CLINICAL TRIAL / NCT00392327
Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma/PNET
- Interventional
- Active
- NCT00392327
Contact Information
Efficacy of Carboplatin Administered Concomitantly With Radiation and Isotretinoin as a Pro-Apoptotic Agent in Other Than Average Risk Medulloblastoma/PNET Patients
This randomized phase III trial studies different chemotherapy and radiation therapy regimens to compare how well they work in treating young patients with newly diagnosed, previously untreated, high-risk medulloblastoma. Drugs used in chemotherapy, such as vincristine sulfate, cisplatin, cyclophosphamide, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. 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.
PRIMARY OBJECTIVES:
I. To determine whether carboplatin radiosensitization increases long term event-free
survival for high risk medulloblastoma/primitive neuroectodermal tumor (PNET) patients.
II. To determine whether isotretinoin increases long term event-free survival for high risk
medulloblastoma/PNET patients.
SECONDARY OBJECTIVES:
I. To compare residual disease response to radiation alone versus radiation plus carboplatin.
II. To identify molecular prognostic indicators suitable for patient stratification in future
trials.
III. To evaluate the health-related quality of life (HRQOL) during phases of active treatment
specific to treatment modalities.
IV. To describe the neuropsychological functioning of the study population and to evaluate
the relationship between neuropsychological status and health related quality of life.
OUTLINE: Patients are randomized to Arm A or Arm B (Arms C and D closed to accrual as of
Amendment 3 1/27/15).
ARM A (standard chemoradiotherapy and standard maintenance therapy):
CHEMORADIOTHERAPY: Patients undergo radiation therapy once daily (QD) five days a week for 6
weeks. Patients also receive vincristine sulfate intravenously (IV) over 1 minute once weekly
for 6 weeks. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance
therapy.
MAINTENANCE THERAPY: Patients receive cisplatin IV over 6 hours on day 1, vincristine sulfate
IV over 1 minute on days 1 and 8, and cyclophosphamide IV over 1 hour on days 2 and 3.
Patients also receive filgrastim 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 B (standard chemoradiotherapy plus carboplatin and standard maintenance therapy):
CHEMORADIOTHERAPY: Patients receive vincristine sulfate and undergo radiation therapy as in
Arm I. Patients also receive carboplatin IV over 15 minutes on each day of radiation therapy.
Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy.
MAINTENANCE THERAPY: Patients receive maintenance therapy as in Arm I.
ARM C (standard chemoradiotherapy, standard maintenance therapy plus isotretinoin, and
continuation therapy with isotretinoin - CLOSED TO ACCRUAL 1/27/15):
CHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in Arm I. Six weeks after completion
of chemoradiotherapy, patients proceed to maintenance therapy.
MAINTENANCE THERAPY: Patients receive isotretinoin orally (PO) twice daily (BID) on day 1 and
days 16-28 and cisplatin, vincristine sulfate, cyclophosphamide, and filgrastim 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 isotretinoin PO BID on days 15-28 every 28 days for up
to 6 courses in the absence of disease progression or unacceptable toxicity.
ARM D (standard chemoradiotherapy plus carboplatin, standard maintenance therapy plus
isotretinoin, and continuation therapy with isotretinoin - CLOSED TO ACCRUAL 1/27/15):
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.
After completion of study treatment, patients are followed up periodically for 1 year.
Gender
All
Age Group
3 Years to 21 Years
Accepting Healthy Volunteers
No
Inclusion Criteria:
- Newly diagnosed, previously untreated: (1) M0 medulloblastoma with > 1.5 cm^2
residual; (2) M+ medulloblastoma; patients with diffusely anaplastic medulloblastoma
are eligible regardless of M-stage or residual tumor
- As of amendment # 2, enrollment of patients with supratentorial PNET has been
discontinued
- All patients with M4 disease are not eligible
- A pre-operative magnetic resonance imaging (MRI) scan of the brain with and without
contrast is required; NOTE: computed tomography (CT) scans are NOT sufficient for
study eligibility
- Post-operative head MRI scan with and without contrast (preferably within 72
hours post-surgery); for patients who undergo stereotactic biopsy only, either a
pre or post-operative MRI is sufficient; for patients with M2 and M3 disease, a
post-op MRI is strongly encouraged, but not mandatory
- Spinal MRI imaging with and without gadolinium is required within 10 days of
surgery if done pre-operatively or within 28 days of surgery if done
post-operatively; for posterior fossa tumors, pre-operative MRI scans are
preferred
- Lumbar cerebrospinal fluid (CSF) cytology examination must be obtained pre-operatively
or within 31 days following surgery; the optimal time for obtaining CSF is prior to
surgery or 1-3 weeks following surgery; ventricular CSF (either pre- or post-op) may
be used only if a post-operative spinal tap is contraindicated; if a spinal tap is
contraindicated and there is no ventricular CSF available, then CSF cytology can be
waived for patients with supratentorial tumors or if there is documentation of spinal
subarachnoid metastases (M3); patients who are categorized as M1 must have either an
intra-operative positive CSF (via lumbar puncture at the end of the procedure) or a
positive lumbar CSF obtained > 7 days post-operatively
- Patients must have a Karnofsky performance level of >= 30 for patients > 16 years of
age or a Lansky performance scale of >= 30 for patients =< 16 years of age and life
expectancy > 8 weeks
- No previous chemotherapy or radiation therapy
- Corticosteroids should not be used during chemotherapy administration as an antiemetic
- Selected strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4
(cytochrome P450 3A4) include azole antifungals, such as fluconazole, voriconazole,
itraconazole, ketoconazole, and strong inducers include drugs such as rifampin,
phenytoin, phenobarbitol, carbamazepine, and St. John's wort; the use of these drugs
should be avoided with vincristine (vincristine sulfate)
- CYP450 3A4 stimulators or inhibitors should be avoided or used with great caution when
taking cyclophosphamide; aprepitant should also be used with caution with etoposide or
vincristine chemotherapy
- Cisplatin should be used with caution with nephrotoxic drug; aminoglycoside should be
avoided or used with caution during or shortly after cisplatin administration and
concomitant use with amphotericin B should probably also be avoided; patients
receiving cisplatin and other potentially ototoxic drugs such as aminoglycoside or
loop diuretics concomitantly should be closely monitored for signs of ototoxicity
- Plasma levels of anticonvulsant agents should be monitored and doses adjusted
during therapy with cisplatin
- No other experimental therapy is permitted while on study
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:
- 0.8 mg/dL (2 to < 6 years of age)
- 1.0 mg/dL (6 to < 10 years of age)
- 1.2 mg/dL (10 to < 13 years of age)
- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
- 1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age)
- Total bilirubin < 1.5 x upper limit of normal (ULN) for age
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
upper limit of normal (ULN) for age; for patients on anti-seizure medications, SGOT
(AST) or SGPT (ALT) must be < 5 x ULN
- Absolute neutrophil count (ANC) >= 1,000/uL
- Platelets >= 100,000/uL (untransfused)
- Hemoglobin >= 8 g/dl (may be transfused)
- Female patients who are post-menarchal must have a negative pregnancy test; lactating
female patients must agree not to breast-feed while on this trial; males or females of
reproductive potential may not participate unless they have agreed to use an effective
contraceptive method
- All patients and/or their parents or legal guardians must sign a written informed
consent
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met