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A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT03914625
Recruitment Status : Suspended (Other - FDA Partial Clinical Hold)
First Posted : April 16, 2019
Last Update Posted : January 12, 2023
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE April 12, 2019
First Posted Date  ICMJE April 16, 2019
Last Update Posted Date January 12, 2023
Actual Study Start Date  ICMJE June 28, 2019
Estimated Primary Completion Date September 30, 2029   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 23, 2022)
  • Disease free survival (DFS) in randomization eligible patients with higher risk features (SR-High) or standard risk average (SR-Avg) B-ALL patients based on randomization with addition of blinatumomab [ Time Frame: 5.3 years ]
    Will be assessed in SR-High patients and SR-Avg B-ALL patients who are negative for MRD by flow cytometry but have detectable or indeterminate MRD as measured by high throughput sequencing (HTS) at end of induction (EOI), and patients with double trisomy of chromosomes 4 and 10 (DT) with MRD (flow) 0.01% - < 0.1%. DFS is calculated as the time from randomization at the end of consolidation to first event (relapse, second malignancy, remission death) or censored at date of last contact. Five year DFS estimates will be calculated from the point of randomization for both groups. Two-sided 95% confidence intervals will be calculated.
  • DFS in boys in the SR-favorable subset of SR B-ALL with or without Down syndrome (DS) [ Time Frame: 5.1 years ]
    DFS is calculated as the time from end of induction to first event (relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and two-sided 80% confidence interval will be calculated.
Original Primary Outcome Measures  ICMJE
 (submitted: April 12, 2019)
  • Post-Consolidation disease free survival (DFS) with addition of 2 cycle of blinatumomab in patients with standard risk (SR) B-lymphoblastic leukemia (B-ALL) and higher risk features, and patients with standard risk average (SR-Avg) B-ALL [ Time Frame: 5 years ]
    Efficacy design and standard survival analysis methods used to detect improvement in post-Consolidation DFS due to the addition of 2 cycles of blinatumomab to standard therapy in patients with SR B-ALL and higher risk features, and patients with SR-Avg B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of induction (EOI), and patients with double trisomy of chromosomes 4 and 10 (DT) with MRD (flow) 0.01% - <0.1%.
  • DFS in boys in the SR-favorable subset of SR B-ALL [ Time Frame: 5 years ]
    Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 13, 2022)
  • DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of interim maintenance (IM)1, regardless of sex [ Time Frame: 5.1 years ]
    DFS is calculated as the time from end of induction to first event (relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and a two-sided 95% confidence interval will be calculated.
  • DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen [ Time Frame: 5.1 years ]
    DFS is calculated as the time from end of induction to first event (relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and a two-sided 95% confidence interval will be calculated.
  • Treatment-related mortality in Down syndrome high risk (DS-high) patients after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of DI) with 3 cycles of blinatumomab [ Time Frame: 2.3 years ]
    Percent of DS-high patients with treatment related mortalities will be reported with 95% confidence interval.
  • DFS of DS-High B-ALL patients when intensive elements of chemotherapy are replaced with 3 cycles of blinatumomab [ Time Frame: 5.3 years ]
    DFS is calculated as the time from the end of consolidation to first event (relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and a two-sided 80% confidence interval will be calculated.
  • DFS of patients with localized B-lymphoblastic lymphoma (B-LLy) receiving standard risk acute lymphoblastic leukemia therapy [ Time Frame: 5 years ]
    DFS is calculated as the time from study enrollment to first event (disease progression, relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and a two-sided 95% confidence interval will be calculated.
  • Change in neurocognitive functioning from baseline to end-of-therapy between children from poor (defined as presence of household material hardship [HMH], including either food, housing or energy insecurity) and non-poor families (absence of HMH) [ Time Frame: 3.3 years ]
    Neurocognitive functioning will be measured by the CogState Cognitive Composite at end of induction therapy and at follow-up one year off-therapy among patients with ALL ages 4-< 10 years at the time of diagnosis. Mean and 95% confidence interval for change scores will be reported by HMH group.
  • Caregiver burden as measured by the Mean Total score from the Care of My Child with Cancer questionnaire among a subset of children enrolled in the HMH and neurocognitive outcome study [ Time Frame: 1 year ]
    The Mean Total score from the Care of My Child with Cancer questionnaire from end of Maintenance Cycle 1. Mean scores and 95% confidence intervals will be reported by randomization group.
  • Caregiver burden as measured by the At-Work Productivity Loss summary score from the Caregiver Work Limitations questionnaire among a subset of children enrolled in the HMH and neurocognitive outcome study [ Time Frame: 1 year ]
    The Mean Total score from the Care of My Child with Cancer questionnaire from end of Maintenance Cycle 1. Mean scores and 95% confidence intervals will be reported by randomization group.
  • Peripheral blood (PB) samples using HTS MRD vs. bone marrow (BM) results at EOI [ Time Frame: 1 year ]
    Will use the Kendall's Tau-b rank correlation coefficient accounting for the left censoring inherent to sensitivity of the method. A high positive value would be strong evidence that the PB retains the relative information contained in the BM readings. An estimate and two-sided 95% Confidence interval will be calculated using banked SR-Average and SR-High samples at EOI.
