Official Title: “Efficacy of Carboplatin Administered Concomitantly With Radiation and Isotretinoin as a Pro-Apoptotic Agent in Other Than Average Risk Medulloblastoma/PNET Patients”

RATIONALE: 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) may kill more tumor cells. Isotretinoin may help chemotherapy work better by making tumor cells more sensitive to the drugs. Radiation therapy uses high-energy x-rays to kill tumor cells. Carboplatin may make tumor cells more sensitive to radiation therapy. It is not yet known which chemotherapy and radiation therapy regimen is more effective in treating brain tumors.

PURPOSE: This randomized phase III trial is studying different chemotherapy and radiation therapy regimens to compare how well they work in treating young patients with newly diagnosed, previously untreated, high-risk medulloblastoma or supratentorial primitive neuroectodermal tumor.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label

Study Primary Completion Date: December 2012

OBJECTIVES:

Primary - Determine whether carboplatin radiosensitization increases long-term, event-free survival of pediatric patients with newly diagnosed, previously untreated, high-risk medulloblastoma or supratentorial primitive neuroectodermal tumors. - Determine whether isotretinoin increases long-term, event-free survival of these patients.

Secondary - Compare residual disease response to radiotherapy alone versus radiotherapy and carboplatin in these patients. - Identify molecular prognostic indicators suitable for patient stratification in future trials.

OUTLINE: This is a randomized, open-label, factorial-designed, multicenter study. Patients are stratified according to location of disease and dissemination status (M0 medulloblastoma with > 1.5 cm² residual tumor vs M+ medulloblastoma vs M0 supratentorial primitive neuroectodermal tumor [SPNET] with < 1.5 cm² residual tumor vs M0 SPNET with > 1.5 cm² residual tumor vs M+ SPNET). Patients are randomized* to 1 of 4 treatment arms.

NOTE: *Patients with a history of clinical depression are nonrandomly assigned to arm I or II and do not receive isotretinoin. - Arm I (standard chemoradiotherapy and standard maintenance therapy): - Chemoradiotherapy: Patients undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40 and receive vincristine IV over 1 minute on days 1, 8, 15, 22, 29, and 36. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. - Maintenance therapy: Patients receive cisplatin IV over 6 hours on day 1, vincristine IV over 1 minute on days 1 and 8, and cyclophosphamide IV over 1 hour on days 2 and 3. Patients also receive filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 4 and continuing until blood counts recover (at least 10 days).

Treatment repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. - Arm II (standard chemoradiotherapy plus carboplatin and standard maintenance therapy): - Chemoradiotherapy: Patients receive carboplatin IV over 15 minutes once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40 and undergo radiotherapy and receive vincristine as in arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. - Maintenance therapy: Patients receive maintenance therapy as in arm I. - Arm III (standard chemoradiotherapy, standard maintenance therapy plus isotretinoin, and continuation therapy with isotretinoin): - Chemoradiotherapy: Patients undergo chemoradiotherapy as in arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. - Maintenance therapy: Patients receive oral isotretinoin twice daily on day 1 and days 16-28 and cisplatin, vincristine, cyclophosphamide, and G-CSF as in arm I maintenance therapy. Treatment repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. Patients then proceed to continuation therapy. - Continuation therapy: Patients receive oral isotretinoin twice daily on days 15-28.

Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. - Arm IV (standard chemoradiotherapy plus carboplatin, standard maintenance therapy plus isotretinoin, and continuation therapy with isotretinoin): - Chemoradiotherapy: Patients undergo chemoradiotherapy as in arm II. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. - Maintenance therapy: Patients receive maintenance therapy as in arm III. Patients then proceed to continuation therapy. - Continuation therapy: Patients receive continuation therapy as in arm III. Quality of life is assessed at baseline and periodically during study treatment (for patients ages 3 to 18). Neuropsychological evaluations are performed on all patients at baseline and at 2½-3 years after completion of study treatment.

