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 when given before a peripheral stem cell transplant in
treating young patients with newly diagnosed supratentorial primitive neuroectodermal tumours
or high-risk medulloblastoma. Drugs used in chemotherapy work in different ways to stop the
growth of tumour cells, either by killing the cells or by stopping them from dividing. Giving
more than one drug (combination chemotherapy) together with a peripheral stem cell
transplant may allow more chemotherapy to be given so that more tumour cells are killed. 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:
- 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 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).
- To Determine Number and Nature of Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort
PRIMARY OBJECTIVES:
I. Determine if treatment of pediatric patients with newly diagnosed supratentorial primitive
neuroectodermal CNS tumours or high-risk medulloblastoma with intensive induction chemotherapy
comprising vincristine, etoposide, cyclophosphamide, and cisplatin in combination with
high-dose methotrexate and leucovorin calcium followed by consolidation chemotherapy
comprising carboplatin and thiotepa and peripheral blood stem cell rescue results in a higher
complete response rate then in patients treated with the same regimen without high-dose
methotrexate and leucovorin calcium.
SECONDARY OBJECTIVES:
I. Determine whether biologic characterization of these tumours will refine therapeutic
stratification separating atypical teratoid rhabdoid tumours from primitive neuroectodermal
tumours (PNETs) and possibly identifying other markers of value for stratification within the
group of PNETs.
II. Compare event-free survival and patterns of failure in patients treated with these
regimens.
III. Compare the acute, chronic, and late effects of these regimens, particularly in terms of
tolerance to the same consolidation regimen after treatment with 2 different induction
regimens, in these patients.
IV. Compare the gastrointestinal and nutritional toxicities of these regimens in these
patients.
V. Compare the quality of life outcomes in patients treated with these regimens.
VI. Compare the neuropsychological effects of these regimens in these patients.
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 54 and continuing until
blood counts recover. Patients also receive autologous peripheral blood stem cells (PBSC) IV
on day 4. Treatment repeats every 3 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
