PRIMARY OBJECTIVES:
I. To evaluate the efficacy of sodium thiosulfate (STS) infusion administered during cisplatin-containing chemotherapy cycles (compared to a historical cohort selected from ACNS0331 which received chemotherapy without STS) in reducing hearing loss in children with newly-diagnosed average-risk medulloblastoma.
II. To estimate and monitor event-free survival (EFS) in this study against a carefully selected cohort from ACNS0331 to guard against loss of efficacy due to STS.
SECONDARY OBJECTIVES:
I. To estimate and monitor overall survival (OS) in this study against a carefully selected control cohort from ACNS0331.
II. To estimate the incidence of ototoxicity-related cisplatin dose modifications in the average-risk cohort.
III. To estimate the incidence of cisplatin-related nephrotoxicity in both the average-risk and low-risk cohorts.
IV. To evaluate full scale intelligence neurocognitive outcomes and trajectories of patients with average-risk medulloblastoma treated with STS compared to the control cohort from ACNS0331.
V. To evaluate quality of life and psychosocial outcomes and trajectories of patients with average-risk medulloblastoma treated with STS compared to published norms.
VI. To estimate and monitor EFS and OS in patients with low-risk features treated using a reduced craniospinal radiation approach.
VII. To evaluate the trajectory of hearing loss in medulloblastoma patients treated with STS.
VIII. To evaluate household material hardship as a social determinant of neurocognitive, quality of life, and psychosocial outcomes in patients with average-risk and low risk medulloblastoma.
EXPLORATORY OBJECTIVES:
I. To obtain paired blood and tumor tissue to be banked for future biology studies involving comprehensive molecular analysis, including but not limited to whole exome sequencing, ribonucleic acid (RNA) sequencing, and methylation.
II. To bank blood and cerebrospinal fluid for future studies. III. To evaluate attention, processing speed, memory, and executive function neurocognitive outcomes and trajectories, as well as hearing-related quality of life outcomes and trajectories, of patients with average-risk medulloblastoma treated with STS.
IV. To evaluate neurocognitive, quality of life, and psychosocial outcomes of patients with low-risk features treated using a reduced craniospinal radiation approach.
OUTLINE:
CHEMORADIOTHERAPY: Patients undergo radiation therapy on weeks 1-7 and receive vincristine intravenously (IV) once weekly on weeks 2-7 in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Beginning 4 weeks after chemoradiotherapy, patients receive lomustine orally (PO) on day 1 of cycles 1, 2, 4, 5, 7, and 8, cisplatin IV over 6 hours on day 1 of cycles 1, 2, 4, 5, 7, and 8, sodium thiosulfate IV over 15 minutes on day 1 of cycles 1, 2, 4, 5, 7, and 8, and cyclophosphamide IV over 30-60 minutes on days 1 and 2 of cycles 3, 6, and 9. Patients also receive vincristine IV on days 1, 8, and 15 of cycles 1, 2, 4, 5, 7, and 8, and on days 1 and 8 of cycles 3, 6, and 9. Treatment repeats every 6 weeks (cycles 1, 2, 4, 5, 7 and 8) or every 4 weeks (cycles 3, 6, and 9) for up to 9 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for years 1-2, every 6 months for years 3-4, and then annually for years 5-10.
Inclusion Criteria:
- PRE-ENROLLMENT: Patients must be greater than or equal to 3 years and less than 22
years of age at the time of enrollment on Step 0
- PRE-ENROLLMENT: Patient is suspected to have newly-diagnosed medulloblastoma by
institutional diagnosis
- Please note: Patients with a pending result of cerebrospinal Fluid (CSF) cytology
tests are eligible for enrollment on NCI-2014-02057 (APEC14B1) and the
Medulloblastoma Pre Enrollment Eligibility Screening (Step 0)
- PRE-ENROLLMENT: Patient and/or their parents or legal guardians have signed informed
consent for APEC14B1 Part A - Eligibility Screening and Molecular Characterization
- PRE-ENROLLMENT: The required specimens are projected to be submitted through APEC14B1
as soon as possible (ASAP), preferably within 5 days of definitive surgery
- PRE-ENROLLMENT: All patients must have rapid central pathology review on APEC14B1
prior to study enrollment on ACNS2031 step 1 in order to avoid discordant diagnoses
and to verify diagnosis criterion for treatment on ACNS2031.
