This protocol is a comprehensive, iterative investigation of embryonal tumor with multilayered rosettes (ETMR). The protocol focuses on validating survival outcomes in newly diagnosed patients using a standard backbone therapy and collecting biospecimens for correlative studies to inform future treatments.

Patients will be grouped into one of three cohorts depending on their disease status following surgery and plan for radiotherapy:

Cohort 1 – Gross-total resection, non-metastatic, early radiotherapy
Cohort 2 – Gross-total resection, non-metastatic, high-dose chemotherapy
Cohort 3 – Metastatic or residual disease

ETMR is an aggressive pediatric brain tumor for which there is currently no standard of care and there is a lack of prospective data regarding the best treatment option. This absence of data will impede our ability to properly evaluate the efficacy of new therapeutic approaches for ETMR as they emerge.

Primary Objective:
Cohort 1: To determine the six-month progression-free survival (PFS6) of patients with newly diagnosed, gross-totally resected, non-metastatic ETMR, using a regimen of induction chemotherapy and early focal radiotherapy.

Secondary Objectives:
Cohort 1:
To determine the two-year progression-free survival (PFS) and overall survival (OS) of patients with newly diagnosed, non-metastatic ETMR.

Cohort 2:
To determine the two-year progression-free survival (PFS) and overall survival (OS) of patients with newly diagnosed, gross-totally resected, non-metastatic ETMR.

Cohort 3:
To determine the two-year progression-free survival (PFS), overall survival (OS) and objective response rate of patients with newly diagnosed, incompletely resected and/or metastatic ETMR

Inclusion Criteria:
– Participants must have either a molecularly or histologically confirmed embryonal tumor with multilayered rosettes.
– For enrollment, a confirmation of a minimum of 10-20 unstained FPPE slides or 1 block (15-20 mg) with tumor content of 40% or greater is required. Anything less must be discussed and approved by the study chairs prior to enrollment.
– Cohort 1 participants must not have received any prior tumor-directed therapy other than surgical resection.
– Cohort 2 and 3 participants may receive tumor-directed therapy prior to enrollment. These patients must be discussed with study chairs prior to enrollment.
– Radiation: Participants must not have received prior radiation for their tumor.
– Age: Participants of any age are eligible.
– Timing: Patients should begin induction chemotherapy within 28 days of the most recent definitive surgical procedure. Patients beginning therapy beyond
– Cohort eligibility is defined below:
Cohort 1:
•Gross-total resection
•Eligible for early radiotherapy, please see age criteria below
•No evidence of metastatic disease
Cohort 2:
•Gross-total resection
•High dose chemotherapy, please see age criteria below
•No evidence of metastatic disease
Cohort 3A:
•Metastatic or residual disease
•Early radiotherapy
Cohort 3B:
•Metastatic or residual disease
•High dose chemotherapy

Radiotherapy Age Criteria (at the time of planned radiation)
o>12 months of age for patients with infratentorial tumor, or
o>15 months of age for patients with supratentorial tumor
For patients being treated on radiotherapy-containing arms, the legal parent/guardian or patient and the physician must be willing to allow the use of radiotherapy for treatment.

– Performance Score: Karnofsky >/= 50 for participants > 16 years of age and Lansky >/= 50 for participants </= 16 years of age. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
-Adequate organ function
-As chemotherapeutic agents used in this trial are known to be teratogenic, women and men of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 4 months after completion of study therapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
– Patients must be enrolled on PNOC COMP prior to enrollment on PNOC031 if PNOC COMP is open to accrual at the enrolling institution.
– A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.

Exclusion Criteria:
-Cohort 1 only: Patients who have received any prior tumor-directed therapy other than surgical intervention
– Participants who are receiving any other tumor directed investigational agents.
– History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in study.
– Uncontrolled intercurrent illness.
– Women of childbearing potential must not be pregnant or breast-feeding.

Support is provided by Solving Kids Cancer.