Summary

Eligibility
for people ages up to 2 years (full criteria)
Location
at San Francisco, California and other locations
Dates
study started

Description

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 tumors 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 tumors or 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

Details

PRIMARY OBJECTIVES:

  1. To determine if treatment of infants with high risk primitive neuroectodermal tumors (PNET) central nervous system (CNS) tumors 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:

  1. To determine whether biologic characterization of these tumors will refine therapeutic stratification separating atypical teratoid rhabdoid tumors (AT/RT) from primitive neuroectodermal tumors (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.

  1. To describe and compare the quality of life outcomes and neuropsychological effects of these intense systemic therapies.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to diagnosis* (M0 medulloblastoma with ≥ 1.5 cm² residual tumor 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 tumor 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 tumor).

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.

Keywords

Untreated Childhood Medulloblastoma Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor Medulloblastoma Neuroectodermal Tumors Neuroectodermal Tumors, Primitive Leucovorin Cyclophosphamide Thiotepa Carboplatin Methotrexate Etoposide Vincristine Etoposide phosphate Levoleucovorin cisplatin filgrastim leucovorin calcium vincristine sulfate autologous hematopoietic stem cell transplantation laboratory biomarker analysis quality-of-life assessment

Eligibility

For people ages up to 2 years

Inclusion Criteria:

  • Diagnosis of 1 of the following:
  • High-risk medulloblastoma defined by any of the following:
  • Residual disease > 1.5 cm²
  • Lumbar cerebral spinal fluid cytology positive for tumor cells by analysis of fluid collected either before definitive surgery or ≥ 10 days after definitive surgery unless contraindicated
  • M0 disease in children < 8 months of age at diagnosis
  • M2 or M3 metastatic disease by MRI
  • M4 disease
  • Supratentorial primitive neuroectodermal tumor (PNET)(any M-stage)
  • Anaplastic medulloblastoma regardless of M-stage or residual tumor
  • M0 classic, non-desmoplastic medulloblastoma (R1) with radiographically measurable residual disease < 1.5 cm2

  • MRI evidence of spinal disease
  • Tumor must be negative for INI1 gene
  • Has undergone definitive surgery within the past 31 days
  • No atypical teratoid rhabdoid tumors
  • Biological specimens must be available for correlative laboratory studies
  • Life expectancy > 8 weeks
  • Creatinine clearance or radioisotope glomerular filtration rate ≥ 60 mL/min
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT < 2 times ULN
  • Shortening fraction ≥ 27% by echocardiogram
  • Ejection fraction ≥ 47% by radionuclide angiogram
  • No evidence of dyspnea at rest
  • Pulse oximetry > 94% on room air
  • Absolute neutrophil count > 1,000/mm³
  • Platelet count > 100,000/mm³ (transfusion independent)
  • Hemoglobin > 8 g/dL (RBC transfusions allowed)
  • Prior corticosteroids allowed
  • No prior radiation therapy or chemotherapy

Locations

  • University of California San Francisco Medical Center-Parnassus
    San Francisco California 94143 United States
  • Children's Hospital Central California
    Madera California 93636-8762 United States

Details

Status
in progress, not accepting new patients
Start Date
Sponsor
Children's Oncology Group
ID
NCT00336024
Phase
Phase 3
Study Type
Interventional
Last Updated