Anaplastic Medulloblastoma, Medulloblastoma, Supratentorial Embryonal Tumor, Not Otherwise Specified, Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor
Conditions
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.
Detailed description
PRIMARY OBJECTIVES: I. To determine if treatment of infants with high risk primitive neuroectodermal tumors (PNET) central nervous system (CNS) tumors with intensive chemotherapy plus high-dose methotrexate and peripheral blood stem cell rescue results in a higher complete response rate then the same regimen without methotrexate. SECONDARY OBJECTIVES: I. To determine whether biologic characterization of these tumors will refine therapeutic stratification separating atypical teratoid rhabdoid tumors (AT/RT) from primitive neuroectodermal tumors (PNETs) and possibly identifying other markers of value for stratification within the group of PNETs. II. To determine if event free survival (EFS) and patterns of failure differ between the methotrexate arm versus the arm without methotrexate. III. To compare the acute, chronic and late effects of these two very intensive regimens, especially as to the tolerance of the same consolidation regimen following the differing induction regimens. IV. To compare the gastrointestinal and nutritional toxicities of these intense regimens. V. To describe and compare the quality of life outcomes and neuropsychological effects of these intense systemic therapies. OUTLINE: Patients are randomized to 1 of 2 treatment arms INDUCTION THERAPY: ARM I: Patients receive vincristine IV over 1 minute 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 over 1 minute on days 1, 8, and 15; high-dose methotrexate IV over 4 hours on day 1; and leucovorin calcium IV or orally (PO) 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 5 and continuing until blood counts recover. Patients also receive autologous peripheral blood stem cells (PBSC) IV on day 4. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up periodically for 4 years and then annually thereafter.
Interventions
DRUGMethotrexate
Given IV
DRUGCisplatin
Given IV
DRUGCyclophosphamide
Given IV
DRUGEtoposide
Given IV
BIOLOGICALFilgrastim
Given IV or SC
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLeucovorin Calcium
Given IV or orally
PROCEDUREAutologous Hematopoietic Stem Cell Transplantation
Undergo autologous PBSC resuce
DRUGCarboplatin
Given IV
OTHERQuality-of-Life Assessment
Ancillary studies
DRUGThiotepa
Given IV
DRUGVincristine Sulfate
Given IV
Sponsors
Children's Oncology Group
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 2 Years
Healthy volunteers
No
Inclusion criteria
* High-risk medulloblastoma defined by any of the following: * \> 1.5 cm\^2 residual disease for any medulloblastoma histology, or * Lumbar cerebral spinal fluid (CSF) cytology positive for tumor cells by analysis of fluid collected either before definitive surgery or at least 10 days after definitive surgery unless contraindicated, or * Magnetic resonance imaging (MRI) evidence of M2 or M3 metastatic disease, or * M4 disease * Supratentorial primitive neuroectodermal tumor (PNET) (any M-stage) will be eligible for study entry * Children less than 8 months of age at the time of definitive surgery with or without measurable radiographic residual tumor with M0 stage medulloblastoma will be eligible for study entry * Patients with anaplastic medulloblastoma are eligible regardless of M-stage or residual tumor * Patients with M0 classic, non-desmoplastic medulloblastoma (R1) with radiographically measurable residual disease \< 1.5 cm\^2 are eligible * Cranial MRI (with and without gadolinium) must be done pre-operatively; post-operatively, cranial MRI (with and without gadolinium) must be done, preferably within 48 hours of surgery; entire spinal MRI must be obtained either pre-operatively (with gadolinium) or post-operatively (at least 10 days following surgery) prior to study enrollment (with and without gadolinium); patients with MRI evidence of spinal disease are eligible for this study * Evaluation of lumbar CSF cytology (cytospin preparation for microscopic evaluation) must be performed either pre-operatively or at least 10 days after definitive surgery unless contraindicated * Patient must have a life expectancy \> 8 weeks * Patient must have received no prior radiation therapy or chemotherapy other than corticosteroids; corticosteroids are allowable for all patients * Creatinine clearance or radioisotope glomerular filtration rate \>= 60 mL/min * Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age, and * Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamic pyruvic transaminase (SGPT) (alanine transaminase \[ALT\]) \< 2 x ULN for age * Shortening fraction \>= 27% by echocardiogram, or * Ejection fraction \>= 47% by radionuclide angiogram * No evidence of dyspnea at rest * Pulse oximetry \> 94% on room air * Peripheral absolute neutrophil count (ANC) \> 1,000/uL * Platelet count \> 100,000/uL (transfusion