Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumours or High-Risk Medulloblastoma

Official Title

A Phase III Randomized Trial for the Treatment of Newly Diagnosed Supratentorial PNET and High Risk Medulloblastoma in Children <36 Months Old With Intensive Induction Chemotherapy With Methotrexate Followed by Consolidation With Stem Cell Rescue Versus the Same Therapy Without Methotrexate

Summary:

This randomized phase III trial is studying two different combination chemotherapy regimens to compare how well they work in treating young patients with newly diagnosed supratentorial primitive neuroectodermal tumours or high-risk medulloblastoma when given before additional intense chemotherapy followed by peripheral blood stem cell rescue. It is not yet known which combination chemotherapy regimen is more effective when given before a peripheral stem cell transplant in treating supratentorial primitive neuroectodermal tumours or medulloblastoma.

Trial Description

Primary Outcome:

• Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate

Secondary Outcome:

• Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort
• Percentage of Participants With Event Free Survival (EFS)
• Patterns of Failure
• Percentage of Participants With Any Acute Adverse Events
• Number of Participants With Acute Hearing Loss and No Acute Hearing Loss
• Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory HypothyroidismHypothyroidism/Subclinical Compensatory Hypothyroidism
• Number of Participants With Chronic Central Hypothyroidism
• Number of Participants With Chronic Low Somatomedin C
• Number of Participants With Chronic Diabetes Insipidus
• Number of Participants With Secondary Malignancies
• Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss
• Rates of Gastrointestinal Toxicities
• Rates of Nutritional Toxicities
• Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI).

PRIMARY OBJECTIVES:
I. To determine if treatment of infants with high risk primitive neuroectodermal tumours (PNET) central nervous system (CNS) tumours with intensive chemotherapy plus high-dose methotrexate and peripheral blood stem cell rescue results in a higher complete response rate then the same regimen without methotrexate. SECONDARY OBJECTIVES:
I. To determine whether biologic characterization of these tumours will refine therapeutic stratification separating atypical teratoid rhabdoid tumours (AT/RT) from primitive neuroectodermal tumours (PNETs) and possibly identifying other markers of value for stratification within the group of PNETs. II. To determine if event free survival (EFS) and patterns of failure differ between the methotrexate arm versus the arm without methotrexate. III. To compare the acute, chronic and late effects of these two very intensive regimens, especially as to the tolerance of the same consolidation regimen following the differing induction regimens. IV. To compare the gastrointestinal and nutritional toxicities of these intense regimens. V. To describe and compare the quality of life outcomes and neuropsychological effects of these intense systemic therapies. OUTLINE:

This is a randomized, multicentre study. Patients are stratified according to diagnosis* (M0 medulloblastoma with ≥ 1.5 cm² residual tumour vs M1 medulloblastoma [positive lumbar CSF cytology] vs M2, M3, or M4 medulloblastoma vs supratentorial PNET [any M-stage] vs M0 medulloblastoma < 8 months without residual disease or with < 1.5 cm² radiographic measurable residual tumour vs anaplastic M0 medulloblastoma without residual disease or with < 1.5 cm² radiographic measurable residual vs classic M0 (nondesmoplastic) medulloblastoma with < 1.5 cm² radiographic measurable residual tumour). NOTE: *All diagnoses are for children < 36 months unless otherwise noted. INDUCTION THERAPY: Patients are randomized to 1 of 2 induction treatment arms. ARM I: Patients receive vincristine IV on days 1, 8, and 15; etoposide IV over 1 hour on days 1-3; cyclophosphamide IV over 1 hour on days 1 and 2; cisplatin IV over 6 hours on day 3; and filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 4 and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive vincristine IV on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or orally every 6 hours beginning on day 2 and continuing until methotrexate levels are in a safe range. Once methotrexate levels are in a safe range, patients then receive etoposide IV over 1 hour on approximately days 4, 5, and 6, cyclophosphamide IV over 1 hour on approximately days 4 and 5, and cisplatin IV over 6 hours on approximately day 6. Patients also receive G-CSF IV or SC beginning 24 hours after the completion of chemotherapy and continuing until blood counts recover. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. In both arms, patients with stable disease or partial response after induction therapy proceed to second-look surgery followed by consolidation therapy. Patients with a complete response after induction therapy proceed directly to consolidation therapy. CONSOLIDATION THERAPY: Beginning no more than 6 weeks after completion of induction therapy, patients receive consolidation therapy comprising carboplatin IV over 2 hours and thiotepa IV over 2 hours on days 1 and 2 and G-CSF IV or SC beginning on day 5 and continuing until blood counts recover. Patients also receive autologous peripheral blood stem cells (PBSC) IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Blood and tissue samples are collected at baseline for correlative studies, including gene expression profiling, biological marker analysis (i.e., cMyc, ErbB2/ErbB4), comparative genome analysis, and mutation analysis. After completion of study therapy, patients are followed up periodically for 4 years and then annually thereafter.

View this trial on ClinicalTrials.gov