- Note: Patients with a pending result of CSF cytology tests are eligible for the
rapid central pathology screening review. Confirmation of CSF negativity is
needed for enrollment on the ACNS2031 protocol.
- PRE-ENROLLMENT: All patients must have rapid central molecular screening review on
APEC14B1 prior to study enrollment on ACNS2031 step 1, in order to avoid discordant
diagnoses and to verify diagnosis criterion for treatment on ACNS2031
- PRE-ENROLLMENT: All patients who have pathology confirmed must have rapid central
imaging screening review on APEC14B1 prior to study enrollment on ACNS2031 step 1
- Note: Patients must not have metastatic disease on cranial or spinal MRI.
Patients with > 1.5 cm^2 residual tumor after initial surgical resection may
undergo a second surgical resection prior to subsequent therapy to render them
eligible for this study. The day of the second resection to remove residual tumor
will be regarded as the day of definitive surgery (Day 0) and must be within a
month (31 days) of the initial resection
- PRE-ENROLLMENT: All patients who have pathology confirmed must have rapid central
audiology review on APEC14B1 prior to study enrollment on ACNS2031 step 1
- Patients must be >= 4 years and =< 21 years of age at the time of enrollment
- Patients must be newly diagnosed and have eligibility confirmed by rapid central
pathology and molecular screening reviews performed on APEC14B1 and via the Molecular
Characterization Initiative
- Average-risk cohort
- Clinico-pathologic criteria:
- M0 disease
- No diffuse anaplastic histology AND
- Molecular criteria:
- SHH, p53wt, GLI2 normal, MYCN normal, no chromosome 14q loss
- Group 3, MYC normal, no isochromosome 17q
- Group 4, no chromosome 11 loss
- Low-risk features cohort
- Clinico-pathologic criteria:
- M0 disease
- No diffuse anaplastic histology AND
- Molecular criteria:
- Group 4, chromosome 11 loss
- Patients must have negative lumbar 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 performed on
APEC14B1. Patients must have =< 1.5 cm^2 cross-sectional area of residual tumor. Whole
brain MRI with and without gadolinium and spine MRI with gadolinium must be performed
- Patients must weigh > 10 kg
- Patients must be enrolled, and protocol therapy must be projected to begin, no later
than 31 days after definitive diagnostic surgery (day 0)
- Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to
enrollment)
- Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to
enrollment)
- Hemoglobin >= 8.0 g/dL (may receive red blood cell count [RBC] transfusions) (within 7
days prior to enrollment)
- A serum creatinine (within 7 days prior to enrollment) based on age/gender as follows:
- 4 to < 6 years (age); 0.8 mg/dL (male) 0.8 mg/dL (female)
- 6 to < 10 years (age); 1 mg/dL (male) 1 mg/dL (female)
- 10 to < 13 years (age); 1.2 mg/dL (male) 1.2 mg/dL (female)
- 13 to < 16 years (age); 1.5 mg/dL (male) 1.4 mg/dL (female)
- >= 16 years (age); 1.7 mg/dL (male) 1.4 mg/dL (female) OR a 24 hour urine
Creatinine clearance >= 70 mL/min/1.73 m^2 (within 7 days prior to enrollment) OR
a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to
enrollment). GFR must be performed using direct measurement with a nuclear blood
sampling method OR direct small molecule clearance method (iothalamate or other
molecule per institutional standard)
- Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
are not acceptable for determining eligibility
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment)
- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
(within 7 days prior to enrollment)
- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
value of 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 assisted ventilation at the
time of study enrollment
- Auditory function defined as:
- Patients must have normal hearing (defined as International Society of Pediatric
Oncology [SIOP] grade 0) in at least one ear confirmed by rapid central audiology
review performed on APEC14B1 prior to enrollment
- All patients and/or their parents or legal guardians must sign a written informed
consent
- 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 magnetic resonance imaging (MRI) evaluation
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
- Patients must not have any known hypersensitivity to STS, sulfates/sulfites, or other
thiol agents (e.g., amifostine, n-acetylcysteine, MESNA, and captopril)
- Pregnancy and Breastfeeding:
- Female patients who are pregnant since fetal toxicities and teratogenic effects
have been noted for several of the study drugs. A pregnancy test is required for
female patients of childbearing potential
- Lactating females who plan to breastfeed their infants
- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation