A Study of Treatment for Medulloblastoma Using Sodium Thiosulfate to Reduce Hearing Loss
Study Details
Study Description
Brief Summary
This phase III trial tests the addition of sodium thiosulfate to standard of care chemotherapy and radiation therapy in treating patients with low or average risk medulloblastoma (a type of cancer in the brain). Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs 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. Although treatment for newly diagnosed average-risk and low-risk medulloblastoma is generally effective at treating the cancer, there are still concerns about the side effects of such treatment. Side effects are unintended problems that arise due to treatment such as learning difficulties, lower amounts of hormones, hearing problems, or other problems in performing daily activities. Patients with medulloblastoma often receive treatment with chemotherapy drugs including cisplatin. Cisplatin may cause hearing loss as a side effect. Previous studies with sodium thiosulfate have shown that it may help reduce or prevent hearing loss caused by cisplatin. This study looks at adding sodium thiosulfate to standard treatment for medulloblastoma (radiation therapy and chemotherapy, including cisplatin) to find out if it reduces hearing loss.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
PRIMARY OBJECTIVES:
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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.
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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:
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To estimate and monitor overall survival (OS) in this study against a carefully selected control cohort from ACNS0331.
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To estimate the incidence of ototoxicity-related cisplatin dose modifications in the average-risk cohort.
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To estimate the incidence of cisplatin-related nephrotoxicity in both the average-risk and low-risk cohorts.
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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.
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To evaluate quality of life and psychosocial outcomes and trajectories of patients with average-risk medulloblastoma treated with STS compared to published norms.
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To estimate and monitor EFS and OS in patients with low-risk features treated using a reduced craniospinal radiation approach.
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To evaluate the trajectory of hearing loss in medulloblastoma patients treated with STS.
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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:
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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.
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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.
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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 of cycles 1, 2, 4, 5, 7, and 8, cyclophosphamide IV over 30-60 minutes on days 1 and 2 of cycles 3, 6, and 9, and mesna IV over 15-30 minutes three times daily (TID) 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (chemoradiotherapy, maintenance) CHEMORADIOTHERAPY: Patients undergo radiation therapy on weeks 1-7 and receive vincristine 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 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 of cycles 1, 2, 4, 5, 7, and 8, cyclophosphamide IV over 30-60 minutes on days 1 and 2 of cycles 3, 6, and 9, and mesna IV over 15-30 minutes TID 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. |
Drug: Cisplatin
Given IV
Drug: Cyclophosphamide
Given IV
Drug: Lomustine
Given PO
Drug: Mesna
Given IV
Other: Quality-of-Life Assessment
Ancillary studies
Radiation: Radiation Therapy
Undergo radiation therapy
Drug: Sodium Thiosulfate
Given IV
Other: Survey Administration
Ancillary studies
Drug: Vincristine
Given IV
|
Outcome Measures
Primary Outcome Measures
- Percentage of patients with >= grade 2 hearing loss [At 4 weeks after the last dose of cisplatin]
Will report the percentage of patients with >= grade 2 hearing loss in the better ear at 4 weeks after the last dose of cisplatin in ACNS2031 and will compare it with the rate from ACNS0331 historical cohort using Fisher's exact test.
- Event-free survival (EFS) [From initiation of the protocol treatment to the occurrence of disease progression, disease recurrence, death from any cause, or occurrence of a second malignant neoplasm, assessed up to 10 years]
Will estimate the EFS distribution using Kaplan-Meier method.
Secondary Outcome Measures
- Overall survival (OS) [Up to 10 years]
Will calculate the OS distribution using Kaplan Meier method.
- Incidence of ototoxicity-related cisplatin dose modifications in the average-risk cohort [Up to 10 years]
Will be calculated by dividing the total number of ototoxicity-related cisplatin dose modifications by the cumulative dose of cisplatin. Summary statistics including mean, standard deviation (SD), median and range will be used to summarize the data by cohorts.
- Frequency of cisplatin-related nephrotoxicity [Up to 10 years]
Summary statistics will be reported including mean, median, standard deviation and range by cohorts.
- Full scale intelligence neurocognitive outcomes and trajectories of patients with average-risk medulloblastoma treated with sodium thiosulfate (STS) [Up to 5 years]
Will be compared to the control cohort from ACNS0331. A psychologist-administered battery will be used to assess longitudinal trajectories in the estimated full scale intelligence quotient (FSIQ) using the Wechsler Intelligence Scale Vocabulary and Block Design subtest. Box-plots will be drawn for each time point to visually look for change over time. Will estimate pairwise changes in FSIQ between 9 month and 30-month and between 9-month and 60-month measurements. Summary statistics will be provided for each time point and for each pairwise change including mean, standard deviation, median and range. Will compare FSIQ between two time points using parametric or non-parametric one-sample approaches depending on the normality of the data.
- Quality of life and psychosocial outcomes of patients with average-risk medulloblastoma treated with STS [Up to 5 years]
Will compare quality of life (general) and psychosocial (adaptive, social, emotional, behavioral) outcomes from this study between baseline and post treatment as well as to the published healthy norms.
