Nutritional and Metabolic Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Central Nervous System Germinoma

Pineal Germ Cell Tumor

Antineoplastic Agents

All Drugs and Chemicals

Dermatologic Agents

Carboplatin

Etoposide

Etoposide phosphate

Podophyllotoxin

Enzyme Inhibitors

Keratolytic Agents

Tubulin Modulators

Antimitotic Agents

Patients receive carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with localized germinoma achieving PR with normalization of markers who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients undergo MRI and optional blood and tissue sample collection throughout the study. Patients may undergo LP for CSF sample collection during screening and follow up.

Patients receive carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with localized germinoma with normalization of markers who fail to achieve CR or PR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days. Patients undergo MRI and optional blood and tissue sample collection throughout the study. Patients may undergo LP for CSF sample collection during screening and follow up.

Patients receive carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with metastatic germinoma achieving CR undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients with metastatic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients undergo MRI and optional blood and tissue sample collection throughout the study. Patients may undergo LP for CSF sample collection during screening and follow up.

Patients receive carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with metastatic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days. Patients undergo MRI and optional blood and tissue sample collection throughout the study. Patients may undergo LP for CSF sample collection during screening and follow up.

Patients receive carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with basal ganglia and thalamic germinoma achieving CR undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients with basal ganglia and thalamic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients undergo MRI and optional blood and tissue sample collection throughout the study. Patients may undergo LP for CSF sample collection during screening and follow up.

Patients receive carboplatin IV over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with basal ganglia and thalamic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days. Patients undergo MRI and optional blood and tissue sample collection throughout the study. Patients may undergo LP for CSF sample collection during screening and follow up.

3-Dimensional Conformal Radiation Therapy

Biospecimen Collection

Intensity-Modulated Radiation Therapy

Lumbar Puncture

Magnetic Resonance Imaging

Questionnaire Administration

Surgical Procedure

Mohamed S Abdelbaki

This phase II trial studies how well lower dose radiotherapy after chemotherapy works in treating children with central nervous system (CNS) germinomas. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Researchers want to see if lowering the dose of standard radiotherapy (RT) after chemotherapy can help get rid of CNS germinomas with fewer long-term side effects.

PRIMARY OBJECTIVE:

I. To determine whether 12 Gy whole ventricular irradiation (WVI) and 12 Gy tumor boost would maintain similar efficacy compared to ACNS1123 stratum 2 as measured by event-free survival (EFS) in eligible patients with localized primary central nervous system (CNS) germinoma who present with serum and/or cerebrospinal fluid (CSF) human chorionic gonadotropin-beta (hCGβ) ≤ 100 IU/L and normal alpha-fetoprotein (AFP), and meet complete response (CR) or continued complete response (CCR) criteria following chemotherapy/second-look surgery (Stratum 1).

SECONDARY OBJECTIVES:

I. To estimate the EFS distribution for patients with localized midline - including bifocal - CNS germinoma with partial response (PR) after chemotherapy, followed by 18 Gy WVI and 12 Gy tumor boost (Stratum 2).

II. To estimate the EFS distribution for patients with localized midline - including bifocal - CNS germinoma with less than a PR after chemotherapy, followed by 24 Gy WVI and 12 Gy tumor boost (Stratum 3).

III. To estimate the overall survival (OS), response rates to chemotherapy and radiotherapy (RT), as well as the patterns of failure of the various cohorts based on tumor characteristics, treatment regimen, and treatment modality.

IV. To determine the impact of tumor characteristics, treatment regimen and treatment modalities on the long-term neuroendocrine function for patients with CNS germinomas.

V. To prospectively evaluate processing speed of children and young adults with CNS germinoma through the Children's Oncology Group (COG) Standardized assessment battery.

EXPLORATORY OBJECTIVES:

I. To estimate the EFS distribution for patients with metastatic germinomas treated with chemotherapy followed by craniospinal irradiation (CSI) (18 Gy for CR/CCR \[Stratum 4\]) or (24 Gy for less than CR \[Stratum 5\]) with a 12 Gy tumor boost to the pre-treatment volume, including metastatic sites.

II. To estimate the EFS distribution for patients with basal ganglia and thalamic germinomas (BGTG) treated with chemotherapy followed by whole brain irradiation (WBI) (18 Gy for CR/CCR \[Stratum 6\]) or (24 Gy for less than CR \[Stratum 7\]) with a 12 Gy tumor boost to the pre-treatment volume.

III. To prospectively collect blood, cerebrospinal fluid, and tumor tissue at diagnosis and second-look surgery (if feasible) for future biology studies.

