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

Tracking Information
First Submitted Date ICMJE	June 8, 2006
First Posted Date ICMJE	June 12, 2006
Last Update Posted Date	November 8, 2017
Study Start Date ICMJE	August 2007
Actual Primary Completion Date	December 31, 2016 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: November 6, 2017)	Complete response (CR) 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.
Original Primary Outcome Measures ICMJE	Not Provided
Change History	Complete list of historical versions of study NCT00336024 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: November 6, 2017)	Event Free Survival (EFS) [ Time Frame: Baseline to up to 5 years ]Event Free Probability where EFS time is 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 probability and 95% confidence interval will be provided. The difference in incidence for the two treatment regimens will be compared using a one-sided log-rank test with a significance level 0.1.; 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.; Toxicity rates of any Acute Adverse Events Reported [ 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.; Toxicity rates of Acute Hearing Loss [ Time Frame: Beginning of treatment to up to 9 years ]Toxicities reported as "Impaired Hearing Loss" with grade >3 or more will be considered in this analysis. Descriptive statistics such as number and percentage between the two treatment regimens will be reported and will be compared using Fisher exact test.; Rate of chronic Primary Hypothyroidism/Subclinical Compensatory Hypothyroidism [ Time Frame: Beginning of treatment to up to 9 years ]Primary Hypothyroidism or Subclinical Compensatory Hypothyroidism is defined as patients with Free T4 level < Normal or equal to Normal with TSH level > Normal. As numbers are too small, descriptive statistics such as number and percentage will be reported for this analysis.; Rate of chronic Central Hypothyroidism [ Time Frame: Beginning of treatment to up to 9 years ]Central Hypothyroidism is defined as Free T4 level < Normal with TSH < Normal or equal to Normal. As numbers are too small, descriptive statistics such as number and percentage will be reported for this analysis.; Rate of 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 and percentage will be reported for this analysis.; Rate of 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.; 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.; Rates of 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.; Rates of gastrointestinal toxicities [ Time Frame: In each 21 day cycle ]Rates of gastrointestinal toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number and percentage of patients). The difference in percentage of patients with gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.; Rates of nutritional toxicities [ Time Frame: In each 21 day cycle ]Rates of nutritional toxicities reported as Adverse Events during therapy for each cycle will be summarized using standard descriptive methods (such as number and percentage of patients). The difference in percentage of patients with nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.; Quality of life and neuropsychological (NP) scores as assessed by the Children Oncology Group (COG) Standard Neuropsychological and Behavioral Battery [ Time Frame: From baseline to up to 9 years ]Parent-report questionnaires will be completed to gather information about the patient's function, specifically in terms of attention, memory, executive abilities, and behavioral/social/emotional adaptation. Long-term effects of treatment on neuropsychological and quality of life outcomes will be primarily descriptive. Correlational analyses will be conducted, with Pearson product moment correlations computed for continuous data and chi-square analyses conducted for discrete data. COG administration denied participation in planned neuropsychological data collection at initiation of study until study accrual 3/4 over and unable to accomplish effectively at that point. So standardized neuropsychological data or QOL data not available for analysis.; To determine number and nature of molecular sub-types of MB, CNS-PNETs/EBTs represented in the ACNS0334 cohort [ Time Frame: At baseline ]The number of patients with molecular subtypes of MB, CNS-PNETs/EBTs will be reported along with 95% CI. No data available for analysis at this time-point.
Original Secondary Outcome Measures ICMJE	Not Provided
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma
Official Title ICMJE	A Phase III Randomized Trial for the Treatment of Newly Diagnosed Supratentorial PNET and High Risk Medulloblastoma in Children &lt;36 Months Old With Intensive Induction Chemotherapy With Methotrexate Followed by Consolidation With Stem Cell Rescue Versus the Same Therapy Without Methotrexate
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.
Detailed Description	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.
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Untreated Childhood Medulloblastoma; Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor
Intervention ICMJE	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
Study Arms	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. Interventions: Drug: etoposide Drug: cyclophosphamide Drug: cisplatin Biological: filgrastim Drug: carboplatin Drug: thiotepa Drug: vincristine sulfate Procedure: autologous hematopoietic stem cell transplantation Other: laboratory biomarker analysis Procedure: 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. Interventions: 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
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Estimated Enrollment ICMJE; (submitted: November 8, 2006)	96
Original Enrollment ICMJE	Not Provided
Actual Study Completion Date	December 31, 2016
Actual Primary Completion Date	December 31, 2016 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	up to 2 Years (Child)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Australia, Canada, Puerto Rico, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00336024
Other Study ID Numbers ICMJE	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 )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Children's Oncology Group
Study Sponsor ICMJE	Children's Oncology Group
Collaborators ICMJE	National Cancer Institute (NCI)
Investigators ICMJE	Principal Investigator: Claire Mazewski, MD Children's Oncology Group
PRS Account	Children's Oncology Group
Verification Date	February 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP