Chemotherapy with Radiation Therapy or Autologous Stem Cell Rescue for the Treatment of Embryonal Tumor with Multilayered Rosettes in Patients with Gross-Total Resection, Residual Disease, or Metastatic Disease

Status: active

This phase II trial studies how well short, intensive courses of chemotherapy with either early radiation therapy or stem cell rescue works in treating embryonal tumor with multilayered rosettes (ETMR) in patients that have had the tumor completely removed (gross-total resection), that have tumor that remains after resection (residual disease), or that have tumor that has spread from where it first started (primary site) to other places in the body (metastatic disease). Chemotherapy drugs, such as vincristine, cisplatin, doxorubicin, cyclophosphamide, topotecan, cytarabine, temozolomide, dactinomycin, carboplatin, and thiotepa, 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. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Autologous stem cell rescue is a method of replacing immature blood-forming cells that were destroyed by treatment with anticancer drugs. The stem cells help the bone marrow recover and make healthy blood cells. Stem cell rescue is usually done using the patient's own stem cells that were saved before treatment. Giving short, intensive courses of chemotherapy with either early radiation therapy or autologous stem cell rescue may be an effective treatment for ETMR in patients with gross-total resection, residual disease, or metastatic disease.

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 formalin-fixed paraffin-embedded (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
Participants must not have received prior radiation for their tumor
Participants of any age are eligible
Patients should begin induction chemotherapy within 28 days of the most recent definitive surgical procedure. Patients beginning therapy beyond 28 days from surgery, will need to discuss with study chairs
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) ** > 12 months of age for patients with infratentorial tumor, or ** > 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
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
Peripheral absolute neutrophil count (ANC) > 75,000/mm^3
Platelet count > 75,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 72 hours prior to enrollment)
A serum creatinine =< 1.5 x upper limit normal (ULN) based on age and gender
Total bilirubin =< 1.5 x upper limit of normal (ULN) for age; in presence of Gilbert’s syndrome, total bilirubin =< 3 x ULN or direct bilirubin =< 1.5 x ULN
Alanine aminotransferase (ALT) =< 3 x ULN
Aspartate aminotransferase (AST) =< 3 x ULN
Participants with seizure disorder may be enrolled if well controlled. Patients on enzyme inducing anticonvulsants may be excluded pending interaction(s) with study drugs
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 Protocol for Embryonal Tumor with Multilayered Rosettes (ETMR) (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

Additional locations may be listed on ClinicalTrials.gov for NCT06861244.

State:

United States

California

San Francisco

University of California San Francisco

Status: Active

Contact: Sabine Mueller

Phone: 415-476-3831

Email: Sabine.Mueller@ucsf.edu

Maryland

Baltimore

Johns Hopkins University/Sidney Kimmel Cancer Center

Status: Active

Contact: Kenneth J. Cohen

Phone: 410-614-5055

Email: kcohen@jhmi.edu

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.

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.

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Chemotherapy with Radiation Therapy or Autologous Stem Cell Rescue for the Treatment of Embryonal Tumor with Multilayered Rosettes in Patients with Gross-Total Resection, Residual Disease, or Metastatic Disease

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