- EFS in patients with low-risk features treated using a reduced craniospinal radiation approach [Up to 10 years]
KM estimates of the EFS distributions for the low-risk cohort will be provided.
- OS in patients with low-risk features treated using a reduced craniospinal radiation approach [Up to 10 years]
KM estimates of the OS distributions for the low-risk cohort will be provided.
- Number of medulloblastoma patients with >= grade 2 hearing loss treated with STS [Up to 60 months]
The number of patients with >= Grade 2 hearing loss using the SIOP scale in the evaluable ear at each time point will be summarized along with its 95% confidence interval.
- Household material hardship as a social determinant of neurocognitive, quality of life, and psychosocial outcomes in patients with average-risk and low-risk medulloblastoma [Up to 60 months post-enrollment]
The Household Survey will be administered to parents at various timepoints to measure household material hardship. Summary statistics will be provided for each time point including mean, standard deviation, median and range for each outcome measure of interest.
Other Outcome Measures
- Paired blood and tumor tissue banking or future studies [Up to 5 years]
Will obtain paired blood and tumor tissue to be banked for future biology studies involving comprehensive molecular analysis.
- Blood and cerebrospinal fluid banking for future studies [Up to 5 years]
Will bank blood and cerebrospinal fluid for future studies.
- Hearing related-quality of life (HEAR-QL) of patients with average-risk medulloblastoma treated with STS [Up to 5 years]
Hearing and Audiology Survey will examine parent and patient-perceived hearing loss, hearing aid use, and barriers to hearing aid use through descriptive statistics.
- HEAR-QL of patients with low-risk features treated using a reduced craniospinal radiation approach [Up to 5 years]
Hearing and Audiology Survey will examine parent and patient-perceived hearing loss, hearing aid use, and barriers to hearing aid use through descriptive statistics.
- Attention, processing speed, memory, and executive function neurocognitive outcomes and trajectories of patients with average-risk medulloblastoma treated with STS [Up to 5 years]
Eligibility Criteria
Criteria
Inclusion Criteria:
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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
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PRE-ENROLLMENT: Patient is suspected to have newly-diagnosed medulloblastoma by institutional diagnosis
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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)
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PRE-ENROLLMENT: Patient and/or their parents or legal guardians have signed informed consent for APEC14B1 Part A - Eligibility Screening and Molecular Characterization
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PRE-ENROLLMENT: The required specimens are projected to be submitted through APEC14B1 as soon as possible (ASAP), preferably within 5 days of definitive surgery
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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.
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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.
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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
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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
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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
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PRE-ENROLLMENT: All patients who have pathology confirmed must have rapid central audiology review on APEC14B1 prior to study enrollment on ACNS2031 step 1
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Patients must be >= 4 years and =< 21 years of age at the time of enrollment
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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
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Average-risk cohort
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Clinico-pathologic criteria:
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M0 disease
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No diffuse anaplastic histology AND
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Molecular criteria:
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SHH, p53wt, GLI2 normal, MYCN normal, no chromosome 14q loss
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Group 3, MYC normal, no isochromosome 17q
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Group 4, no chromosome 11 loss
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Low-risk features cohort
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Clinico-pathologic criteria:
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M0 disease
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No diffuse anaplastic histology AND
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Molecular criteria:
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Group 4, chromosome 11 loss
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Patients must have negative lumbar CSF cytology
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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
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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
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Patients must weigh > 10 kg
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Patients must be enrolled, and protocol therapy must be projected to begin, no later than 31 days after definitive diagnostic surgery (day 0)
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Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment)
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Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)
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Hemoglobin >= 8.0 g/dL (may receive red blood cell count [RBC] transfusions) (within 7 days prior to enrollment)
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A serum creatinine (within 7 days prior to enrollment) based on age/gender as follows:
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4 to < 6 years (age); 0.8 mg/dL (male) 0.8 mg/dL (female)
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6 to < 10 years (age); 1 mg/dL (male) 1 mg/dL (female)
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10 to < 13 years (age); 1.2 mg/dL (male) 1.2 mg/dL (female)
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13 to < 16 years (age); 1.5 mg/dL (male) 1.4 mg/dL (female)
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= 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 m2 (within 7 days prior to enrollment) OR a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m2 (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)
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Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
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Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
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Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment)
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Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
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Central nervous system function defined as:
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Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
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Patients must not be in status epilepticus, a coma or assisted ventilation at the time of study enrollment
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Auditory function defined as:
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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
Exclusion Criteria:
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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
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Patients must not have received any prior radiation therapy or chemotherapy (tumor-directed therapy) other than surgical intervention and/or corticosteroids
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Patients must not have any known hypersensitivity to STS, sulfates/sulfites, or other thiol agents (e.g., amifostine, n-acetylcysteine, MESNA, and captopril)
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Pregnancy and Breastfeeding:
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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
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Lactating females who plan to breastfeed their infants
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Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
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All patients and/or their parents or legal guardians must sign a written informed consent
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All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Children's Oncology Group
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Ralph Salloum, Children's Oncology Group
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ACNS2031
- NCI-2022-04866
- ACNS2031
- ACNS2031
- U10CA180886