Clinical trial NCT06942039: Pilot Study of IT Topotecan and Maintenance Chemotherapy for HR-EBTs in Children < 6 Years, Post Consolidation
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: EARLY_PHASE1
Conditions: CNS Embryonal Tumor
CNS, Medulloblastoma
Atypical Teratoid Rhabdoid Tumor
Medulloblastoma, Childhood
Medulloblastoma, Group 3
Medulloblastoma, Group 4
Pineoblastoma
Neuroblastoma
Embryonal Tumor With Multilayered Rosettes
Embryonal Tumor With Abundant Neuropil and True Rosettes
Ependymoblastoma
Medulloepithelioma
CNS Embryonal Tumor With Rhabdoid Features
CNS Embryonal Tumor, Nos
Keywords: HR-EBT
Lead sponsor: C17 Council
Sponsor class: OTHER
First posted: 2025-04-24
Enrollment: 15
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All patients will receive 3 cycles of induction with IT chemotherapy and 3 cycles of consolidation therapy. Patients will then receive either Maintenance A or Maintenance B based on their risk profile.
Primary purpose: TREATMENT

Brief summary: Pilot study to determine feasibility of adding intrathecal chemotherapy and maintenance therapy after high dose chemotherapy for treatment of newly diagnosed HR-EBTs in patients less than 6 years of age.

Detailed description: This is a pilot study to determine feasibility of adding intrathecal (IT) chemotherapy and maintenance therapy after high dose chemotherapy for treatment of newly diagnosed HR-EBTs in patients less than 6 years of age. Patients meeting all inclusion criteria will receive 3 cycles of multiagent chemotherapy induction (vinCRIStine, cyclophosphamide, CISplatin, etoposide) with IT cytarabine and hydrocortisone, and 3 cycles of consolidation with CARBOplatin, thiotepa, and autologous stem cell rescue (as per CCG 99703). Maintenance chemotherapy will then be given immediately after the completion of consolidation therapy and consist of risk-stratified oral chemotherapy using either "Maintenance A" (48 weeks) using tamoxifen and retinoic acid or "Maintenance B" (54 weeks) using metronomic isotretinoin, celecoxib, etoposide, temozolomide, and cyclophosphamide. Both arms of maintenance will receive monthly IT topotecan.

Following the end of treatment, patients will be scheduled for a follow-up visit every 3 months for 24 months to evaluate PFS and OS. Approximately 15 patients will be recruited as part of this clinical study.

Patients aged between 0 and 6 years old at the time of enrollment will be eligible. This study will only enrol patients with high risk Central Nervous System Embryonal Brain Tumors (CNS-EBTs) with histologic and/or molecular confirmation of diagnosis for ATRT intrinsic to the brain and spinal cord, group 3 and group 4 MB, pineoblastoma, CNS neuroblastoma, 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.

Response to treatment will be evaluated using the modified RAPNO (Response Assessment in Pediatric Neuro-Oncology) 1.

This study will also explore the genetic landscape of CNS HR-EBTs. Our biological study will include genomic analyses of tumor and CSF with use of epigenomic analyses (methylation profiling) arrays, Nanostring sub-typing studies, Next generation sequencing analyses for DNA and/or RNA.

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.

Primary outcomes:
measure: To determine the feasibility of adding intrathecal (IT) topotecan and maintenance therapy after high dose chemotherapy for treatment of newly diagnosed HR-EBTs in patients less than 6 years of age.
timeFrame: At completion of maintenance therapy (approximately 48-54 weeks after start of maintenance therapy)
measure: To test the feasibility of centralized diagnostics and national tumour board review for clinical management of HR-EBTs
timeFrame: Within 4 weeks after definitive surgical resection, prior to start of induction chemotherapy
measure: To establish a national HR infant brain tumor trial platform for future studies
timeFrame: At study completion (anticipated average duration of 2 years per participant)
Secondary outcomes:
measure: To determine progression free and overall survival and patterns of failure for all enrolled patients
timeFrame: Up to 24 months following completion of maintenance therapy
measure: To describe the toxicities of adding intrathecal (IT) chemotherapy and maintenance therapy after high dose chemotherapy for treatment of newly diagnosed HR-EBTs in patients less than 6 years of age
timeFrame: 30 days after last dose of study treatment
Other outcomes:
measure: To test the feasibility of prospective banking of tumor tissue, serial plasma and cerebrospinal fluid (CSF) for all enrolled patients
timeFrame: Through completion of study treatment (anticipated duration of 18-24 months per participant)
Locations:
Study officials:
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