independent) * Hemoglobin greater than 8 g/dL (may have received red blood cell \[RBC\] transfusions allowed) * Hold trimethoprim/sulfamethoxazole (Bactrim) on the day of high-dose methotrexate (HDMTX) infusion and continue to hold until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M) * Avoid probenecid, penicillins, cephalosporins, aspirin, proton pump inhibitors and nonsteroidal anti-inflammatory drug (NSAIDS) on the day of methotrexate and continue until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M) as renal excretion of methotrexate is inhibited by these agents * Avoid IV contrast media, urinary acidifiers, phenytoin, and fosphenytoin on the day of methotrexate and until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M) * Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and carbamazepine) should be avoided * Clinically significant drug interactions have been reported when using vincristine with strong cytochrome P450 (CYP450) family 3 subfamily A member 4 (3A4) inhibitors and inducers; selected strong inhibitors of 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate | At the end of consolidation treatment | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | At baseline | The number of patients will be reported for this analysis by Molecular Sub-types of MB, CNS-PNETs/EBTs |
| Percentage of Participants With Event Free Survival (EFS) | 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 80% 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. |
| Patterns of Failure | Baseline to up to 5 years | 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. |
| Percentage of Participants With Any Acute Adverse Events | Beginning of treatment to the end of consolidation | 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. |
| Number of Participants With Acute Hearing Loss and No Acute Hearing Loss | Beginning of treatment to the end of consolidation | 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. |
| Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory HypothyroidismHypothyroidism/Subclinical Compensatory Hypothyroidism | Off-treatment 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. |
| Number of Participants With Chronic Central Hypothyroidism | Off-treatment 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. |
| Number of Participants With Chronic Low Somatomedin C | Off-treatment 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. |
| Number of Participants With Chronic Diabetes Insipidus | Beginning of off-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.. |
| Number of Participants With Secondary Malignancies | Off-treatment up to 9 years | The number of patients who had secondary malignancy will be reported for this analysis due to small numbers. |
| Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss | Off-treatment 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 | Beginning of treatment to the end of consolidation | 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. |
| Rates of Nutritional Toxicities | Beginning of treatment to the end of consolidation | 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. |
| Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI). | 60 months (+/- 3 months) | 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. |
Countries
Australia, Canada, Puerto Rico, United States
Contacts
PRINCIPAL_INVESTIGATORClaire M Mazewski
Children's Oncology Group
Participant flow
Recruitment details
Children less than 36 months with high risk medulloblastoma/PNET were enrolled in the study. The first eligible patient was enrolled on October 22, 2007 and the last patient was enrolled on April 23, 2014.
Pre-assignment details
This is a Phase 3 randomized trial designed to determine whether or not the addition of high dose Methotrexate will achieve a higher complete response rate.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) 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. | 39 |
| Arm II (Patients Treated With MTX) 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. | 38 |
| Total | 77 |
Baseline characteristics
| Characteristic | Arm II (Patients Treated With MTX) | Total | Arm I (Patients Treated Without Methotrexate (MTX)) |
|---|---|---|---|
| Age, Continuous | 1.73 years STANDARD_DEVIATION 0.87 | 1.85 years STANDARD_DEVIATION 0.82 | 1.97 years STANDARD_DEVIATION 0.75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 15 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 59 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) White | 30 Participants | 60 Participants | 30 Participants |
| Sex: Female, Male Female | 18 Participants | 38 Participants | 20 Participants |
| Sex: Female, Male Male | 20 Participants | 39 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 18 / 39 | 15 / 38 |
| other Total, other adverse events | 39 / 39 | 36 / 38 |
| serious Total, serious adverse events | 8 / 39 | 3 / 38 |
Outcome results
Primary
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.
