Clinical Trials /

Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma

NCT00392327

Description:

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.

Related Conditions:
  • Medulloblastoma
Recruiting Status:

Suspended

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma
  • Official Title: Efficacy of Carboplatin Administered Concomitantly With Radiation and Isotretinoin as a Pro-Apoptotic Agent in Other Than Average Risk Medulloblastoma/PNET Patients

Clinical Trial IDs

  • ORG STUDY ID: ACNS0332
  • SECONDARY ID: NCI-2009-00336
  • SECONDARY ID: COG-ACNS0332
  • SECONDARY ID: CDR0000511991
  • SECONDARY ID: ACNS0332
  • SECONDARY ID: ACNS0332
  • SECONDARY ID: R01CA114567
  • SECONDARY ID: U10CA180886
  • SECONDARY ID: U10CA098543
  • NCT ID: NCT00392327

Conditions

  • Untreated Childhood Medulloblastoma
  • Untreated Childhood Pineoblastoma
  • Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

Interventions

DrugSynonymsArms
Vincristine SulfateKyocristine, Oncovin, VCR, VincasarArm I (chemoradiotherapy)
CarboplatinArm II (chemoradiotherapy)
CisplatinArm I (chemoradiotherapy)
CyclophosphamideArm I (chemoradiotherapy)
FilgrastimG-CSF, Nivestim, r-metHuG-CSFArm I (chemoradiotherapy)
IsotretinoinArm III (chemoradiotherapy, isotretinoin)

Purpose

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. 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.

Detailed Description

      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 1 of 4 treatment arms.

      ARM I (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 II (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 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 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 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.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (chemoradiotherapy)Active ComparatorCHEMORADIOTHERAPY: Patients undergo radiation therapy QD five days a week for 6 weeks. Patients also receive vincristine sulfate 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 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.
  • Vincristine Sulfate
  • Cisplatin
  • Cyclophosphamide
Arm II (chemoradiotherapy)ExperimentalCHEMORADIOTHERAPY: 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.
  • Vincristine Sulfate
  • Carboplatin
  • Cisplatin
  • Cyclophosphamide
Arm III (chemoradiotherapy, isotretinoin)ExperimentalCHEMORADIOTHERAPY: Patients undergo chemoradiotherapy as in Arm I. Six weeks after completion of chemoradiotherapy, patients proceed to maintenance therapy. MAINTENANCE THERAPY: Patients receive isotretinoin PO 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.
  • Vincristine Sulfate
  • Cisplatin
  • Cyclophosphamide
  • Isotretinoin
Arm IV (chemoradiotherapy, isotretinoin)ExperimentalCHEMORADIOTHERAPY: 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.
  • Vincristine Sulfate
  • Carboplatin
  • Cisplatin
  • Cyclophosphamide
  • Isotretinoin

Eligibility Criteria

        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

          -  Patients taking Accutane (isotretinoin) for acne must discontinue drug use with this
             indication prior to enrollment; corticosteroids should not be used during chemotherapy
             administration as an antiemetic

               -  Isotretinoin is contraindicated in patients with parabens allergy and patients
                  with soybean allergy; concurrent use with tetracyclines should be avoided; intake
                  of vitamin A should be limited for the duration of isotretinoin treatment

          -  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:

               -  0.4 mg/dL (1 month to < 6 months of age)

               -  0.5 mg/dL (6 months to < 1 year of age)

               -  0.6 mg/dL (1 to < 2 years of age)

               -  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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS) percentage
Time Frame:Time from disease progression or recurrence, occurrence of a second malignant neoplasm, or death from any cause, assessed up to 10 years
Safety Issue:
Description:Based on stratified logrank test, with stratification on all randomization stratifiers as well as on the factorial treatment group not the subject of the analysis.

Secondary Outcome Measures

Measure:Tumor response to radiation therapy with or without carboplatin
Time Frame:Up to 10 years
Safety Issue:
Description:Using a two-sided test of proportions with type I error 5%, this sample size will provide at least 80% power to detect a 30% difference in post-radiation therapy response rate between the two treatment groups.
Measure:Time to death
Time Frame:Up to 10 years
Safety Issue:
Description:Survival percentage will be computed from time to death.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Oncology Group

Last Updated

August 29, 2017