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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00336024




Registration number
NCT00336024
Ethics application status
Date submitted
8/06/2006
Date registered
12/06/2006
Date last updated
12/05/2020

Titles & IDs
Public title
Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma
Scientific 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
Secondary ID [1] 0 0
NCI-2009-00338
Secondary ID [2] 0 0
ACNS0334
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Untreated Childhood Medulloblastoma 0 0
Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor 0 0
Condition category
Condition code
Cancer 0 0 0 0
Children's - Brain
Cancer 0 0 0 0
Brain
Cancer 0 0 0 0
Children's - Other
Cancer 0 0 0 0
Sarcoma (also see 'Bone') - soft tissue
Cancer 0 0 0 0
Neuroendocrine tumour (NET)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - etoposide
Treatment: Drugs - cyclophosphamide
Treatment: Drugs - cisplatin
Other interventions - filgrastim
Treatment: Drugs - carboplatin
Treatment: Drugs - thiotepa
Treatment: Drugs - methotrexate
Treatment: Drugs - leucovorin calcium
Treatment: Drugs - vincristine sulfate
Treatment: Surgery - autologous hematopoietic stem cell transplantation
Other interventions - laboratory biomarker analysis
Treatment: Surgery - quality-of-life assessment

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 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

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 5 and continuing until blood counts recover. Patients also receive autologous PBSC IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.


Treatment: Drugs: etoposide
Given IV

Treatment: Drugs: cyclophosphamide
Given IV

Treatment: Drugs: cisplatin
Given IV

Other interventions: filgrastim
Given IV or SC

Treatment: Drugs: carboplatin
Given IV

Treatment: Drugs: thiotepa
Given IV

Treatment: Drugs: methotrexate
Given IV

Treatment: Drugs: leucovorin calcium
Given IV or orally

Treatment: Drugs: vincristine sulfate
Given IV

Treatment: Surgery: autologous hematopoietic stem cell transplantation
Undergo autologous PBSC rescue

Other interventions: laboratory biomarker analysis
Correlative studies

Treatment: Surgery: quality-of-life assessment
Ancillary studies

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Intervention code [3] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate - 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.
Timepoint [1] 0 0
At the end of consolidation treatment
Secondary outcome [1] 0 0
Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort - The number of patients will be reported for this analysis by Molecular Sub-types of MB, CNS-PNETs/EBTs
Timepoint [1] 0 0
At baseline
Secondary outcome [2] 0 0
Percentage of Participants With Event Free Survival (EFS) - 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.
Timepoint [2] 0 0
Baseline to up to 5 years
Secondary outcome [3] 0 0
Patterns of Failure - The patterns of failure for relapse/disease progression will be provided for patients treated with/without methotrexate drug in three categories, namely local, distant, and both local and distant. The number of patients with each type of failure will be listed per arm. The two groups will be compared to determine if the pattern of failure distribution is different between the two arms using Fisher exact test.
Timepoint [3] 0 0
Baseline to up to 5 years
Secondary outcome [4] 0 0
Percentage of Participants With Any Acute Adverse Events - 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.
Timepoint [4] 0 0
Beginning of treatment to the end of consolidation
Secondary outcome [5] 0 0
Number of Participants With Acute Hearing Loss and No Acute Hearing Loss - 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.
Timepoint [5] 0 0
Beginning of treatment to the end of consolidation
Secondary outcome [6] 0 0
Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory HypothyroidismHypothyroidism/Subclinical Compensatory Hypothyroidism - 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.
Timepoint [6] 0 0
Off-treatment up to 9 years
Secondary outcome [7] 0 0
Number of Participants With Chronic Central Hypothyroidism - 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.
Timepoint [7] 0 0
Off-treatment up to 9 years
Secondary outcome [8] 0 0
Number of Participants With Chronic Low Somatomedin C - 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.
Timepoint [8] 0 0
Off-treatment up to 9 years
Secondary outcome [9] 0 0
Number of Participants With Chronic Diabetes Insipidus - The number of patients who had "Diabetes Insipidus" and on DDAVP will be reported for this analysis due to small numbers..
Timepoint [9] 0 0
Beginning of off-treatment to up to 9 years
Secondary outcome [10] 0 0
Number of Participants With Secondary Malignancies - The number of patients who had secondary malignancy will be reported for this analysis due to small numbers.
Timepoint [10] 0 0
Off-treatment up to 9 years
Secondary outcome [11] 0 0
Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss - 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.
Timepoint [11] 0 0
Off-treatment up to 9 years
Secondary outcome [12] 0 0
Rates of Gastrointestinal Toxicities - 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.
Timepoint [12] 0 0
Beginning of treatment to the end of consolidation
Secondary outcome [13] 0 0
Rates of Nutritional Toxicities - 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.
Timepoint [13] 0 0
Beginning of treatment to the end of consolidation
Secondary outcome [14] 0 0
Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI). - 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.
Timepoint [14] 0 0
60 months (+/- 3 months)