Time frame: At the end of consolidation treatment
Population: Per protocol, only evaluable patients are included.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate | Complete response | 13 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate | No Complete response | 16 Participants |
| Arm II (Patients Treated With MTX) | Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate | Complete response | 15 Participants |
| Arm II (Patients Treated With MTX) | Number of Patients Who Have Either a Complete Response (CR) Rate or No Complete Response Rate | No Complete response | 15 Participants |
Comparison: The CR rates between these two groups will be compared at a significance level of 0.1 using one-sided Chi-square test.p-value: 0.35Chi-squared
Secondary
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.
Time frame: 60 months (+/- 3 months)
Population: Of the 77 eligible participants in ACNS0334, only 4 patients completed assessments in ALTE07C1 study. The targeted number of participants to achieve target power and statistically reliable results was not achieved and therefore the data is statistically uninterpretable.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI). | Total Quality of Life Score | 60.5 scores on a scale |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI). | Intelligence Quotient | 77.0 scores on a scale |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI). | Processing Speed Index | 82.0 scores on a scale |
| Arm II (Patients Treated With MTX) | Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI). | Total Quality of Life Score | 56.5 scores on a scale |
| Arm II (Patients Treated With MTX) | Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI). | Intelligence Quotient | 78.5 scores on a scale |
| Arm II (Patients Treated With MTX) | Median/Range of Patients for Total Quality of Life (QOL) Score, Intelligence Quotient (IQ) and Processing Speed Index (PSI). | Processing Speed Index | 89.0 scores on a scale |
Secondary
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.
Time frame: Beginning of treatment to the end of consolidation
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Acute Hearing Loss and No Acute Hearing Loss | Acute Hearing Loss | 7 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Acute Hearing Loss and No Acute Hearing Loss | No Acute Hearing Loss | 32 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Acute Hearing Loss and No Acute Hearing Loss | Acute Hearing Loss | 6 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Acute Hearing Loss and No Acute Hearing Loss | No Acute Hearing Loss | 32 Participants |
Comparison: The rate of acute hearing loss between two treatment regimens will be be compared using Fisher exact test.p-value: 1Fisher Exact
Secondary
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.
Time frame: Off-treatment up to 9 years
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Chronic Central Hypothyroidism | 1 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Chronic Central Hypothyroidism | 1 Participants |
Secondary
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..
Time frame: Beginning of off-treatment to up to 9 years
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Chronic Diabetes Insipidus | 1 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Chronic Diabetes Insipidus | 1 Participants |
Secondary
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.
Time frame: Off-treatment up to 9 years
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss | Chronic/Late Hearing Loss | 12 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss | No Chronic/Late Hearing Loss | 27 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss | Chronic/Late Hearing Loss | 13 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Chronic/Late Hearing Loss and No Chronic/Late Hearing Loss | No Chronic/Late Hearing Loss | 25 Participants |
Comparison: The rate of chronic hearing loss between two treatment regimens will be be compared using Fisher exact test.p-value: 0.8Fisher Exact
Secondary
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.
Time frame: Off-treatment up to 9 years
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Chronic Low Somatomedin C | 2 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Chronic Low Somatomedin C | 5 Participants |
Secondary
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.
