Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations

B Acute Lymphoblastic Leukemia Clinical Trial

Official title:

A Phase III Randomized Trial for Newly Diagnosed High Risk B-Lymphoblastic Leukemia (B-ALL) Including a Stratum Evaluating Dasatinib (NSC#732517) in Patients With Ph-like Tyrosine Kinase Inhibitor (TKI) Sensitive Mutations

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02883049
• Other study ID #: NCI-2011-03797
• Secondary ID: NCI-2011-03797S1
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: February 29, 2012
• Est. completion date: September 22, 2024

Study information

• Verified date: February 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial studies how well combination chemotherapy works in treating young patients with newly diagnosed B acute lymphoblastic leukemia that is likely to come back or spread, and in patients with Philadelphia chromosome (Ph)-like tyrosine kinase inhibitor (TKI) sensitive mutations. Chemotherapy drugs, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) and giving the drugs in different doses and in different combinations may kill more cancer cells.

Description:

PRIMARY OBJECTIVES: I. To determine if the administration of post-Induction age-adjusted intrathecal triple therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance high-dose methotrexate (IMHDM) backbone will improve 5-year disease-free survival (DFS) of children with high-risk (HR) B-acute lymphoblastic leukemia (ALL) compared to age-adjusted intrathecal (IT) methotrexate (MTX). (Completed effective March 19, 2018) II. To determine, in a randomized fashion, if the cyclophosphamide + etoposide containing regimen (Experimental Arm 1) will improve the 4-year DFS of children, adolescents, and young adults with very high-risk (VHR) B-ALL compared to a modified MBFM-IMHDM regimen that contains a second IM (Control Arm). (Completed effective February 15, 2017) SECONDARY OBJECTIVES: I. To determine the toxicity and tolerability of post-Induction age-adjusted ITT compared to age-adjusted IT MTX in children with HR B-ALL. (Completed effective March 19, 2018) II. To determine the toxicity and tolerability of Experimental Arm 1 compared to the Control Arm in children, adolescents, and young adults with VHR B-ALL. (Completed effective February 15, 2017) III. To determine whether a single-arm, modified Induction with limited anthracycline exposure and post-Induction therapy regimen with MBFM-interim maintenance intermediate dose methotrexate (IMIDM) and reduced vincristine (vincristine sulfate)/steroid pulse frequency and enhanced supportive care in children with Down syndrome (DS) and HR B-ALL will result in a >= 65% 5-year DFS and < 10% Induction mortality. IV. To describe the outcomes for children and young adults with Philadelphia chromosome (Ph)-like B-ALL and a predicted TKI-sensitive mutation treated with dasatinib plus MBFM-IMHDM. V. To determine the toxicity and tolerability of MBFM-IMIDM in children with DS and HR B-ALL. VI. To estimate overall survival (OS) rates both overall and by regimen a) for HR B-ALL and b) VHR B-ALL patients. VII. To determine the incidence of osteonecrosis (ON), defined by magnetic resonance (MR) imaging, and to characterize the natural history of clinically silent ON in children, adolescents, and young adults 10 years of age and greater and to assess the role of drugs (i.e., asparaginase and methotrexate) in addition to corticosteroids, in the risk for development of ON. (Completed accrual July 2016) VIII. To determine if the prevalence of cognitive deficits measured by CogState, in children (ages 6 to < 13 years) with HR- and VHR B-ALL at 1 year off therapy, is significantly higher than the normative population (> 14%) in the following domains: working memory, executive function, visual motor, processing speed, and visual attention. EXPLORATORY OBJECTIVE: I. To determine if the reduction of minimal residual disease (MRD) from end-Induction to end-Consolidation is greater for children, adolescents, and young adults with VHR B-ALL receiving Experimental Arm 1 compared to the Control Arm. (Closed effective October 20, 2017) OUTLINE: INDUCTION THERAPY: Patients without Down syndrome receive induction chemotherapy comprising cytarabine intrathecally (IT) on day 1 (and twice weekly thereafter for CNS2 patients [except for days 8 and 29]); vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, and 22; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22; dexamethasone orally (PO) or IV twice daily (BID) on days 1-14 (patients under 10 years old) or prednisone PO or IV BID on days 1-28 (patients at least 10 years old); pegaspargase IV over 1-2 hours on day 4; and methotrexate IT on days 8 and 29 for CNS1 and CNS2 patients (plus days 15 and 22 for CNS3 patients). Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. Participants are stratified to 1 of 3 disease groups: HR B-ALL, VHR B-ALL and PH-like B-ALL a predicted TKI-sensitive mutation. GROUP I - HR B-ALL: Patients are randomized to 1 of 2 treatment arms. (RANDOMIZATION CLOSED 03/19/2018) CONSOLIDATION THERAPY (C): ARM A HR B-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO once daily (QD) on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22; vincristine sulfate IV over 1 minute on days 15, 22, 43, and 50; and pegaspargase IV over 1-2 hours on days 15 and 43. Patients with continuing clinical evidence of testicular leukemia undergo radiotherapy (RT) QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. ARM B HR B-ALL C: Patients receive consolidation therapy as in Arm I HR B-ALL C. Patients also receive ITT comprising methotrexate, hydrocortisone sodium succinate, and cytarabine on days 1, 8, 15, and 22. Patients with testicular leukemia also undergo RT as in Arm I HR B-ALL C. (CLOSED 03/19/2018) INTERIM MAINTENANCE THERAPY (IM) ARM A HR B-ALL IM: Patients receive IM therapy comprising vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; methotrexate IT on days 1 and 29; and mercaptopurine PO on days 1-56. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. ARM B HR B-ALL IM: Patients receive ITT on days 1 and 29 and IM therapy as in Arm I HR-ALL IM. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. (CLOSED 03/19/2018) DELAYED INTENSIFICATION THERAPY (DI): ARM A HR B-ALL DI: Patients receive DI therapy comprising vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on days 1, 29, and 36; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO QD on days 29-42. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. ARM B HR B-ALL DI: Patients receive ITT on days 1, 29, and 36 and DI therapy as in Arm I HR B-ALL DI. (CLOSED 03/19/2018) MAINTENANCE THERAPY (M): ARM A HR B-ALL M: Patients receive maintenance therapy comprising vincristine sulfate IV over 1 minute on days 1, 29, and 57; methotrexate IT on day 1 (also day 29 of courses 1-4); prednisone PO BID on days 1-5, 29-33 (may receive methylprednisolone IV if PO is not tolerated), and 57-61; mercaptopurine PO QD on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. ARM B HR B-ALL M: Patients receive ITT on day 1 (also day 29 of courses 1-4) and maintenance therapy as in Arm I HR B-ALL M. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. (CLOSED 03/19/2018) GROUP II: VHR B-ALL: Patients are randomized to 1 of 3 treatment arms. (RANDOMIZATION CLOSED 02/15/2017) CONSOLIDATION THERAPY PART I: In all arms, patients receive cyclophosphamide IV over 30-60 minutes on day 1; cytarabine IV over 1-30 minutes or SC on days 1-4 and 8-11; mercaptopurine PO QD on days 1-14; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 patients); vincristine sulfate IV over 1 minute on days 15 and 22; and pegaspargase IV over 1-2 hours on day 15. Patients with continuing clinical evidence of testicular leukemia undergo RT QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY PART II: ARM A VHR B-ALL C (CONTROL ARM): Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; mercaptopurine PO QD on days 29-42; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. ARM B VHR B-ALL C (EXPERIMENTAL ARM 1): Patients receive consolidation therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 60-120 minutes on days 29-33; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED 02/15/2017) ARM C VHR B-ALL C (EXPERIMENTAL ARM 2): Patients receive clofarabine IV over 2 hours on days 29-33 and consolidation therapy as in Arm B VHR B-ALL C. (CLOSED 9/12/2014) INTERIM MAINTENANCE THERAPY PART I: In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION THERAPY PART I: In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on day 1; and pegaspargase IV over 1-2 hours on day 4. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION THERAPY PART II: ARM A VHR B-ALL DI (CONTROL ARM): Patients receive DI therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; thioguanine PO QD on days 29-42; methotrexate IT on days 29 and 36; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. ARM B VHR B-ALL DI (EXPERIMENTAL ARM 1): Patients receive DI therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 60-120 minutes on days 29-33; methotrexate IT on days 29 and 36; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED 02/15/2017) ARM C VHR B-ALL DI (EXPERIMENTAL ARM 2): Patients receive clofarabine IV over 2 hours on days 29-33 and DI therapy as in Arm II B VHR B-ALL DI. (Closed as of 9/12/2014) INTERIM MAINTENANCE THERAPY PART II: In all arms, patients receive vincristine sulfate IV over 1 minute and methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. MAINENTANCE THERAPY: Patients with CNS3 disease at diagnosis undergo RT QD over 4 weeks (10 fractions total). In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61 (may receive methylprednisolone IV if PO is not tolerated); methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (except on methotrexate IT days); mercaptopurine PO QD on days 1-84; methotrexate IT on day 1 (also day 29 of courses 1 and 2 for CNS patients who did not undergo RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities. GROUP III: PH-LIKE PREDICTED TKI-SENSITIVE KINASE MUTATION: CONSOLIDATION THERAPY: Patients receive dasatinib PO QD on days 1-56, cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32 and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15 and 22 (days 1 and 8 only for CNS3 patients), vincristine sulfate IV over 1 minute on days 15, 22, 43 and 50, and pegaspargase IV over 1-2 hours on days 15 and 43. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. INTERIM MAINTENANCE THERAPY I: Patients receive dasatinib PO QD on days 1-63, vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46, methotrexate IT on days 1 and 29, and mercaptopurine PO on days 1-56. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION THERAPY: Patients receive dasatinib PO QD on days 1-56, vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50, dexamethasone PO or IV on days 1-7 and 15-21, doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8 and 15, methotrexate IT on days 1, 29 and 36, pegaspargase IV over 1-2 hours on days 4 and 43, cyclophosphamide IV over 30-60 minutes day 29, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, and thioguanine PO on days 29-42. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. INTERIM MAINTENANCE THERAPY II: Patients dasatinib PO QD on days 1-56, vincristine sulfate IV over 1 minute days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31 and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours days 2 and 22. MAINTENANCE THERAPY: Patients receive dasatinib PO QD on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29 and 57, prednisone PO BID or IV on days 1-5, 29-33 and 57-61, methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 (omit on days when MTX [IT] is given), mercaptopurine PO on days 1-84, methotrexate IT on day 1 (also day 29 of course 1 and 2, for patients who did not receive CNS radiation). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities. Participants with Down syndrome are assigned to DS HR B-ALL: INDUCTION THERAPY: All patients receive cytarabine IT on day 1; vincristine sulfate IV over 1 minute on days 1 and 8, dexamethasone PO or IV BID (patients under 10 years old) or prednisone PO BID (patients at least 10 years old) on days 1-14 (may receive methylprednisolone IV if PO is not tolerated), pegaspargase IV over 1-2 hours on day 4; methotrexate IT on day 8; and leucovorin calcium PO on days 10-11. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. RAPID EARLY RESPONDERS (RER): Patients receive induction therapy comprising vincristine sulfate IV over 1 minute on days 15 and 22; dexamethasone PO BID (patients under 10 years old) or prednisone PO BID (patients at least 10 years old) on days 15-28; methotrexate IT on day 29 (also days 15 and 22 for CNS3 patients); and leucovorin calcium PO on days 31-32 (also days 17-18 and 24-25 for CNS3 patients). Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. SLOW EARLY RESPONDERS (SER): Patients receive daunorubicin hydrochloride IV over 1-15 minutes on day 15 and Induction therapy as RER patients. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: All patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO QD on days 1-14 and 29-42; vincristine sulfate IV over 1 minute on days 15, 22, 43, and 50; pegaspargase IV over 1-2 hours on days 15 and 43; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 patients); and leucovorin calcium PO on days 3-4, 10-11, 17-18, and 24-25. Patients with continuing clinical evidence of testicular leukemia undergo RT QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. INTERIM MAINTENANCE THERAPY: Patients receive vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 2-3, 17-18, 31-32, and 45-46; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION THERAPY: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO BID or IV on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO QD on days 29-42; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; methotrexate IT on days 1, 29, and 36; and leucovorin calcium PO on days 3-4, 31-32 and 38-39. MAINTENANCE THERAPY: Patients with CNS3 disease undergo RT QD, 5 days a week, for 2 weeks (10 fractions total). Patients receive vincristine sulfate IV over 1 minute on day 1; prednisone PO BID or IV on days 1-5 (may receive methylprednisolone IV if PO not tolerated); methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO QD on days 1-84; and methotrexate IT on day 1 (also day 29 of courses 1-4 for CNS3 patients who did not undergo RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities. After completion of study treatment, patients are followed up periodically for 10 years.

