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

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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	N/A - 6 Years
Gender	All

More Inclusion & Exclusion 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.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06942039
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Early Phase 1
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	C17 Council
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	N/A
Principal Investigator Affiliation	N/A
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	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

Additional Details

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.

Arms & Interventions

Arms

Experimental: Comprehensive Multimodal Therapy Including Induction, Consolidation, and Risk-Adapted Maintenance

Participants will undergo a comprehensive treatment regimen beginning with three 21-day cycles of Induction chemotherapy including intrathecal (IT) cytarabine with hydrocortisone, cyclophosphamide, etoposide, vinCRIStine, and cisplatin. Peripheral blood stem cells will be collected during this phase for later use. Patients who achieve complete response (CR) proceed directly to Consolidation; those who do not may undergo second-look surgery or national tumor board review. Consolidation consists of three 28-day cycles of CARBOplatin and thiotepa followed by autologous stem cell rescue. Patients then proceed to up to 48-54 weeks of Maintenance chemotherapy based on risk stratification. Low-risk patients receive monthly IT topotecan and a 28-day metronomic regimen including tamoxifen and ISOtretinoin. High-risk patients receive monthly IT topotecan and a more intensive regimen every 9 weeks including ISOtretinoin, celecoxib, etoposide, cyclophosphamide, and temozolomide.

Interventions

Drug: - Cytarabine IT

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).

Drug: - hydrocortisone

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

Drug: - Cisplatin

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).

Drug: - Vincristine

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).

Drug: - Etoposide

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.

Drug: - Cyclophosphamide

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.

Drug: - Mesna

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).

Drug: - Filgrastim

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.

Drug: - carboplatin

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

Drug: - Thiotepa

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

Drug: - Topotecan IT

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.

Drug: - Tamoxifen

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.

Drug: - ISOtretinoin

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.

Drug: - Celecoxib

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.

Drug: - etoposide phosphate

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.

Drug: - Temozolomide

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.