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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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ClinicalTrials.gov Identifier: NCT00336024
Recruitment Status : Completed
First Posted : June 12, 2006
Results First Posted : October 24, 2018
Last Update Posted : October 24, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief 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.

Condition or disease Intervention/treatment Phase
Untreated Childhood Medulloblastoma Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor Drug: etoposide Drug: cyclophosphamide Drug: cisplatin Biological: filgrastim Drug: carboplatin Drug: thiotepa Drug: methotrexate Drug: leucovorin calcium Drug: vincristine sulfate Procedure: autologous hematopoietic stem cell transplantation Other: laboratory biomarker analysis Procedure: quality-of-life assessment Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 91 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 22, 2007
Actual Primary Completion Date : December 31, 2016
Actual Study Completion Date : December 31, 2016


Arm Intervention/treatment
Active Comparator: Arm I (induction+consolidation chemotherapy, autologous PBSC))

Patients receive vincristine sulfate 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. Treatment repeats every 3 weeks for 3 courses.

Within 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 filgrastim (G-CSF) IV or SC beginning on day 54 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP

Biological: filgrastim
Given IV or SC
Other Names:
  • G-CSF
  • Neupogen

Drug: carboplatin
Given IV
Other Names:
  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin

Drug: thiotepa
Given IV
Other Names:
  • Oncotiotepa
  • STEPA
  • TESPA
  • Tespamin
  • TSPA

Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS

Procedure: autologous hematopoietic stem cell transplantation
Undergo autologous PBSC transplantation

Other: laboratory biomarker analysis
Correlative studies

Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment

Experimental: Arm II (induction+consolidation chemotherapy, autologous PBSC)

Patients receive vincristine sulfate 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. 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. Treatment repeats every 3 weeks for 3 courses.

Within 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 filgrastim (G-CSF) IV or SC beginning on day 54 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP

Biological: filgrastim
Given IV or SC
Other Names:
  • G-CSF
  • Neupogen

Drug: carboplatin
Given IV
Other Names:
  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin

Drug: thiotepa
Given IV
Other Names:
  • Oncotiotepa
  • STEPA
  • TESPA
  • Tespamin
  • TSPA

Drug: methotrexate
Given IV
Other Names:
  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX

Drug: leucovorin calcium
Given IV or orally
Other Names:
  • CF
  • CFR
  • LV

Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS

Procedure: autologous hematopoietic stem cell transplantation
Undergo autologous PBSC transplantation

Other: laboratory biomarker analysis
Correlative studies

Procedure: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment




Primary Outcome Measures :
  1. Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate [ Time Frame: From baseline to up to 9 years ]
    At the end of consolidation, the number of evaluable patients treated with intensive chemotherapy with methotrexate who achieved CR or not will be compared to those who achieved CR or not after treated with the same intensive chemotherapy without methotrexate. The CR rates between these two groups will be compared at a significance level of 0.1 using one-sided Chi-square test. Complete Response (CR) requires: CR for target lesions: disappearance of all target lesions, CR for non-target lesions: disappearance of all non-target lesions and no new lesions. No CR is any response not fitting the definition of CR.


Secondary Outcome Measures :
  1. Percentage of Participants With Event Free Survival (EFS) [ Time Frame: Baseline to up to 5 years ]
    EFS was defined as time from enrollment to the occurrence of first event (disease progression/relapse, secondary malignancy, death from any cause) or date of last contact for patients who are event-free. The percentage of participants with EFS and 90% confidence interval were provided. The difference in incidence for the two treatment regimens were compared using a one-sided log-rank test with a significance level of 0.1.

  2. Patterns of Failure [ Time Frame: Baseline to up to 5 years ]
    The patterns of failure for relapse/disease progression will be provided for patients treated with/without methotrexate drug. The two groups will be compared to detect a statistically significant difference using Fisher exact test.

  3. Percentage of Participants With Any Acute Adverse Events. [ Time Frame: Beginning of treatment to up to 9 years ]
    Event is defined as the first occurrence of any acute toxicity. Estimates will be obtained using life-table methods. Patients who have progression or recurrence of disease will be censored in this analysis. Difference in incidence for the two treatment regimens will be compared using log-rank test.

  4. Number of Participants With Acute Hearing Loss and No Acute Hearing Loss [ Time Frame: Beginning of treatment to up to 9 years ]
    Per protocol, hearing was assessed pretreatment and at regular specified intervals during treatment and off therapy, using DPOAE, audiogram or Brainstem Evoked Auditory. Per CTCAE V4.0 grade 3 Hearing impaired is defined as follows; Pediatric (on a 1,2,3,4, 6 and 8 kHz audiogram): hearing loss sufficient to indicate therapeutic intervention, including hearing aids, threshold shift >20 dB at 3 kHz and above in at least one ear, additional speech-language related services as indicated. Per CTCAE V4.0 grade 4 Hearing impaired is defined as follows; Pediatric Audiologic indication for cochlear implant and additional speech-language related services as indicated.