Other known NCT identifiers

• NCT01406756

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 5949
• Est. completion date: September 22, 2024
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 31 Years

Eligibility

Inclusion Criteria:

• Patients must be enrolled on APEC14B1 and consented to Eligibility Screening on the Part A consent form prior to enrollment on AALL1131
• White Blood Cell Count (WBC) Criteria
• Age 1-9.99 years: WBC >= 50 000/uL
• Age 10-30.99 years: Any WBC
• Age 1-30.99 years: Any WBC with:
• Testicular leukemia
• CNS leukemia (CNS3)
• Steroid pretreatment
• Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health Organization [WHO] classification) (also termed B-precursor acute lymphoblastic leukemia); patients with Down syndrome are also eligible
• Organ function requirements for patients with Ph-like ALL and a predicted TKI-sensitive mutation: patients identified as Ph-like with a TKI-sensitive kinase mutation must have assessment of organ function performed within 3 days of study entry onto the dasatinib arm of AALL1131
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70mL/min/1.73

m^2 or a serum creatinine based on age/gender as follows:

• Age: Maximum Serum Creatinine (mg/dL)
• 1 to < 6 months: 0.4 (male) 0.4 (female)
• 6 months to < 1 year: 0.5 (male) 0.5 (female)
• 1 to < 2 years: 0.6 (male) 0.6 (female)
• 2 < 6 years: 0.8 (male) 0.8 (female)
• 6 to < 10 years: 1.0 (male) 1.0 (female)
• 10 to < 13 years: 1.2 (male) 1.2 (female)
• 13 to < 16 years: 1.5 (male) 1.4 (female)
• > 16 years: 1.7 (male) 1.4 (female)
• Direct bilirubin =< 3 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 10 x upper limit of normal (ULN) for age
• Shortening fraction >= 27% by echocardiogram, or ejection fraction >= 50% by gated radionuclide study
• Patients must have an electrocardiogram (EKG) fewer than 6 days prior to enrollment on the dasatinib arm; patients who have had cardiac assessments by echocardiogram or radionuclide scan at the beginning of induction do not need to have these repeated prior to study entry; correct QT interval (QTc) < 450 msec on baseline electrocardiogram as measured by the Friderica or Bazett formula
• No major conduction abnormality (unless a cardiac pacemaker is present)
• No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% at sea level if there is clinical indication for determination
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled; however, drugs that induce CYP3A4/5 (carbamazepine, oxcarbazepine, phenytoin, primidone, phenobarbital) should be avoided
• Eligibility criteria for the Longitudinal, Computerized Assessment of Neurocognitive Functioning study
• Patients must be aged 6 to 13 years at time of B-ALL diagnosis, enrolled on AALL1131
• Patients must be English-, French- or Spanish-speaking (languages in which the assessment is available)
• Patients must have no known history of neurodevelopmental disorder prior to diagnosis of B-ALL (e.g., Down syndrome, Fragile X, William's Syndrome, mental retardation)
• Patients must have no significant visual impairment that would prevent computer use and recognition of the visual test stimuli
• Eligibility criteria for the National Cancer Institute (NCI) standard risk patients from AALL0932 enrolling on this study at the end of Induction
• Effective March 19, 2018, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the HR

