Intrathecal topotecan with maintenance chemotherapy after consolidation for high‑risk embryonal brain tumors in children under 6

A Pilot Study of Intrathecal Topotecan and Maintenance Chemotherapy in the Post-consolidation Setting for the Treatment of High-risk Embryonal Central Nervous System Tumours in Children Less Than 6 Years of Age

This study will test whether monthly intrathecal topotecan plus a year of oral maintenance chemotherapy after high‑dose consolidation is feasible and tolerable for children under 6 with high‑risk embryonal brain tumors.

Quick facts

• Phase: Early Phase 1
• Study type: Interventional
• Enrollment: 15 (estimated)
• Ages: N/A to 6 Years
• Sex: All
• Sponsor: C17 Council (Academic / other)
• Drugs / interventions: chemotherapy, cyclophosphamide
• Locations: 12 sites (Calgary, Alberta and 11 other locations)
• Trial ID: NCT06942039 on ClinicalTrials.gov

What this trial studies

This pilot trial enrolls children aged 0–6 with newly diagnosed high‑risk CNS embryonal tumors (including ATRT, group 3/4 medulloblastoma, pineoblastoma, CNS neuroblastoma, ETMR, and similar diagnoses). Participants receive three cycles of multiagent induction chemotherapy with intrathecal cytarabine and hydrocortisone, followed by three cycles of consolidation with carboplatin, thiotepa, and autologous stem cell rescue per CCG‑99703. After consolidation, patients receive risk‑stratified oral maintenance therapy (one of two 48–54 week regimens) with monthly intrathecal topotecan. About 15 patients will be enrolled and followed every 3 months for 24 months to track progression‑free and overall survival and to document feasibility and toxicity.

Who should consider this trial

Good fit: Children aged 0 to 6 years with histologic or molecular confirmation of high‑risk CNS embryonal tumors (including ATRT, group 3/4 medulloblastoma, pineoblastoma, CNS neuroblastoma, ETMR, and related entities), including those with metastatic disease and any extent of resection, are ideal candidates.

Not a fit: Children older than 6 years, patients with lower‑risk embryonal tumors or non‑embryonal CNS tumors, and those who cannot tolerate high‑dose chemotherapy or autologous stem cell rescue are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could improve central nervous system disease control and reduce relapse risk in very young children while identifying a tolerable maintenance strategy after intensive consolidation.

How similar studies have performed: Intrathecal chemotherapy and metronomic/maintenance regimens have been used in other pediatric brain tumor programs with limited and mixed results, and this exact combination after high‑dose consolidation is largely novel and untested in a formal pilot.

Eligibility criteria

Inclusion Criteria:

1. Tumor Tissue Sample
2. Age: Patient must be aged ≥ 0 years to ≤ 6 years at the time of definitive confirmation of histologic diagnosis of eligible CNS tumor.
3. Diagnoses. Participants must have Central nervous system (CNS) HR-EBT including atypical teratoid rhabdoid tumour (ATRT), group 3 and group 4 medulloblastoma (MB), pineoblastoma, CNS neuroblastoma, embryonal tumor with multi-layered rosettes (ETMR including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI-1 intact) and CNS embryonal tumor, not otherwise specified. Metastatic disease included. Any extent of resection included.
4. Cranial and Spine MRI. A baseline MRI brain and spine with and without contrast is required for all patients. cranial MRI (with and without gadolinium) must be done pre-operatively. Post-operatively, cranial MRI (with and without gadolinium) must be done.
5. Lumbar Puncture (LP) CSF for cytopathology (strongly recommended but not mandatory; if medically feasible). A baseline LP CSF cytology either pre-operatively or post-operatively at least 10 days after definitive surgery for all patients if medically feasible (This is not mandatory and will not make the patient ineligible).
6. Life expectancy: Patients must have a life expectancy of greater than 8 weeks from diagnosis.
7. Performance level: Patients must have a performance status corresponding of a Lansky score ≥ 50.
8. Organ Function Requirements: Participants must have normal organ and marrow function as defined below:

Adequate renal function defined as:

\- Creatinine clearance (12-24-hour urine collection) or radioisotope glomerular filtration rate (GFR) ≥ 60 ml/min/1.73m2

Adequate cardiac function defined as:

* Shortening fraction of ≥ 27% by echocardiogram, or
* Ejection fraction of ≥ 47% by radionuclide angiogram.

Adequate pulmonary function defined as:

\- No evidence of dyspnea at rest and a pulse oximetry \> 94% on room air.

Adequate Bone Marrow Function defined as:

* Peripheral absolute neutrophil count (ANC) \> 1000/μL
* Platelet Count \> 100,000/μL (without transfusion for 3 days)
* Hemoglobin greater than 8 gm/dL (may have received red blood cell (RBC) transfusions)

Adequate liver function defined as:

* Total bilirubin ≤ 1.5X upper limit of normal (ULN) within normal institutional limits for age (patients with documented Gilbert's Disease may be enrolled with Study Chair approval and total bilirubin ≤ 2.0 × ULN)
* Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 100 U/L

Exclusion criteria:

1. Patients who are receiving any other conventional anti-cancer agents or investigational agents.
2. Patients who received previous therapy including radiotherapy or chemotherapy other than corticosteroids.
3. Presence of another malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
4. Concomitant medications restrictions: Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and carbamazepine), selected strong inhibitors of cytochrome P450 3A4 include azole antifungals, such as fluconazole, voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John's wort or CYP450 3A4 stimulators or inhibitors.
5. Other uncontrollable medical disease: Patient has a severe and uncontrollable medical disease (i.e., uncontrolled diabetes, hyperglycemia, chronic renal disease or active uncontrolled infection), has chronic liver disease (i.e., chronic active hepatitis and cirrhosis), hypercholesterolemia (serum cholesterol \>300 mg/dL), intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active hyperparathyroidism, or psychiatric illness/social situations that would limit compliance with study requirements.
6. Patients who have a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C.
7. Ineligible diagnoses for study entry by neuropathology: This includes sonic hedgehog (SHH) and wingless (WNT) MBs, all ependymomas, all choroid plexus carcinomas, all high grade glial and glio-neuronal tumors, all diffuse midline gliomas, all primary CNS germ cell tumors, all primary CNS sarcomas, all primary or metastatic CNS lymphomas and solid leukemic lesions (chloromas, granulocytic sarcomas).
8. The participant or parent(s)/guardian(s) cannot comply with the study visit schedule and other protocol requirements, in the investigator's opinion.

All patients must meet inclusion/exclusion criteria prior to starting any protocol therapy.

Where this trial is running

Calgary, Alberta and 11 other locations

• Alberta Children's Hospital — Calgary, Alberta, Canada (Recruiting)
• BC Children's Hospital — Vancouver, British Columbia, Canada (Recruiting)
• CancerCare Manitoba (CCMB) — Winnipeg, Manitoba, Canada (Not_yet_recruiting)
• IWK Health Centre — Halifax, Nova Scotia, Canada (Not_yet_recruiting)
• McMaster Children's Hospital — Hamilton, Ontario, Canada (Not_yet_recruiting)
• London Health Sciences Centre — London, Ontario, Canada (Recruiting)
• CHU Sainte-Justine — Montreal, Quebec, Canada (Recruiting)
• Montreal Children's Hospital (McGill) — Montreal, Quebec, Canada (Not_yet_recruiting)
• CHU de Québec-Université Laval — Québec, Quebec, Canada (Not_yet_recruiting)
• Centre hospitalier universitaire de Sherbrooke (CHUS) — Sherbrooke, Quebec, Canada (Not_yet_recruiting)
• Stollery Children's Hospital — Edmonton, Canada (Not_yet_recruiting)
• The Hospital for Sick Children — Toronto, Canada (Recruiting)

Study contacts

• Study coordinator: Sylvia Cheng

Conditions CNS Embryonal Tumor; CNS, Medulloblastoma; Atypical Teratoid Rhabdoid Tumor; Medulloblastoma, Childhood; Medulloblastoma, Group 3; Medulloblastoma, Group 4; Pineoblastoma; Neuroblastoma