This prospective, open-label, single-arm, multicenter study will evaluate the efficacy and safety of arsenic trioxide (ATO) combined with chemotherapy in pediatric patients with relapsed or refractory SHH-activated medulloblastoma and/or TP53-mutant medulloblastoma. Eligible participants will be 18 months to 18 years of age.
Participants will receive six cycles of induction chemotherapy containing ATO in combination with etoposide and either cisplatin or cyclophosphamide. The primary outcome is the objective response rate (ORR), defined as the proportion of participants achieving a complete response or partial response, assessed according to the Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria by an independent review committee.
Secondary outcomes include overall survival, progression-free survival, and treatment-related safety, including adverse events and serious adverse events. A total of 78 participants are planned for enrollment.
Histologically confirmed SHH-activated medulloblastoma meeting at least one of the following conditions: Tumor recurrence demonstrated by imaging or cerebrospinal fluid examination after standard treatment consisting of surgery, radiotherapy, and chemotherapy; or Refractory medulloblastoma, defined as an increase in tumor size of more than 25% or the appearance of new lesions after two cycles of standard first-line chemotherapy.
Medulloblastoma with a TP53 mutation identified by genetic testing of tumor tissue, including at least one of the following: A TP53 mutation present at initial diagnosis; A newly detected TP53 mutation during subsequent treatment in a patient with relapsed medulloblastoma; or A newly detected TP53 mutation during subsequent treatment in a patient with refractory medulloblastoma.
Age ≥18 months and ≤18 years.
Written informed consent obtained from the participant's legal guardian. Participants must meet either Inclusion Criterion 1 or Inclusion Criterion 2, in addition to Inclusion Criteria 3 and 4.
History of another malignancy for which the participant received chemotherapy and abdominal radiotherapy.
Severe progressive or persistent heart failure, defined as New York Heart Association (NYHA) class III or IV heart failure or a left ventricular ejection fraction (LVEF) <50%.
Severe progressive or persistent renal failure, defined as a glomerular filtration rate (GFR) <30 mL/min/1.73 m² or serum creatinine >5 mg/dL (442 μmol/L).
Severe hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥5 times the age-appropriate upper limit of normal (ULN), or total serum bilirubin ≥3 times the age-appropriate ULN.
Single group
Arsenic Trioxide (ATO)
DrugArsenic trioxide 0.18 mg/kg/day is administered by intravenous infusion over more than 8 hours on Days 1-10 of each 21-day induction cycle.
ETOPOSIDE - Study
DrugEtoposide 100 mg/m²/day is administered by intravenous infusion over more than 3 hours on Days 3-5 of each induction cycle.
Cisplatin
DrugCisplatin 90 mg/m² is administered by intravenous infusion over 6 hours on Day 3 of induction Cycles 1, 3, and 5.
Cyclophosphamide
DrugCyclophosphamide 800 mg/m² is administered by intravenous infusion over 3 hours on Day 3 of induction Cycles 2, 4, and 6.
Methotrexate
DrugIntrathecal methotrexate is administered on Day 5 according to age-based dosing specified in the protocol.
Dexamethasone
DrugIntrathecal dexamethasone is administered with methotrexate on Day 5 according to age-based dosing specified in the protocol.
Objective Response Rate (ORR)
The proportion of evaluable participants who achieve a complete response (CR) or partial response (PR) according to the Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, as assessed by an Independent Review Committee (IRC). ORR is calculated as the number of participants with CR or PR divided by the number of participants evaluable for tumor response.
Overall Survival (OS) Rate
Overall survival is defined as the time from study enrollment to death from any cause. Survival status will be determined from medical records and follow-up data.
Progression-Free Survival (PFS)
Progression-free survival is defined as the time from study enrollment to disease progression or death from any cause, whichever occurs first. Disease progression will be assessed according to RAPNO criteria using clinical, imaging, and follow-up data, with assessment by the Independent Review Committee.
Incidence of Adverse Events (AEs)
The incidence and severity of adverse events will be assessed in all participants according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. Adverse events will be monitored throughout treatment and follow-up.
Incidence of Serious Adverse Events (SAEs)
The incidence of serious adverse events will be evaluated throughout treatment and follow-up. Serious adverse events include events resulting in death, being life-threatening, requiring or prolonging hospitalization, causing persistent or significant disability, or other medically important events.
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