B-ALL stratum of this study at the end of Induction:

• Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with day 8 peripheral blood (PB) minimal residual disease (MRD) >= 1% and day 29 bone marrow (BM) MRD < 0.01%
• With favorable cytogenetics (ETV6-RUNX1 or double trisomies 4+10), with any day 8 PB MRD and day 29 BM MRD >= 0.01%
• Both NCI standard risk (SR) and HR patients without Down syndrome and with testicular disease at diagnosis, who do not meet other VHR criteria
• Effective Amendment 6, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the VHR stratum

of AALL1131:

• Intrachromosomal amplification of chromosome 21 (iAMP21)
• Mixed-lineage leukemia (MLL) rearrangement
• Hypodiploidy (n < 44 chromosomes and/or a deoxyribonucleic acid [DNA] index < 0.81)
• Induction failure (M3 BM at day 29)
• Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with day 29 BM MRD >= 0.01%
• Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS HR

B-ALL stratum of this study at the end of Induction:

• Day 29 MRD >= 0.01%
• MLL rearrangement
• Hypodiploidy (n < 45 chromosomes and/or DNA index < 0.81)
• DS HR B-ALL patients initially enrolled on AALL0932 or this study who have Induction failure (M3 BM day 29) or Philadelphia chromosome (BCR-ABL1) will not be eligible for post-Induction therapy on either trial (AALL0932 or AALL1131)
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met

Exclusion Criteria:

• With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B-ALL or any cancer diagnosed prior to the initiation of protocol therapy on AALL1131; patients cannot have secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy; patients receiving prior steroid therapy may be eligible for AALL1131
• Patients with BCR-ABL1 fusion are not eligible for post-induction therapy on this study but may be eligible to enroll in a successor Children's Oncology Group (COG) Philadelphia positive (Ph+) ALL trial by day 15 Induction
• DS HR B-ALL patients with Induction failure or BCR-ABL1
• Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs
• Lactating females are not eligible unless they have agreed not to breastfeed their infant
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation

Related Conditions & MeSH terms

• B Acute Lymphoblastic Leukemia
• Central Nervous System Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Testicular Leukemia

Intervention

Drug:
• Clofarabine
Given IV
• Cyclophosphamide
Given IV
• Cytarabine
Given IT, IV, or SC
• Dasatinib
Given PO
• Daunorubicin Hydrochloride
Given IV
• Dexamethasone
PO or IV
• Doxorubicin Hydrochloride
Given IV
• Etoposide
Given IV
• Hydrocortisone Sodium Succinate
Given IT

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Leucovorin Calcium
Given PO or IV
• Mercaptopurine
Given PO
• Methotrexate
Given IT and IV
• Pegaspargase
Given IV
• Prednisone
Given PO or IV

Radiation:
• Radiation Therapy
Undergo radiation therapy

Drug:
• Thioguanine
Given PO
• Vincristine Sulfate
Given IV

Locations

Country	Name	City	State
Australia	Monash Medical Center-Clayton Campus	Clayton	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal Children's Hospital-Brisbane	Herston	Queensland
Australia	John Hunter Children's Hospital	Hunter Regional Mail Centre	New South Wales
Australia	Women's and Children's Hospital-Adelaide	North Adelaide	South Australia
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	Perth Children's Hospital	Perth	Western Australia
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Queensland Children's Hospital	South Brisbane	Queensland
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Children's Hospital	London	Ontario
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Ireland	Our Lady's Children's Hospital	Dublin	Co Dublin
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Starship Children's Hospital	Grafton	Auckland
Puerto Rico	San Jorge Children's Hospital	San Juan
Puerto Rico	University Pediatric Hospital	San Juan
Switzerland	Swiss Pediatric Oncology Group - Geneva	Geneva
Switzerland	Swiss Pediatric Oncology Group - Lausanne	Lausanne
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	Texas Tech University Health Sciences Center-Amarillo	Amarillo	Texas
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital	Asheville	North Carolina
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Augusta University Medical Center	Augusta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Tufts Children's Hospital	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	T C Thompson Children's Hospital	Chattanooga	Tennessee
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Columbia Regional	Columbia	Missouri
United States	Prisma Health Richland Hospital	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	El Paso Children's Hospital	El Paso	Texas
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Hurley Medical Center	Flint	Michigan
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Greenville Cancer Treatment Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Tripler Army Medical Center	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada
United States	Summerlin Hospital Medical Center	Las Vegas	Nevada
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Mattel Children's Hospital UCLA	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Palms West Radiation Therapy	Loxahatchee Groves	Florida
United States	Covenant Children's Hospital	Lubbock	Texas
United States	UMC Cancer Center / UMC Health System	Lubbock	Texas
United States	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Vannie Cook Children's Clinic	McAllen	Texas
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Banner Children's at Desert	Mesa	Arizona
United States	Miami Cancer Institute	Miami	Florida
United States	Nicklaus Children's Hospital	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	NYU Winthrop Hospital	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	USA Health Strada Patient Care Center	Mobile	Alabama
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Tulane University School of Medicine	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois
United States	Kaiser Permanente-Oakland	Oakland	California
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Orlando Health Cancer Institute	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Advocate Children's Hospital-Park Ridge	Park Ridge	Illinois
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Naval Medical Center - Portsmouth	Portsmouth	Virginia
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Carilion Children's	Roanoke	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Naval Medical Center -San Diego	San Diego	California
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Santa Barbara Cottage Hospital	Santa Barbara	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Overlook Hospital	Summit	New Jersey
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Tampa General Hospital	Tampa	Florida
United States	Scott and White Memorial Hospital	Temple	Texas
United States	Mercy Children's Hospital	Toledo	Ohio
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center	Torrance	California
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Saint Mary's Hospital	West Palm Beach	Florida
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Ireland,  New Zealand,  Puerto Rico,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The Reduction in MRD From End-Induction (EOI) to End-Consolidation (EOC) for Children, Adolescents, and Young Adults With VHR B-ALL Receiving Experimental Arms 1 Compared to the Control Arm	(Closed effective Amendment 6) Mean change in MRD from EOI to EOC will be calculated for VHR patients on Experimental Arm 1 and Control Arm.	Up to 90 days