Time frame: Off-treatment up to 9 years
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory HypothyroidismHypothyroidism/Subclinical Compensatory Hypothyroidism | 3 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Chronic Primary Hypothyroidism/Subclinical Compensatory HypothyroidismHypothyroidism/Subclinical Compensatory Hypothyroidism | 5 Participants |
Secondary
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
Time frame: At baseline
Population: 12 patients without molecular data, because of lack of sufficient materials or poor quality of the data, were not included in this analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Pineoblastoma | 3 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | High-grade glioma | 1 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Medulloblastoma, sonic hedgehog subgroup | 5 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Medulloblastoma, group 3 subgroup | 15 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Medulloblastoma, group 4 subgroup | 0 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Embryonal tumor with multilayered rosettes | 9 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Atypical teratoid/rhabdoid tumor | 1 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Pleomorphic xanthoastrocytoma | 0 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | High-grade glioma | 0 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Embryonal tumor with multilayered rosettes | 5 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Pineoblastoma | 7 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Medulloblastoma, sonic hedgehog subgroup | 6 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Pleomorphic xanthoastrocytoma | 1 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Medulloblastoma, group 3 subgroup | 10 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Atypical teratoid/rhabdoid tumor | 0 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Molecular Sub-types of MB, CNS-PNETs/EBTs Represented in the ACNS0334 Cohort | Medulloblastoma, group 4 subgroup | 2 Participants |
Secondary
Number of Participants With Secondary Malignancies
The number of patients who had secondary malignancy will be reported for this analysis due to small numbers.
Time frame: Off-treatment up to 9 years
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Number of Participants With Secondary Malignancies | 1 Participants |
| Arm II (Patients Treated With MTX) | Number of Participants With Secondary Malignancies | 0 Participants |
Secondary
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.
Time frame: Baseline to up to 5 years
Population: All Eligible Participants who relapsed/disease progressed in the study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Patterns of Failure | Local | 7 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Patterns of Failure | Distant | 8 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Patterns of Failure | Both Local and Distant | 5 Participants |
| Arm II (Patients Treated With MTX) | Patterns of Failure | Local | 6 Participants |
| Arm II (Patients Treated With MTX) | Patterns of Failure | Distant | 7 Participants |
| Arm II (Patients Treated With MTX) | Patterns of Failure | Both Local and Distant | 3 Participants |
Comparison: The two groups will be compared for patterns of failure to detect a statistically significant difference using Fisher exact test.p-value: 1Fisher Exact
Secondary
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.
Time frame: Beginning of treatment to the end of consolidation
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Percentage of Participants With Any Acute Adverse Events | 97.4 percentage of participants |
| Arm II (Patients Treated With MTX) | Percentage of Participants With Any Acute Adverse Events | 97.2 percentage of participants |
Comparison: Difference in incidence for the two treatment regimens will be compared using log-rank test.p-value: 0.74Log Rank
Secondary
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.
Time frame: Baseline to up to 5 years
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Percentage of Participants With Event Free Survival (EFS) | 43.6 percentage of participants with EFS |
| Arm II (Patients Treated With MTX) | Percentage of Participants With Event Free Survival (EFS) | 54.9 percentage of participants with EFS |
Comparison: 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.p-value: 0.2Log Rank
Secondary
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.