IV. To prospectively measure the incidence of cerebral vascular events (stroke or transient ischemic attacks) in the follow-up period and longitudinally evaluate and model the cognitive, social and behavioral functioning of children and young adults with CNS germinoma through the COG Standardized assessment battery, and compare these outcomes based on tumor characteristics, treatment regimen, and treatment modality.

OUTLINE:

INDUCTION PHASE: All patients receive carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Patients are then assigned to 1 of 7 strata.

STRATUM I: Patients with localized germinoma achieving CR with normalization of markers undergo 3-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 16 days. Patients achieving PR with normalization of markers may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 16 days. Patients with normalization of markers who fail to achieve CR or PR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 16 days. Patients with bifocal germinoma undergo 3DRT or IMRT QD 5 days a week for 16 days.

STRATUM II: Patients with localized germinoma achieving PR with normalization of markers who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 20 days.

STRATUM III: Patients with localized germinoma with normalization of markers who fail to achieve CR or PR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days.

STRATUM IV: Patients with metastatic germinoma achieving CR undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients with metastatic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 20 days.

STRATUM V: Patients with metastatic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days.

STRATUM VI: Patients with basal ganglia and thalamic germinoma achieving CR undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients with basal ganglia and thalamic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 20 days.

STRATUM VII: Patients with basal ganglia and thalamic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days.

Patients with non-normalized tumor markers or PD and no second-look surgery or viable tumor during second-look surgery discontinue protocol therapy.

All patients undergo magnetic resonance imaging (MRI) and optional blood and tissue sample collection throughout the study. Patients may undergo lumbar puncture (LP) for CSF sample collection during screening and follow up.

After completion of study treatment, patients are followed up every 3 months for 12 months, every 4 months for 24 months, and then annually for up to 120 months.

A Study of Lower Radiotherapy Dose to Treat Children With CNS Germinoma

A Phase II Trial Evaluating Chemotherapy Followed by Response-Based Reduced Radiation Therapy for Patients With Central Nervous System Germinomas

Will use KM methods to visualize and summarize EFS and will use similar considerations for Cox models as the analysis of Stratum 1.

Will be recorded as a part of routine study monitoring. The analyses to be performed with the collected samples will be detailed in a future amendment or in a separate biology study protocol as appropriate.

Will be assessed by the COG Standardized assessment battery. Will be measured in these patients over time, and available data will be summarized by appropriate plots and descriptive statistics.

Will be compared to ACNS1123 stratum 2 as measured by EFS in eligible and evaluable patients assigned to Stratum 1. Will use the Kaplan-Meier (KM) method to visualize and summarize EFS, and will report the 2- and 3-year EFS estimates with respective 80% two-sided confidence intervals.

Will report the response rates using the respective sample proportions and exact binomial two-sided 95% confidence intervals. Will descriptively report the locations of failures (local only, distant only or combination of local and distant).

Will use KM methods to visualize and summarize stratum-specific OS. For a given stratum, if an adequate sample size and number of events is observed, then Cox models will be used to study the association with OS of demographic, clinical and treatment-related variables including radiation therapy modality (proton versus photon), patient age, tumor location. Other definitions for OS may also be considered (e.g., using time from enrollment) to fully address this objective.

Will be summarized by the Kalbfleisch-Prentice cumulative incidence function (CIF) approach, separately by stratum. Competing risks will include disease progression and death, and patients without events or competing risks will be censored at the time of their last follow-up. Will assess the association with tumor location as well as RT modality as feasible within the constraints of sample size and number of neuroendocrine events using Fine-Gray models. Other endocrine dysfunctions (e.g., thyroid hormone deficiency, adrenal hormone deficiency, hypogonadism, and central precocious puberty) will be respectively summarized in a similar manner.

Will be assessed by the Children's Oncology Group (COG) Standardized assessment battery. Will be measured in these patients over time, and available data will be summarized by appropriate plots and descriptive statistics.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Lower Radiotherapy Dose to Treat Children With CNS Germinoma	NCT06368817	Central Nervous... Diabetes Insipi... Pineal Region G... Suprasellar Ger...	3-Dimensional C... Biospecimen Col... Carboplatin Etoposide Intensity-Modul... Lumbar Puncture Magnetic Resona... Questionnaire A... Surgical Proced...	3 Years - 30 Years	Children's Oncology Group
A Study of Lower Radiotherapy Dose to Treat Children With CNS Germinoma	NCT06368817	Central Nervous... Diabetes Insipi... Pineal Region G... Suprasellar Ger...	3-Dimensional C... Biospecimen Col... Carboplatin Etoposide Intensity-Modul... Lumbar Puncture Magnetic Resona... Questionnaire A... Surgical Proced...	3 Years - 30 Years	Children's Oncology Group

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