Primary	DFS of Non-DS HR Post-induction Patients Receiving Intrathecal (IT) Methotrexate (MTX) Compared With Patients Receiving Intrathecal Triple Therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) Interim Maintenance High-dose Methotrexate Backbone	DFS time is defined as time from randomization end of induction to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. Compared using 2-sided log rank test, alpha = 5%. (Completed effective March 19, 2018)	At 5 years
Primary	DFS of Non-DS VHR Post-Induction Patients Who Receive a Modified MBFM-IMHDM Regimen That Contains a Second IM (Control Arm) Compared to Patients Receive the Cyclophosphamide + Etoposide Containing Regimen (Experimental Arm 1)	(Completed effective February 15, 2017) DFS time is defined as time from randomization end of induction to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. Compared using a 1-sided log rank test, alpha of 2.5%.	At 4 years
Secondary	Toxicity and Tolerability of Post-induction Age-adjusted ITT Compared to Age-adjusted IT MTX in Children With HR B-ALL	(Completed effective March 19, 2018) Percentage of patients who experienced Grade 3 or higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, will be estimated for each randomized arm.	Up to 10 years
Secondary	Toxicity and Tolerability of Experimental Arm 1 and Control Arm in Patients With VHR B-ALL	Percentage of patients who experienced Grade 3 or higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, will be estimated for each randomized arm. (Closed effective February 15, 2017)	Up to 10 years
Secondary	Induction Mortality in Patients With DS and HR B-ALL Treated With Modified Induction	Percentage of deaths in induction will be calculated.	At 1 month
Secondary	5-year DFS in Patients With Down Syndrome (DS) and HR B-ALL Treated With Modified Induction and Post-Induction Therapy Regimen With MBFM-IMIDM	DFS time is defined as time from end of induction to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. 5-year DFS will be estimated using the Kaplan-Meier method.	At 5 years
Secondary	DFS for Children and Young Adults With Ph-like B-ALL and a Predicted Tyrosine Kinase Inhibitor (TKI)-Sensitive Mutation Treated With Dasatinib Plus MBFM-IMHDM	DFS time is defined as time from randomization end of induction to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. 4-year DFS will be estimated using the Kaplan-Meier method.	Up to 4 years
Secondary	Toxicity and Tolerability of MBFM-interim Maintenance Intermediate Dose Methotrexate (IMIDM) in Children With Down Syndrome	Percentage of patients who experienced Grade 3 or higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, will be estimated.	Up to 10 years
Secondary	Overall Survival (OS) Rate for HR B-ALL Patients, Overall and by Randomized Arm	OS time is defined as time from enrollment to death or date of last contact for patients who are alive. 5-year OS will be estimated for the two randomized arms using the Kaplan-Meier method.	At 5 years
Secondary	Overall Survival (OS) Rate for VHR B-ALL Patients, Overall and by Randomized Arm.	OS of VHR-B-ALL post-Induction patients who receive a modified MBFM-IMHDM regimen that contains a second IM (Control Arm) compared to patients receive the cyclophosphamide + etoposide containing regimen (Experimental Arm 1). OS time is defined as time from enrollment to death or date of last contact for patients who are alive. 4-year OS will be estimated for the two randomized arms using the Kaplan-Meier method.	At 4 years
Secondary	Incidence of Osteonecrosis (ON) Defined by Magnetic Resonance (MR) Imaging in Children, Adolescents, and Young Adults 10 Years of Age and Greater	Incidence of ON among patients who have submitted MRI screening data will be estimated.	Up to 10 years
Secondary	The Prevalence of Cognitive Deficits Measured by CogState (Domain: Working Memory), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy	The percentage of patients with abnormal results (Z = -1.5) in working memory measured by CogState will be estimated.	Up to 10 years
Secondary	The Prevalence of Cognitive Deficits Measured by CogState (Domain: Executive Function), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy	The percentage of patients with abnormal results (Z = -1.5) in executive function measured by CogState will be estimated.	Up to 10 years
Secondary	The Prevalence of Cognitive Deficits Measured by CogState (Domain: Visual Learning), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy	The percentage of patients with abnormal results (Z = -1.5) in visual learning measured by CogState will be estimated.	Up to 10 years
Secondary	The Prevalence of Cognitive Deficits Measured by CogState (Domain: Processing Speed), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy	The percentage of patients with abnormal results (Z = -1.5) in processing speed measured by CogState will be estimated.	Up to 10 years
Secondary	The Prevalence of Cognitive Deficits Measured by CogState (Domain: Visual Attention), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy	The percentage of patients with abnormal results (Z = -1.5) in visual attention measured by CogState will be estimated.	Up to 10 years

External Links

•   Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.