PRIMARY OBJECTIVE:
I. 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. (Cohort 1)
SECONDARY OBJECTIVES:
I. To determine the two-year progression-free survival (PFS) and overall survival (OS) of patients with newly diagnosed, non-metastatic ETMR. (Cohort 1)
II. 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 2)
III. 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. (Cohort 3)
EXPLORATORY OBJECTIVES:
I. To validate the utility of a liquid micro-ribonucleic acid (miRNA) biomarker in blood and cerebrospinal fluid (CSF) as a correlative marker of a patient’s disease status.
II. To better define the genomic landscape of ETMR.
III. To develop in vitro ETMR cultures and patient derived xenograft (PDX) models to further preclinical research.
OUTLINE: Patients are assigned to 1 of 4 cohorts.
COHORT 1:
INDUCTION 1: Patients receive vincristine intravenously (IV) on day 1 of weeks 1-6, cisplatin IV on day 1 week 1 and day 5 week 4, topotecan intrathecally (IT) or intra-Ommaya (IO) on day 1 of weeks 1 and 4, topotecan IV on days 1-5 of week 4, doxorubicin IV over 48 hours on days 2-3 of week 1 and days 1-2 of week 4, cyclophosphamide IV over 72 hours on days 2-4 of week 1, and cytarabine IT or IO on day 1 of weeks 2 and 5. Patients with initially positive CSF cytology also receive cytarabine IT or IO on day 1 of weeks 3 and 6 until a negative CSF is achieved. Treatment continues for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
RADIATION + TEMOZOLOMIDE: Within 28 days of induction 1, patients undergo radiation therapy per institutional guidelines once daily (QD) 5 times a week for 30 treatment sessions (42-day period) in the absence of disease progression or unacceptable toxicity. Patients also receive temozolomide orally (PO) QD on days 1-42 of radiation therapy in the absence of disease progression or unacceptable toxicity.
INDUCTION 2: After completion of radiation + temozolomide, patients receive vincristine IV on day 1 of weeks 7-12, cisplatin IV on day 5 week 7, cyclophosphamide IV over 1 hour on day 1 week 7, topotecan IV on days 1-5 of week 7, cyclophosphamide IV over 72 hours on days 2-4 of week 10, dactinomycin IV on days 1-5 of week 10, topotecan IT or IO on day 1 of weeks 7 and 10, and cytarabine IT or IO on day 1 of weeks 8-9 and 11-12. Treatment continues for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
COHORT 2:
INDUCTION: Patients receive vincristine IV on day 1 of weeks 1-6, cisplatin IV on day 5 of weeks 1 and 4, doxorubicin IV over 48 hours on days 1-2 of weeks 1 and 4, topotecan IV on days 1-5 of weeks 1 and 2, topotecan IT or IO on day 1 of weeks 1 and 4, and cytarabine IT or IO on day 1 of weeks 2 and 5. Patients with initially positive CSF cytology also receive cytarabine IT or IO on day 1 of weeks 3 and 6 until a negative CSF is achieved. Treatment continues for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo leukapheresis during week 3 or 6.
CONSOLIDATION: Within 28 days of induction, patients receive carboplatin IV over 4 hours and thiotepa IV over 3 hours on days -4 and -3 and autologous hematopoietic cells IV on day 0 of each cycle. Cycles repeat every 4 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
RADIATION + TEMOZOLOMIDE: Within 28 days of consolidation, patients may optionally receive radiation + temozolomide therapy as described in cohort 1 in the absence of disease progression or unacceptable toxicity.
COHORT 3A:
INDUCTION 1: Patients receive Induction 1 therapy as described in cohort 1 in the absence of disease progression or unacceptable toxicity.
RADIATION + TEMOZOLOMIDE: Within 28 days of induction 1 or second look surgery if applicable, patients receive radiation + temozolomide therapy as described in cohort 1 in the absence of disease progression or unacceptable toxicity. Patients with residual tumor may undergo surgical resection at the discretion of the treating team following recovery from radiation.
INDUCTION 2: After completion of radiation + temozolomide or within 7 days of surgical resection, patients receive induction 2 therapy as described in cohort 1 in the absence of disease progression or unacceptable toxicity.
COHORT 3B:
INDUCTION: Patients receive induction therapy as described in cohort 2 in the absence of disease progression or unacceptable toxicity. Patients with residual tumor may undergo surgical resection at the discretion of the treating team following recovery from induction therapy.
CONSOLIDATION: Within 28 days of induction therapy or within 10 days of surgical resection, patients receive consolidation therapy as described in cohort 2 in the absence of disease progression or unacceptable toxicity.
RADIATION + TEMOZOLOMIDE: Within 28 days of consolidation, patients may optionally receive radiation + temozolomide therapy as described in cohort 1 in the absence of disease progression or unacceptable toxicity.
Additionally, all patients undergo echocardiography (ECHO), lumbar puncture (LP), magnetic resonance imaging (MRI), and collection of blood and tissue samples throughout the study.
After completion of study treatment, patients are followed up at 30 days and then per A Protocol for Children and Young Adults Diagnosed with a Central Nervous System (CNS) Tumor to Assess Cognitive, Quality of Life (QOL), and Comprehensive Effects of Therapies (PNOC COMP) until death or withdrawal from study.
