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Pilot Study of IT Topotecan and Maintenance Chemotherapy for HR-EBTs in Children < 6 Years, Post Consolidation

ConditionsCNS Embryonal TumorCNS, MedulloblastomaAtypical Teratoid Rhabdoid TumorMedulloblastoma, ChildhoodMedulloblastoma, Group 3Medulloblastoma, Group 4PineoblastomaNeuroblastomaEmbryonal Tumor With Multilayered RosettesEmbryonal Tumor With Abundant Neuropil and True RosettesEpendymoblastomaMedulloepitheliomaCNS Embryonal Tumor With Rhabdoid FeaturesCNS Embryonal Tumor, Nos
Trial statusRecruiting
Trial phaseEarly Phase 1
Trial typeInterventional
Biological sexAll
AgeUp to 6
SponsorC17 Council

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Tumor Tissue Sample

Age: Patient must be aged ≥ 0 years to ≤ 6 years at the time of definitive confirmation of histologic diagnosis of eligible CNS tumor.

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.

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.

Disqualifiers

Patients who are receiving any other conventional anti-cancer agents or investigational agents.

Patients who received previous therapy including radiotherapy or chemotherapy other than corticosteroids.

Presence of another malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.

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.

Trial design

Design model

Single group

Treatments tested in this trial

  • Cytarabine IT

    Drug

    Age-based dosing as a part of double IT therapy (cytarabine, hydrocortisone) during induction (3 cycles, 1 cycle = 21 days) alongside CISplatin, vinCRIStine, etoposide, cyclophosphamide, mesna and filgrastim (G-CSF).

  • hydrocortisone

    Drug

    Double IT therapy (cytarabine, hydrocortisone) during induction (3 cycles, 1 cycle = 21 days) alongside CISplatin, vinCRIStine, etoposide, cyclophosphamide, mesna and filgrastim (G-CSF).

  • Cisplatin

    Drug

    Intravenous CISplatin given on Day 1 during induction (3 cycles, 1 cycle = 21 days) alongside double IT therapy, vinCRIStine, etoposide, cyclophosphamide, mesna and filgrastim (G-CSF).

  • Vincristine

    Drug

    Intravenous VinCRIStine given on Days 1, 8 \& 15 during induction (3 cycles, 1 cycle = 21 days) alongside double IT therapy, CISplatin, etoposide, cyclophosphamide, mesna and filgrastim (G-CSF).

  • Etoposide

    Drug

    Induction: Intravenous Etoposide given on Days 1, 2 \& 3 during induction (3 cycles, 1 cycle = 21 days) alongside double IT therapy, CISplatin, vinCRIStine, cyclophosphamide, mesna and filgrastim (G-CSF). Maintenance Arm B (for high-risk patients): Oral Etoposide given on Days 1-21 every 9 weeks (max 6 cycles, 1 cycle = 9 weeks) in combination with IT Topotecan, ISOtretinoin, Celecoxib, Cyclophosphamide and Temozolomide.

  • Cyclophosphamide

    Drug

    Induction: Intravenous high-dose Cyclophosphamide given on Days 2 \& 3 during induction (3 cycles, 1 cycle = 21 days) alongside double IT therapy, CISplatin, vinCRIStine, etoposide, mesna and filgrastim (G-CSF). Maintenance Arm B (for high-risk patients): Oral Cyclophosphamide given on Days 1-21 every 9 weeks (max 6 cycles, 1 cycle = 9 weeks) in combination with IT Topotecan, ISOtretinoin, Celecoxib, Etoposide and Temozolomide.

  • Mesna

    Drug

    Induction: Intravenous Mesna given at hour 0 of Cyclophosphamide delivery and 3, 6, 9 \& 12 hours post-dose during induction (3 cycles, 1 cycle = 21 days).

  • Filgrastim

    Drug

    Induction: Subcutaneous or intravenous Filgrastim (G-CSF) given 24-48 hrs after last dose of chemotherapy and/or as per institutional guidelines until count recovery. Consolidation: Subcutaneous or intravenous Filgrastim (G-CSF) given 24-48 hours after last stem cell infusion and/or per institutional guidelienes until count recovery.

  • carboplatin

    Drug

    Consolidation: Intravenous Carboplatin given on days -3 \& -2 during consolidation alongside thiotepa and filgrastim.

  • Thiotepa

    Drug

    Consolidation: Intravenous Thiotepa given on days -3 \& -2 during consolidation alongside carboplatin and filgrastim.

  • Topotecan IT

    Drug

    Maintenance A (for low-risk patients): IT Topotecan on Day 1 of each cycle (max 12 cycles, 1 cycle = 28 days) alongside Tamoxifen and ISOtretinoin. Maintenance B (for high-risk patients): IT Topotecan every 4 weeks (max 6 cycles, 1 cycle = 9 weeks) alongside ISOtretinoin, Celecoxib, Etoposide, Cyclophosphamide and Temozolomide.

  • Tamoxifen

    Drug

    Maintenance A (for low-risk patients): Oral Tamoxifen twice daily, Days 1-28 (max 12 cycles, 1 cycle = 28 days) alongside ISOtretinoin and IT Topotecan.

  • ISOtretinoin

    Drug

    Maintenance A (for low-risk patients): Oral ISOtretinoin twice daily on Days 15-28 of each cycle (max 12 cycles, 1 cycle = 28 days) alongside Tamoxifen and IT Topotecan. Maintenance B (for high-risk patients): Oral ISOtretinoin twice daily on Days 1-21, every 6 weeks (max 6 cycles, 1 cycle = 9 weeks) alongside IT Topotecan, Celecoxib, Etoposide, Cyclophosphamide and Temozolomide.

  • Celecoxib

    Drug

    Maintenance B (for high-risk patients): Oral Celecoxib twice daily on Days 1-21, every 6 weeks (max 6 cycles, 1 cycle = 9 weeks) alongside IT Topotecan, ISOtretinoin, Etoposide, Cyclophosphamide and Temozolomide.

  • etoposide phosphate

    Drug

    During Induction and Maintenance B (for high-risk patients), etoposide phosphate may be given for subsequent doses to patients who have experienced etoposide allergic reactions.

  • Temozolomide

    Drug

    Maintenance B (for high-risk patients): Oral Temozolomide daily on Days 1-21, every 9 weeks (max 6 cycles, 1 cycle = 9 weeks) alongside IT Topotecan, ISOtretinoin, Etoposide, Cyclophosphamide and Celecoxib.

Treatment groups

15 Participants
are divided into 1 treatment group
Group A: Comprehensive Multimodal Therapy Including Induction, Consolidation, and Risk-Adapted MaintenanceExperimental treatment 16 interventions

Trial outcomes

Primary outcomes

1

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.

Feasibility failure will be defined by ≥5 patients who stop maintenance therapy (all IT and oral agents) due to excessive toxicity, deemed attributable to maintenance therapy

Time frame
At completion of maintenance therapy (approximately 48-54 weeks after start of maintenance therapy)
2

To test the feasibility of centralized diagnostics and national tumour board review for clinical management of HR-EBTs

Feasibility of centralized diagnostics will be defined as: * 80% of patients will have central review and central molecular testing performed before timely start of therapy (\~4 weeks post-surgery) Feasibility of national tumour board review will be defined as: * 80% of patients will be reviewed within treatment timeline of within \~4 weeks post-surgery

Time frame
Within 4 weeks after definitive surgical resection, prior to start of induction chemotherapy
3

To establish a national HR infant brain tumor trial platform for future studies

Data will be gathered on whether platform is able to support future research projects, facilitate collaboration in Canada, and improve clinical outcomes for this population

Time frame
At study completion (anticipated average duration of 2 years per participant)

Secondary outcomes

1

To determine progression free and overall survival and patterns of failure for all enrolled patients

Time to progression (TTP), progression free survival (PFS) and overall survival (OS) up to two years following completion of treatment

Time frame
Up to 24 months following completion of maintenance therapy
2

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

Incidence of grade ≥3 adverse events (AE) and serious adverse events (SAE) related to study treatment

Time frame
30 days after last dose of study treatment

Other outcomes

1

To test the feasibility of prospective banking of tumor tissue, serial plasma and cerebrospinal fluid (CSF) for all enrolled patients

To determine number of samples collected and bank CSF for potential future circulating tumour DNA (ctDNA analyses)

Time frame
Through completion of study treatment (anticipated duration of 18-24 months per participant)

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

C17 Council

Lead sponsor

Source ClinicalTrials.gov
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