, 1 in June, 1 in July, 1 in September, 1 in October, and 1 in December. In 2018, 4 patients were enrolled: 1 in February, 1 in August, 1 in September, and 1 in December. In 2019, 9 patients were enrolled: 1 in January, 1 in February, 1 in May, 2 in June, 1 in August, 2 in September, and 1 in October. (As of June 24, 2019, two years and eight months after the start of the study, a questionnaire survey was conducted at the facilities that had registered to participate in the clinical trial. At this point, the number of registered cases was 13, which was seven cases less than the planned number of 20 cases, but it was found that eleven cases were not registered during this period due to the age condition of being under three years old) In 2020, 6 patients were enrolled: 1 in January, 1 in April, 1 in May, 2 in September, and 1 in December. In 2021, 5 patients were enrolled: 2 in February, 1 in March, 1 in May, and 1 in August. In 2022, 3 patients were enrolled: 1 in January and 2 in February, with patient enrollment concluding on April 3, 2022.

Adverse Reactions/Adverse Events Surgical treatment Epidural abscess in 1 case (Grade 3) Chemotherapy Regimen E-A (4 cases): No heart failure (Grade 0 in all), hearing impairment in 3 cases (Grade 0) with 1 unevaluated, and increased bilirubin in 3 cases(Grade 0)and 1 (Grade 1). Notable events included Grade 3 and 4 febrile neutropenia (1 case each). Regimen E-B (4 cases): No heart failure, hearing impairment, or bilirubin increase (Grade 0 in all). Peripheral sensory neuropathy occurred in 1 case (Grade 1). Radiation Therapy Group B (20 cases): Alopecia (Grade 0-2 in all cases). Other mild events included otitis media, radiation dermatitis, headache, and vomiting (Grade 0-1). Severe events were rare, with 1 case of central nervous system necrosis with hydrocephalus (Grade 3). Group C (3 cases): Mild alopecia and radiation dermatitis (Grade 0-2). No other adverse events beyond Grade 0. ________________________________________ Complications After initial surgery (32 cases): CSF leakage in 2 cases, cranial nerve injury (including right abducens palsy) in 2 cases, postoperative seizures in 1 case, and swallowing disorder in 1 case. After reoperation (3 cases): Wound site complications in 1 case. ________________________________________ Post-Treatment Outcomes 1 year (25 cases): Central nervous system necrosis(the same case as the Grade 3 adverse event of hydrocephalus listed above), intellectual developmental disorders, T2 hyperintense lesions, and seizures observed in 4 cases. 2 years (20 cases): Cranial nerve disorders, intellectual developmental disorders, cerebellar necrosis, and hearing impairment in 6 cases. 3 years (11 cases): Right upper and lower limb paralysis and mild hemiparesis in 2 cases. 5 and 7 years: No relevant cases.

Treatment Completion Rate In one case of Group C, the tumor could not be completely removed after the second round of chemotherapy, so the planned treatment was changed, and the treatment completion rate was 31/32 cases (96.9%). Progression-Free Survival (PFS) [Primary Endpoint] The 2-year PFS for all cases was 75% (90% CI: 59.7-85.2, 95% CI: 56.2-86.6). Detailed Analysis of PFS [Secondary Endpoint] 2-year PFS by group: Group A: 100% (95% CI: not estimable to 100) Group B: 73.9% (95% CI: 50.9-87.3) Group C: 60.0% (95% CI: 12.6-88.2) 2-year PFS by WHO classification: Anaplastic ependymoma with focal ependymosarcoma component (1 case): not estimable Anaplastic ependymoma, WHO Grade III (24 cases): 70.8% (95% CI: 48.4-84.9) Ependymoma, WHO Grade II (7 cases): 100% (95% CI: not estimable to 100) Overall Survival (OS) [Secondary Endpoint] The 2-year OS for all cases was 96.9% (95% CI: 79.8-99.6). 2-year OS by group: Group A: 100% (95% CI: not estimable to 100) Group B: 95.7% (95% CI: 72.9-99.4) Group C: 100% (95% CI: not estimable to 100) 2-year OS by WHO classification: Anaplastic ependymoma with focal ependymosarcoma component: not estimable Anaplastic ependymoma, WHO Grade III: 100% (95% CI: not estimable to 100) Ependymoma, WHO Grade II: 100% (95% CI: not estimable to 100) Response Rate in Chemotherapy Cases Response(PR): 1/5 case, 20.0% (95% CI: 0.5-71.6) Complete Resection Rate in Reoperations Cases with reoperation: 5/5 cases(100%) Complete resection: 2/5 cases, 40.0% (95% CI: 5.3-85.3) Genomic Analysis Genome analysis was performed in 26 of the 32 cases (81.3%). ZFTA-RELA fusion(+): 14 cases(53.8%) PFA: 9 cases (34.6%) Of the 17 cases of tumors on the tentorium that were analyzable, 14 (82.4%) were positive for the ZFTA-RELA fusion, and of the 9 cases of tumors under the tentorium that were analyzable, all were PFA.

With the aim of establishing the basis for the treatment of pediatric brain tumors, we conducted the first multicenter prospective clinical trial in Japan,and provided multidisciplinary treatment to 32 children with ependymoma. The treatment completion rate was 96.9%. The 2-year PFS rate, the primary endpoint of the study, was 75.0% (90% confidence interval: 59.7-85.2), indicating the efficacy of the treatment and similar to the results of overseas clinical trials using the same treatment method.

Nov. 19, 2025

No

As the results of this clinical study did not include patients under the age of 3, the number of cases enrolled did not reach the planned number, and there was a tendency for good prognoses in cases where complete removal was possible, in the next clinical study of pediatric ependymoma, we will consider the treatment results of other clinical studies and include cases under the age of 3, and we plan to create a research protocol that will enable complete removal to be achieved in more cases, with the aim of establishing a standard treatment.

https://jrct.mhlw.go.jp/latest-detail/jRCTs051180233

Sakamoto Hiroaki

Osaka City General Hospital

2-13-22 Miyakojima-hondori Miyakojima-ku Osaka City, Osaka Prefecture

hssakamot@gmail.com

Yamamoto Testuya

Yokohama City University Hospital

3-9 Fukuura Kanazawa-ku Yokohama City, Kanagawa Prefecture

+81-45-787-2663

epen@yokohama-cu.ac.jp

Complete

Oct. 04, 2016

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

Newly developed intracranial ependymoma, from 3 years old to under 20 years old (no seeding metastatic lesions)

Exclude those subject to any of the following conditions.
1) Active duplication cancers (simultaneous duplicated cancers and metachronous duplicated cancers with disease-free period within 5 years).
2) Heart disease with treatment is merged.
3) Pregnant or lactating women
4) When judging that the doctor in charge is inappropriate

Both

intracranial ependymoma

Surgical resection, chemotherapy, radiotherapy

intracranial ependymoma

Surgical resection, chemotherapy, radiotherapy

ependymoma

Neurosurgery, Induction Chemotherapy, Radiotherapy

Progression-free survival rate (PFS) in 2 years, 5 years, and 7 years

2-year progression-free survival rate (PFS) and 2-year overall survival rate (OS) in each treatment group and histological gradings

+81-6-6645-3456

Feb. 21, 2019

none