Eligibility
Key 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
Minimum age
No limit
Maximum age
2 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
The Children's Hospital at Westmead - Sydney
Recruitment hospital [3] 0 0
Royal Children's Hospital - Parkville
Recruitment hospital [4] 0 0
Princess Margaret Hospital for Children - Perth
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
2145 - Sydney
Recruitment postcode(s) [3] 0 0
3052 - Parkville
Recruitment postcode(s) [4] 0 0
6008 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
Arkansas
Country [4] 0 0
United States of America
State/province [4] 0 0
California
Country [5] 0 0
United States of America
State/province [5] 0 0
Colorado
Country [6] 0 0
United States of America
State/province [6] 0 0
Connecticut
Country [7] 0 0
United States of America
State/province [7] 0 0
Delaware
Country [8] 0 0
United States of America
State/province [8] 0 0
District of Columbia
Country [9] 0 0
United States of America
State/province [9] 0 0
Florida
Country [10] 0 0
United States of America
State/province [10] 0 0
Georgia
Country [11] 0 0
United States of America
State/province [11] 0 0
Hawaii
Country [12] 0 0
United States of America
State/province [12] 0 0
Idaho
Country [13] 0 0
United States of America
State/province [13] 0 0
Illinois
Country [14] 0 0
United States of America
State/province [14] 0 0
Indiana
Country [15] 0 0
United States of America
State/province [15] 0 0
Iowa
Country [16] 0 0
United States of America
State/province [16] 0 0
Kentucky
Country [17] 0 0
United States of America
State/province [17] 0 0
Louisiana
Country [18] 0 0
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Maine
Country [19] 0 0
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Maryland
Country [20] 0 0
United States of America
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Massachusetts
Country [21] 0 0
United States of America
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Michigan
Country [22] 0 0
United States of America
State/province [22] 0 0
Minnesota
Country [23] 0 0
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Mississippi
Country [24] 0 0
United States of America
State/province [24] 0 0
Missouri
Country [25] 0 0
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State/province [25] 0 0
Nevada
Country [26] 0 0
United States of America
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New Jersey
Country [27] 0 0
United States of America
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New Mexico
Country [28] 0 0
United States of America
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New York
Country [29] 0 0
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State/province [29] 0 0
North Carolina
Country [30] 0 0
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State/province [30] 0 0
Ohio
Country [31] 0 0
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Oklahoma
Country [32] 0 0
United States of America
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Oregon
Country [33] 0 0
United States of America
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Pennsylvania
Country [34] 0 0
United States of America
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South Carolina
Country [35] 0 0
United States of America
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South Dakota
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United States of America
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Tennessee
Country [37] 0 0
United States of America
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Texas
Country [38] 0 0
United States of America
State/province [38] 0 0
Utah
Country [39] 0 0
United States of America
State/province [39] 0 0
Vermont
Country [40] 0 0
United States of America
State/province [40] 0 0
Virginia
Country [41] 0 0
United States of America
State/province [41] 0 0
Washington
Country [42] 0 0
United States of America
State/province [42] 0 0
Wisconsin
Country [43] 0 0
Canada
State/province [43] 0 0
Alberta
Country [44] 0 0
Canada
State/province [44] 0 0
British Columbia
Country [45] 0 0
Canada
State/province [45] 0 0
Manitoba
Country [46] 0 0
Canada
State/province [46] 0 0
Nova Scotia
Country [47] 0 0
Canada
State/province [47] 0 0
Ontario
Country [48] 0 0
Canada
State/province [48] 0 0
Quebec
Country [49] 0 0
Puerto Rico
State/province [49] 0 0
Santurce

Funding & Sponsors
Primary sponsor type
Other
Name
Children's Oncology Group
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Cancer Institute (NCI)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This randomized phase III trial is studying two different combination chemotherapy regimens
to compare how well they work in treating young patients with newly diagnosed supratentorial
primitive neuroectodermal tumors or high-risk medulloblastoma when given before additional
intense chemotherapy followed by peripheral blood stem cell rescue. 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.
Trial website
https://clinicaltrials.gov/show/NCT00336024
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Claire Mazewski, MD
Address 0 0
Children's Oncology Group
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications