A Study of Treatment for Medulloblastoma Using Sodium Thiosulfate to Reduce Hearing Loss

Study Overview
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Brief Summary
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This phase III trial tests two hypotheses in patients with low-risk and average-risk medulloblastoma. Medulloblastoma is a type of cancer that occurs in the back of the brain. The term, risk, refers to the chance of the cancer coming back after treatment. Subjects with low-risk medulloblastoma typically have a lower chance of the cancer coming back than subjects with average-risk medulloblastoma. 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 or unintended health conditions that arise due to treatment include learning difficulties, hearing loss or other issues in performing daily activities. Standard therapy for newly diagnosed average-risk or low-risk medulloblastoma includes surgery, radiation therapy, and chemotherapy (including cisplatin). Cisplatin may cause hearing loss as a side effect. In the average-risk medulloblastoma patients, this trial tests whether the addition of sodium thiosulfate (STS) to standard of care chemotherapy and radiation therapy reduces hearing loss. Previous studies with STS have shown that it may help reduce or prevent hearing loss caused by cisplatin. In the low-risk medulloblastoma patients, the study tests whether a less intense therapy (reduced radiation) can provide the same benefits as the more intense therapy. The less intense therapy may cause fewer side effects. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. The overall goals of this study are to see if giving STS along with standard treatment (radiation therapy and chemotherapy) will reduce hearing loss in medulloblastoma patients and to compare the overall outcome of patients with medulloblastoma treated with STS to patients treated without STS on a previous study in order to make sure that survival and recurrence of tumor is not worsened.

Detailed Description
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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.

Official Title
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A Phase 3 Study of Sodium Thiosulfate for Reduction of Cisplatin-Induced Ototoxicity in Children With Average-Risk Medulloblastoma and Reduced Therapy in Children With Medulloblastoma With Low-Risk Features

Conditions
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Medulloblastoma

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Cyclophosphamide
* Drug: Lomustine
* Drug: Mesna
* Other: Quality-of-Life Assessment
* Radiation: Radiation Therapy
* Drug: Sodium Thiosulfate
* Other: Survey Administration
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemoradiotherapy, maintenance)<br>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 1 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<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Lomustine<br>* Given PO<br>* Other names: WR-139017;Drug: Mesna<br>* Given IV<br>* Other names: Ziken;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Drug: Sodium Thiosulfate<br>* Given IV<br>* Other names: Thiosulfuric Acid Disodium Salt;Other: Survey Administration<br>* Ancillary studies<br>Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with >= grade 2 hearing loss | Will estimate the number and percentage of patients with >= Grade 2 hearing loss using the society of pediatric oncology (SIOP) scale (defined as hearing threshold >20 dB at >= 4kHz) 4 weeks after the last dose of cisplatin. If hearing loss is observed in both ears, the worse ear will be used for this primary analysis. Will compare the observed rate of hearing loss in ACNS2031 (this trial) with the rate from the ACNS0331 historical cohort described above using 2-sample 1-sided t-test where a p value < 0.05 will lead to a significant result. Will also 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. | At 4 weeks after the last dose of cisplatin | 
| Event-free survival (EFS) | Will estimate the EFS distribution using Kaplan-Meier method. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Will calculate the OS distribution using Kaplan Meier method. | Up to 10 years | 
| Incidence of ototoxicity-related cisplatin dose modifications in the average-risk cohort | 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. | Up to 10 years | 
| Incidence of cisplatin-related nephrotoxicity in both the average-risk and low-risk cohorts | The frequency of cisplatin-related nephrotoxicity including Grade 3 and higher creatinine increase, acute kidney injury, and chronic kidney disease will be calculated per patient as raw counts. Summary statistics will be reported including mean, median, standard deviation and range by cohorts. | Up to 10 years | 
| Full scale intelligence neurocognitive outcomes and trajectories of patients with average-risk medulloblastoma treated with sodium thiosulfate (STS) | 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. | Up to 5 years | 
| Quality of life and psychosocial outcomes of patients with average-risk medulloblastoma treated with STS | 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. | Up to 5 years | 
| EFS in patients with low-risk features treated using a reduced craniospinal radiation approach | KM estimates of the EFS distributions for the low-risk cohort will be provided. | Up to 10 years | 
| OS in patients with low-risk features treated using a reduced craniospinal radiation approach | KM estimates of the OS distributions for the low-risk cohort will be provided. | Up to 10 years | 
| Trajectory of hearing loss medulloblastoma patients treated with STS | 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. | Up to 60 months | 
| Household material hardship as a social determinant of neurocognitive, quality of life, and psychosocial outcomes in patients with average-risk and low-risk medulloblastoma | 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. | Up to 60 months post-enrollment |