After completion of study treatment, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: carboplatin
  • Given IV
• Drug: cisplatin
  • Given IV
• Drug: cyclophosphamide
  • Given IV
• Drug: filgrastim
  • Given IV or subcutaneously
• Drug: isotretinoin
  • Given orally
• Drug: vincristine sulfate
  • Given IV
• Procedure: radiation therapy
  • Patients undergo radiotherapy 5 days a week for 6 weeks

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Arm I
  • (Standard chemoradiotherapy and standard maintenance therapy): Patients undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40 and receive vincristine IV over 1 minute on days 1, 8, 15, 22, 29, and 36. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. Patients receive cisplatin IV over 6 hours on day 1, vincristine IV over 1 minute on days 1 and 8, and cyclophosphamide IV over 1 hour on days 2 and 3. Patients also receive filgrastim (G-CSF) subcutaneously (SC) or IV beginning on day 4 and continuing until blood counts recover (at least 10 days). Treatment with maintenance therapy repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity.
• Experimental: Arm II
  • (Standard chemoradiotherapy plus carboplatin and standard maintenance therapy): Patients receive carboplatin IV over 15 minutes once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40 and undergo radiotherapy and receive vincristine as in arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. Patients receive maintenance therapy as in arm I.
• Experimental: Arm III
  • (Standard chemoradiotherapy, standard maintenance therapy plus isotretinoin, and continuation therapy with isotretinoin): Patients undergo chemoradiotherapy as in arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. Patients receive oral isotretinoin twice daily on day 1 and days 16-28 and cisplatin, vincristine, cyclophosphamide, and G-CSF as in arm I maintenance therapy. Treatment with maintenance therapy repeats every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. Patients then proceed to continuation therapy. Patients receive oral isotretinoin twice daily on days 15-28. Treatment with continuation therapy repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
• Experimental: Arm IV
  • (Standard chemoradiotherapy plus carboplatin, standard maintenance therapy plus isotretinoin, and continuation therapy with isotretinoin): Patients undergo chemoradiotherapy as in arm II. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. Patients receive maintenance therapy as in arm III. Patients then proceed to continuation therapy. Patients receive continuation therapy as in arm III.

Primary Measures

• Event-free survival (e.g., events comprising disease progression or recurrence, occurrence of a second malignant neoplasm, or death from any cause)
  • Safety Issue?: No

Secondary Measures

• Residual tumor response to radiotherapy with or without carboplatin
  • Safety Issue?: No
• Time to death
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of medulloblastoma or supratentorial primitive neuroectodermal tumor (PNET)
• Newly diagnosed disease
• Previously untreated disease
• Meets 1 of the following criteria:
• M0 medulloblastoma with > 1.5 cm² residual tumor
• M+ medulloblastoma
• M0 or M+ supratentorial PNET
• Diffusely anaplastic medulloblastoma with any M-stage or residual tumor
• Must have undergone stereotactic biopsy or attempted neurosurgical resection of the tumor within the past 31 days
• The following procedures are required:
• Pre-operative MRI of the brain with and without contrast
• Post-operative (preferably within 72 hours after surgery) MRI of the brain with and without contrast**
• Spinal MRI with and without contrast within 7 days before surgery or 28 days after surgery
• Lumbar cerebrospinal fluid (CSF) cytological examination within 31 days after surgery*** NOTE: **Not required for patients with M2 or M3 disease or for patients who undergo stereotactic biopsy only
• NOTE: ***If a spinal tap is contraindicated, and there is no ventricular CSF available, CSF cytology may be waived for patients with supratentorial tumors OR if there is documentation of spinal subarachnoid metastases (M3); patients with M1 disease must have either an intraoperative-positive CSF by lumbar puncture at the end of surgery OR a positive lumbar
• CSF obtained more than 7 days after surgery (to rule out surgically-induced false positives
• No M4 disease

PATIENT CHARACTERISTICS:

• Karnofsky/Lansky performance status 50-100%
• Life expectancy > 8 weeks
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use 2 effective forms of contraception
• Creatinine normal OR creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min
• Bilirubin < 1.5 times upper limit of normal (ULN)
• AST and ALT < 2.5 times ULN (5 times ULN for patients on antiseizure medications)
• Absolute neutrophil count ≥ 1,000/mm³
• Platelet count ≥ 100,000/mm³ (transfusions not allowed)
• Hemoglobin ≥ 8 g/dL (transfusions allowed)

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy or radiotherapy
• No other concurrent experimental therapy
• No concurrent isotretinoin for acne treatment
• No concurrent corticosteroids as an antiemetic during chemotherapy

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 3 Years

Maximum Age for this Clinical Trial: 21 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Children's Oncology Group

Overall Clinical Trial Officials and Contacts

James Olson, MD, PhD Study Chair Fred Hutchinson Cancer Research Center  

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00392327

Study ID Number: CDR0000511991

ClinicalTrials.gov Identifier: NCT00392327

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database