Time frame: Beginning of treatment to the end of consolidation
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | GI Tox Induction Cycle I | 8 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | No GI Tox Induction Cycle I | 31 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | GI Tox Induction Cycle II | 4 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | No GI Tox Induction Cycle II | 35 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | GI Tox Induction Cycle III | 4 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | No GI Tox Induction Cycle III | 35 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | GI Tox Consolidation Cycle I | 11 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | No GI Tox Consolidation Cycle I | 28 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | GI Tox Consolidation Cycle II | 7 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | No GI Tox Consolidation Phase II | 32 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | GI Tox Consolidation Cycle III | 5 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Gastrointestinal Toxicities | No GI Tox Consolidation Cycle III | 34 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | GI Tox Consolidation Cycle III | 6 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | GI Tox Induction Cycle I | 12 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | GI Tox Consolidation Cycle I | 14 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | No GI Tox Induction Cycle I | 26 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | No GI Tox Consolidation Phase II | 28 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | GI Tox Induction Cycle II | 10 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | No GI Tox Consolidation Cycle I | 24 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | No GI Tox Induction Cycle II | 28 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | No GI Tox Consolidation Cycle III | 32 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | GI Tox Induction Cycle III | 8 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | GI Tox Consolidation Cycle II | 10 Participants |
| Arm II (Patients Treated With MTX) | Rates of Gastrointestinal Toxicities | No GI Tox Induction Cycle III | 30 Participants |
Comparison: Rates of gastrointestinal toxicities in Induction Phase I. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.27Chi-squared
Comparison: Rates of gastrointestinal toxicities in Induction Phase II. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.07Chi-squared
Comparison: Rates of gastrointestinal toxicities in Induction Phase III. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.2Chi-squared
Comparison: Rates of gastrointestinal toxicities in Consolidation Phase 1. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.4Chi-squared
Comparison: Rates of gastrointestinal toxicities in Consolidation Phase 2. The difference in the number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.38Chi-squared
Comparison: Rates of gastrointestinal toxicities in Consolidation Phase III. The difference in number of patients with/without gastrointestinal toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.7Chi-squared
Secondary
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.
Time frame: Beginning of treatment to the end of consolidation
Population: Per protocol all eligible patients randomized to treatment should be included in the analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | No Nutritional Disorders Induction Cycle I | 29 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | No Nutritional Disorders Induction Cycle II | 26 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | No Nutritional Disorders Consolidation Cycle I | 27 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | Nutritional Disorders Induction Cycle I | 10 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | Nutritional Disorders Consolidation Cycle II | 9 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | Nutritional Disorders Induction Cycle III | 7 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | No Nutritional Disorders Consolidation Cycle II | 30 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | Nutritional Disorders Induction Cycle II | 13 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | Nutritional Disorders Consolidation Cycle III | 10 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | No Nutritional Disorders Induction Cycle III | 32 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | No Nutritional Disorders Consolidation Cycle III | 29 Participants |
| Arm I (Patients Treated Without Methotrexate (MTX)) | Rates of Nutritional Toxicities | Nutritional Disorders Consolidation Cycle I | 12 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | No Nutritional Disorders Consolidation Cycle III | 33 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | Nutritional Disorders Induction Cycle I | 17 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | No Nutritional Disorders Induction Cycle I | 21 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | Nutritional Disorders Induction Cycle II | 13 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | No Nutritional Disorders Induction Cycle II | 25 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | Nutritional Disorders Induction Cycle III | 12 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | No Nutritional Disorders Induction Cycle III | 26 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | Nutritional Disorders Consolidation Cycle I | 8 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | No Nutritional Disorders Consolidation Cycle I | 30 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | Nutritional Disorders Consolidation Cycle II | 5 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | No Nutritional Disorders Consolidation Cycle II | 33 Participants |
| Arm II (Patients Treated With MTX) | Rates of Nutritional Toxicities | Nutritional Disorders Consolidation Cycle III | 5 Participants |
Comparison: Rates of nutritional toxicities in Induction Phase I. The difference in number of patients with/without nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.08Chi-squared
Comparison: Rates of nutritional toxicities in Induction Phase II. The difference in number of patients with/without nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.9Chi-squared
Comparison: Rates of nutritional toxicities in Induction Phase III. The difference in number of patients with/without nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.17Chi-squared
Comparison: Rates of nutritional toxicities in Consolidation Phase I. The difference in number of patients with/without nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.3Chi-squared
Comparison: Rates of nutritional toxicities in Consolidation Phase II. The difference in number of patients with/without nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.26Chi-squared
Comparison: Rates of nutritional toxicities in Consolidation Phase III. The difference in number of patients with/without nutritional toxicities between the two treatment regimens will be compared using a Chi-square test.p-value: 0.17Chi-squared