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

S
Sandeep Batra, MD

Primary Investigator

Overview

This phase III trial tests two hypotheses in patients with low-risk and average-riskdulloblastoma. 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 withw-risk medulloblastoma typically have a lower chance of the cancer coming back thanubjects with average-risk medulloblastoma. Although treatment for newly diagnosedverage-risk and low-risk medulloblastoma is generally effective at treating the cancer,here 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 orher issues in performing daily activities. Standard therapy for newly diagnosedverage-risk or low-risk medulloblastoma includes surgery, radiation therapy, andhemotherapy (including cisplatin). Cisplatin may cause hearing loss as a side effect. In theverage-risk medulloblastoma patients, this trial tests whether the addition of sodiumhiosulfate (STS) to standard of care chemotherapy and radiation therapy reduces hearing. Previous studies with STS have shown that it may help reduce or prevent hearing lossused by cisplatin. In the low-risk medulloblastoma patients, the study tests whether a lessherapy (reduced radiation) can provide the same benefits as the more intenseherapy. The less intense therapy may cause fewer side effects. Radiation therapy uses highgy 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. The overall goals of this study are to see if giving STS along with standard(radiation therapy and chemotherapy) will reduce hearing loss in medulloblastomad to compare the overall outcome of patients with medulloblastoma treated with STSd without STS on a previous study in order to make sure that survival andurrence of tumor is not worsened.

Description

PRIMARY OBJECTIVES:
I. To evaluate the efficacy of sodium thiosulfate (STS) infusion administered duringg chemotherapy cycles (compared to a historical cohort selected from ACNS0331 which received chemotherapy without STS) in reducing hearing loss in children withwly-diagnosed average-risk medulloblastoma.
II. To estimate and monitor event-free survival (EFS) in this study against a carefullyd 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 selectedhort from ACNS0331.
II. To estimate the incidence of ototoxicity-related cisplatin dose modifications in theverage-risk cohort.
III. To estimate the incidence of cisplatin-related nephrotoxicity in both the average-riskd 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 withverage-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 aduced 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 riskdulloblastoma.
EXPLORATORY OBJECTIVES:
I. To obtain paired blood and tumor tissue to be banked for future biology studies involvinghensive molecular analysis, including but not limited to whole exome sequencing,bonucleic acid (RNA) sequencing, and methylation.
II. To bank blood and cerebrospinal fluid for future studies. III. To evaluate attention,g speed, memory, and executive function neurocognitive outcomes and trajectories, as well as hearing-related quality of life outcomes and trajectories, of patients withverage-risk medulloblastoma treated with STS.
IV. To evaluate neurocognitive, quality of life, and psychosocial outcomes of patients withw-risk features treated using a reduced craniospinal radiation approach.
TLINE
CHEMORADIOTHERAPY: Patients undergo radiation therapy on weeks 1-7 and receive vincristinevenously (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,d 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, anddays 1 and 8 of cycles 3, 6, and 9. Treatment repeats every 6 weeks (cycles 1, 2, 4, 5, 7d 8) or every 4 weeks (cycles 3, 6, and 9) for up to 9 cycles in the absence of diseasegression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for years 1-2,very 6 months for years 3-4, and then annually for years 5-10.

Eligibility

You may be eligible for this study if you meet the following criteria:

  • Conditions:
    Medulloblastoma
  • Age: Between 3 Years - 21 Years
  • Gender: All

Inclusion Criteria:
  • PRE-ENROLLMENT: Patients must be greater than or equal to 3 years and less than 22years of age at the time of enrollment on Step 0
  • PRE-ENROLLMENT: Patient is suspected to have newly-diagnosed medulloblastoma byutional diagnosis
    • Please note: Patients with a pending result of cerebrospinal Fluid (CSF) cytologygible for enrollment on NCI-2014-02057 (APEC14B1) and thedulloblastoma 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 APEC14B1ble (ASAP), preferably within 5 days of definitive surgery
  • PRE-ENROLLMENT: All patients must have rapid central pathology review on APEC14B1udy enrollment on ACNS2031 step 1 in order to avoid discordant diagnosesd to verify diagnosis criterion for treatment on ACNS2031.
    • Note: Patients with a pending result of CSF cytology tests are eligible for thed central pathology screening review. Confirmation of CSF negativity isded 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 discordantdiagnoses and to verify diagnosis criterion for treatment on ACNS2031
  • PRE-ENROLLMENT: All patients who have pathology confirmed must have rapid centralging 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 mayundergo a second surgical resection prior to subsequent therapy to render themgible for this study. The day of the second resection to remove residual tumorwill be regarded as the day of definitive surgery (Day 0) and must be within ah (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 centralhology and molecular screening reviews performed on APEC14B1 and via the MolecularCharacterization 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 postvely to avoid false positive CSF. Ideally, CSF should be obtained betweenday 14 and day 21 to allow for final staging status before enrollment onto theudy. Patients with positive CSF cytology obtained 0 to 14 days after surgeryhould have cytology repeated to determine eligibility and final CSF status.Patients with negative CSF cytology from lumbar puncture obtained 0 to 14 daysurgery do not need cytology repeated. Patients with negative CSF cytologyumbar puncture obtained prior to surgery do not need cytology repeatedvely
  • 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. Wholebrain 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 laterhan 31 days after definitive diagnostic surgery (day 0)
  • Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to)
  • Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to)
  • Hemoglobin >= 8.0 g/dL (may receive red blood cell count [RBC] transfusions) (within 7days 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 urineCreatinine clearance >= 70 mL/min/1.73 m^2 (within 7 days prior to enrollment) ORglomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to). GFR must be performed using direct measurement with a nuclear bloodg method OR direct small molecule clearance method (iothalamate or otherule per institutional standard)
    • Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimatesble 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 thevalue of 45 U/L
  • Central nervous system function defined as:
    • Patients with seizure disorder may be enrolled if on anticonvulsants and welld
    • Patients must not be in status epilepticus, a coma or assisted ventilation at theudy enrollment
  • Auditory function defined as:
    • Patients must have normal hearing (defined as International Society of Pediatricgy [SIOP] grade 0) in at least one ear confirmed by rapid central audiologyview 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) evaluationumbar CSF cytology are not eligible. Patients who are unable to undergo a lumbaruncture 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 otherhiol agents (e.g., amifostine, n-acetylcysteine, MESNA, and captopril)
  • Pregnancy and Breastfeeding:
    • Female patients who are pregnant since fetal toxicities and teratogenic effectshave been noted for several of the study drugs. A pregnancy test is required forhildbearing potential
    • Lactating females who plan to breastfeed their infants
    • Sexually active patients of reproductive potential who have not agreed to use anve contraceptive method for the duration of their study participation

Updated on 05 May 2024. Study ID: ACNS2031
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