  5. Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory Hypothyroidism [ Time Frame: Beginning of treatment to up to 9 years ]
    Thyroid function was assessed as per ACNS0334 Endocrine Guidelines. "Normal" and "Abnormal" are defined at each institution by the laboratory standards where the blood tests are run. Primary Hypothyroidism/Subclinical Compensatory Hypothyroidism is defined as patients with Free T4 level less than "Institutional" Normal or equal to "Institutional" Normal with TSH level greater than "Institutional" Normal.

  6. Number of Participants With Chronic Central Hypothyroidism [ Time Frame: Beginning of treatment to up to 9 years ]
    Thyroid function was assessed as per ACNS0334 Endocrine Guidelines. "Normal" and "Abnormal" are defined at each institution by the laboratory standards where the blood tests are run. Central Hypothyroidism is defined as Free T4 level less than "Institutional" Normal with TSH less than or equal to "Institutional" Normal.

  7. Number of Participants With Chronic Low Somatomedin C [ Time Frame: Beginning of treatment to up to 9 years ]
    Low Somatomedin C is defined as patients with somatomedin C value less than institutional normal. As numbers are too small, descriptive statistics such as number will be reported for this analysis. Growth hormone function was assessed as per ACNS0334 Endocrine Guidelines. Low Somatomedin C levels are defined at each institution by the laboratory standards where the blood tests are run.

  8. Number of Participants With Chronic Diabetes Insipidus [ Time Frame: Beginning of treatment to up to 9 years ]
    The number of patients who had "Diabetes Insipidus" and on DDAVP will be reported for this analysis due to small numbers.

  9. Number of Participants With Secondary Malignancies [ Time Frame: Beginning of treatment to up to 9 years ]
    The number of patients who had secondary malignancy will be reported for this analysis due to small numbers.

  10. Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss [ Time Frame: Beginning of treatment to up to 9 years ]
    The number of patients who are reported to have abnormal hearing, graded according to CTCAE 4.0 or not, with onset while on therapy or when off therapy which persisted after off therapy will be reported and will be compared using Fisher exact test.

  11. Rates of Gastrointestinal Toxicities [ Time Frame: In each 21 day cycle (up to 6 cycles) ]
    Rates of gastrointestinal toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number of patients). The difference in number of patients with gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.

  12. Rates of Nutritional Toxicities [ Time Frame: In each 21 day cycle (up to 6 cycles) ]
    Rates of nutritional toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number of patients). The difference in number of patients with nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.

  13. Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI). [ Time Frame: From baseline to 5.25 years ]

    Three tools are used to assess intelligence (IQ) depending on age. The range of IQ scores is 40-160 (mean=100, SD=15); range for the Processing Speed Index (PSI)=45-155. Higher scores represent better functioning. (1) Wechsler Preschool and Primary Scale of Intelligence-4th Edition (WPPSI-IV) is used for ages 2.5 to 6 years. Bug Search and Cancellation subtests are summed to calculate PSI. (2) Wechsler Intelligence Scales for Children-5th Edition (WISC-V) is used for ages 6 - 16 years. Symbol Search and Coding subtests are summed to calculate PSI. (3) Wechsler Adult Intelligence Scales-4th Edition (WAIS-IV) is used for ages 16 and older. Symbol Search and Coding subtests are summed to calculate PSI.

    The Pediatric Quality of Life Inventory Version 4 (PedsQL) measures health-related quality of life (QOL). Parents complete the measure for children ages 2-17, and patients > 18 complete a self-report version. Total scores range from 0-100, with higher scores representing better QOL.


  14. To Determine Number and Nature of Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort [ Time Frame: From baseline to December 2018 ]
    The number of patients with molecular subtypes of MB, CNS-PNETs/EBTs will be reported along with 95% CI.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 2 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 cm^2
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00336024


  Show 136 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Claire Mazewski, MD Children's Oncology Group

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00336024     History of Changes
Other Study ID Numbers: ACNS0334
NCI-2009-00338 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
COG-ACNS0334 ( Other Identifier: Children's Oncology Group )
U10CA098543 ( U.S. NIH Grant/Contract )
First Posted: June 12, 2006    Key Record Dates
Results First Posted: October 24, 2018
Last Update Posted: October 24, 2018
Last Verified: September 2018

Additional relevant MeSH terms:
Medulloblastoma
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Glioma
Neoplasms, Neuroepithelial
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Etoposide phosphate
Cisplatin
Cyclophosphamide
Carboplatin
Methotrexate
Etoposide
Vincristine
Thiotepa
Lenograstim
Levoleucovorin
Leucovorin
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists