Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma

  • STATUS
    Recruiting
  • End date
    May 31, 2025
  • participants needed
    45
  • sponsor
    Children's Oncology Group
Updated on 29 July 2021
platelet count
cancer
cyclophosphamide
vincristine
anticonvulsants
x-rays
MRI
glomerular filtration rate
residual tumor
neutrophil count
immunohistochemistry
tumor cells
blood transfusion
seizure
brain tumor
lomustine
medulloblastoma
mri of spine

Summary

This phase II trial studies how well reduced doses of radiation therapy to the brain and spine (craniospinal) and chemotherapy work in treating patients with newly diagnosed type of brain tumor called WNT)/Wingless (WNT)-driven medulloblastoma. Recent studies using chemotherapy and radiation therapy have been shown to be effective in treating patients with WNT-driven medulloblastoma. However, there is a concern about the late side effects of treatment, such as learning difficulties, lower amounts of hormones, or other problems in performing daily activities. Radiotherapy uses high-energy radiation from x-rays to kill cancer cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, vincristine sulfate, cyclophosphamide and lomustine, 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. Giving reduced craniospinal radiation therapy and chemotherapy may kill tumor cells and may also reduce the late side effects of treatment.

Description

PRIMARY OBJECTIVE:

I. To estimate the progression-free survival (PFS) of children >= 3 years of age with wingless-type MMTV integration site family (WNT)-driven average-risk medulloblastoma using reduced craniospinal radiotherapy (CSI) (18 Gray [Gy]) with a limited target volume boost to the tumor bed of 36 Gy for a total of 54 Gy and reduced chemotherapy approach (no vincristine [vincristine sulfate] during radiotherapy and reduced-dose maintenance chemotherapy) and to monitor the PFS for early evidence that the outcome is unacceptable.

SECONDARY OBJECTIVES:

I. To prospectively test the hypothesis that deoxyribonucleic acid (DNA) methylation profiling will accurately classify WNT-driven medulloblastoma.

II. To prospectively evaluate and longitudinally model the cognitive, social, emotional, behavioral, and quality of life (QoL) functioning of children who are treated with reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54 Gy) and reduced chemotherapy (reduced cisplatin, vincristine, and lomustine [CCNU]).

EXPLORATORY OBJECTIVES:

I. To explore whether DNA methylation profiling of medulloblastoma samples will result in a predictive classification scheme for the Sonic Hedgehog (SHH), Group 3, and Group 4 medulloblastoma subgroups according to the Heidelberg classifier. This will be addressed in a separate biology protocol.

II. To describe the audiologic and endocrinologic toxicities, as well as peripheral neuropathy, in children treated with reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54 Gy) and reduced cisplatin and vincristine chemotherapy.

OUTLINE

RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks.

MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine orally (PO) on day 1, vincristine sulfate intravenously (IV) over 1 minute or via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day

  1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV over 1 minute or via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually for 6 years.

Details
Condition Medulloblastoma, Glioma, Untreated Childhood Medulloblastoma, Gliomas, CTNNB1 Gene Mutation, Wnt Positive
Treatment radiation therapy, cyclophosphamide, laboratory biomarker analysis, cisplatin, vincristine sulfate, vincristine, Lomustine
Clinical Study IdentifierNCT02724579
SponsorChildren's Oncology Group
Last Modified on29 July 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients must be newly diagnosed and have
Eligibility confirmed by rapid central pathology and molecular screening review on APEC14B1
Classical histologic type (non LC/A) WNT medulloblastoma
Positive nuclear beta-catenin by immunohistochemistry (IHC)
Positive for CTNNB1 mutation
Negative for MYC and MYCN by fluorescence in situ hybridization (FISH)
Patient must have negative lumbar cerebrospinal fluid (CSF) cytology
Note: CSF cytology for staging should be performed no sooner than 14 days post operatively to avoid false positive CSF; ideally, CSF should be obtained between day 14 and day 21 to allow for final staging status before enrollment onto the study; patients with positive CSF cytology obtained 0 to 14 days after surgery should have cytology repeated to determine eligibility and final CSF status; patients with negative CSF cytology from lumbar puncture obtained 0 to 14 days after surgery do not need cytology repeated; patients with negative CSF cytology from lumbar puncture obtained prior to surgery do not need cytology repeated post-operatively
Patients must have eligibility confirmed by Rapid Central Imaging Review on APEC14B1; patients must have =< 1.5 cm^2 maximal cross-sectional area of residual tumor; whole brain magnetic resonance imaging (MRI) with and without gadolinium and spine MRI with gadolinium must be performed
Patients must be enrolled, and protocol therapy must be projected to begin, no later than 36 days after definitive diagnostic surgery (day 0)
Peripheral absolute neutrophil count (ANC) >= 1000/uL
Platelet count >= 100,000/uL (transfusion independent)
Hemoglobin >= 10.0 g/dL (may receive red blood cell [RBC] transfusions)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows
to < 6 years of age: maximum (max) serum creatinine 0.8 mg/dL (males and females)
to < 10 years of age: max serum creatinine 1 mg/dL (males and females)
to < 13 years of age: max serum creatinine 1.2 mg/dL (males and females)
to < 16 years of age: max serum creatinine 1.5 md/dL (males) and 1.4 md/dL (females)
>= 16 years of age: max serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL (females)
The threshold creatinine values were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC)
Total or direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
Serum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (3x ULN); for the purpose of this study, the ULN for SGPT is 45 U/L
Central nervous system function defined as
Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
Patients must not be in status epilepticus, a coma or on assisted ventilation at the time of study enrollment
Patients must have receptive and expressive language skills in English, French, or Spanish to complete the QoL and neurocognitive assessments; if a patient meets these criteria but the parent/guardian speaks a language other than English, French, or Spanish, the patient may still be enrolled and tested, and the parent-report measures should be omitted
All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar CSF cytology are not eligible; patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible
Patients must not have received any prior radiation therapy or chemotherapy (tumor-directed therapy) other than surgical intervention and/or corticosteroids
Pregnancy and Breast Feeding
Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies
Lactating females are not eligible unless they have agreed not to breastfeed their infants
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation
Patients with a history of moderate to profound intellectual disability (i.e., intelligence quotient [Q)]=< 55) are not eligible for enrollment; PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g., dyslexia) are eligible for this study
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