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

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIIBiomarker/Laboratory analysis, TreatmentUnder 3ACNS0334
NCI-2009-00338, CDR0000483683, COG-ACNS0334, NCT00336024

Trial Description

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 tumors or high-risk medulloblastoma. Drugs used in chemotherapy work in different ways to stop the growth of tumor 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 tumor 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 tumors or medulloblastoma.

Further Study Information

PRIMARY OBJECTIVES:

I. Determine if treatment of pediatric patients with newly diagnosed supratentorial primitive neuroectodermal CNS tumors 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 tumors will refine therapeutic stratification separating atypical teratoid rhabdoid tumors from primitive neuroectodermal tumors (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, 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 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.

Eligibility Criteria

Inclusion Criteria:

Prior corticosteroids allowed

No prior radiation therapy or chemotherapy

Hemoglobin > 8 g/dL (RBC transfusions allowed)

Platelet count > 100,000/mm³ (transfusion independent)

Absolute neutrophil count > 1,000/mm³

Pulse oximetry > 94% on room air

No evidence of dyspnea at rest

Ejection fraction ≥ 47% by radionuclide angiogram

Shortening fraction ≥ 27% by echocardiogram

AST and ALT < 2 times ULN

Bilirubin ≤ 1.5 times upper limit of normal (ULN)

Creatinine clearance or radioisotope glomerular filtration rate ≥ 60 mL/min

Life expectancy > 8 weeks

Biological specimens must be available for correlative laboratory studies

No atypical teratoid rhabdoid tumors

Has undergone definitive surgery within the past 31 days

Tumor must be negative for INI1 gene

MRI evidence of spinal disease

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 cm^2

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Children's Oncology Group

  • National Cancer Institute
Claire Marie Mazewski, Principal Investigator

Trial Sites

U.S.A.

Florida
Hollywood

Memorial Regional Hospital/Joe DiMaggio Children's Hospital

Iftikhar Hanif
Ph: 954-265-2234

Iftikhar Hanif
Principal Investigator

Michigan
Kalamazoo

Kalamazoo Center for Medical Studies

Jeffrey S. Lobel
Ph: 800-227-2345

Jeffrey S. Lobel
Principal Investigator

New Jersey
Summit

Overlook Hospital

Steven Lon Halpern
Ph: 973-971-5900

Steven Lon Halpern
Principal Investigator

New York
New York

Memorial Sloan-Kettering Cancer Center

Peter Gustav Steinherz
Ph: 212-639-7202

Peter Gustav Steinherz
Principal Investigator

Ohio
Cleveland

Cleveland Clinic Foundation

Tanya Marie Tekautz
Ph: 866-223-8100

Tanya Marie Tekautz
Principal Investigator

Oregon
Portland

Legacy Emanuel Hospital and Health Center

Janice Faye Olson
Ph: 503-413-2560

Janice Faye Olson
Principal Investigator

South Carolina
Greenville

Greenville Cancer Treatment Center

Nichole Leigh Bryant
Ph: 864-241-6251

Nichole Leigh Bryant
Principal Investigator

Canada

Ontario
Hamilton

Chedoke Hospital at Hamilton Health Sciences

Carol Portwine
Ph: 905-521-2100ext74595

Carol Portwine
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00336024

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.