  • BM using HTS MRD vs. BM by flow cytometry at EOC in patients who were Day 29 MRD positive by flow cytometry [ Time Frame: 1 year ]
    Will use the Kendall's Tau-b rank correlation coefficient accounting for the left censoring inherent to sensitivity of the methods30. A high positive value would be strong evidence that HTS of IgH loci determined-MRD from the BM at EOC retains the relative information contained in the flow-cytometry-determined readings. An estimate and 95% Confidence interval will be calculated using pairs of banked samples at EOC.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2019)
  • DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of interim maintenance (IM)1, regardless of sex [ Time Frame: 5 years ]
    Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
  • DFS for patients with standard-risk favorable (SR-Fav) B-ALL [ Time Frame: 5 years ]
    Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
  • Treatment-related mortality in Down syndrome high risk (DS-high) patients after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of DI) with 3 cycles of blinatumomab [ Time Frame: 5 years ]
  • DFS of DS-High B-ALL patients when intensive elements of chemotherapy are replaced with 3 cycles of blinatumomab [ Time Frame: 5 years ]
    Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
  • DFS of patients with localized B-lymphoblastic lymphoma receiving standard risk acute lymphoblastic leukemia therapy [ Time Frame: 5 years ]
    Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
  • Neurocognitive functioning [ Time Frame: Baseline to 2 years after IM1 ]
    Compare the change in neurocognitive functioning, as measured by the CogState Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4-< 10 years at the time of diagnosis between children from poor families (defined as presence of household material hardship (HMH), including either food, housing or energy insecurity) and non-poor families (absence of HMH).
  • Caregiver burden and patient/proxy-reported symptoms among those enrolled in HMH [ Time Frame: Baseline to 2 years after IM1 ]
    Compare the demands and work limitations on caregivers of children with ALL receiving chemotherapy versus chemotherapy with the addition of blinatumomab and to compare the change in the demands and work limitations over time, measured by the Care of My Child with Cancer questionnaire and the Caregiver Work Limitations questionnaire during post-Induction therapy. Patient/proxy reported symptoms measured by Memorial Symptom Assessment Scale.
Current Other Pre-specified Outcome Measures
 (submitted: August 21, 2020)
  • To explore adaptive and innate immune functions and host genetic factors associated with severe infectious complications in children with DS B-ALL [ Time Frame: 5 years ]
    FlowSom high resolution clustering approach to identify cellular subsets and/or activation states (endophenotypes) that distinguish cases from controls. Perform secondary analysis using the "diffCyt" framework to identify those cell clusters that differ significantly between groups.
  • Neurocognitive, functional, and quality of life outcomes in patients with DS and ALL [ Time Frame: 5 years ]
    Measured by caregiver (parent/legal guardian) using questionnaires that rate executive function, behavior, adaptive skills, and quality of life.
  • Prevalence of minimal marrow disease (MMD) in B-LLy [ Time Frame: 5 years ]
    Correlate MMD at diagnosis with outcome in patients with B-LLy.
Original Other Pre-specified Outcome Measures
 (submitted: April 12, 2019)
  • Adaptive and innate immune functions and host genetic factors associated with severe infectious complications in children with DS B-ALL [ Time Frame: 5 years ]
    FlowSom high resolution clustering approach to identify cellular subsets and/or activation states (endophenotypes) that distinguish cases from controls. Conduct a genome-wide assessment using a case-control approach comparing those who develop grade 4-5 microbiologically documented infections (cases) compared to those who do not (controls).
  • Neurocognitive, functional, and quality of life outcomes in patients with DS and ALL [ Time Frame: 5 years ]
    Measured by caregiver (parent/legal guardian) questionnaires.
  • Prevalence of minimal marrow disease (MMD) in B-LLy [ Time Frame: 5 years ]
    Correlate MMD at diagnosis with outcome in patients with B-LLy.
 
Descriptive Information
Brief Title  ICMJE A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia
Official Title  ICMJE A Phase 3 Trial Investigating Blinatumomab (NSC# 765986) in Combination With Chemotherapy in Patients With Newly Diagnosed Standard Risk or Down Syndrome B-Lymphoblastic Leukemia (B-ALL) and the Treatment of Patients With Localized B-Lymphoblastic Lymphoma (B-LLy)
Brief Summary This phase III trial studies how well blinatumomab works in combination with chemotherapy in treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as blinatumomab, may induce changes in the body's immune system and may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs, such as vincristine, dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine, mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, 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. Leucovorin decreases the toxic effects of methotrexate. Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving blinatumomab and combination chemotherapy may work better than combination chemotherapy alone in treating patients with B-ALL. This trial also assigns patients into different chemotherapy treatment regimens based on risk (the chance of cancer returning after treatment). Treating patients with chemotherapy based on risk may help doctors decide which patients can best benefit from which chemotherapy treatment regimens.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine in a randomized manner if the addition of 2 cycles of blinatumomab to standard therapy improves disease-free survival (DFS) in patients with standard risk (SR) B-ALL and higher risk features (SR-High), and patients with standard-risk average (SR-Avg) B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of induction (EOI).

II. To confirm that boys in the standard-risk favorable (SR-Fav) subset of B-ALL, with or without Down syndrome (DS), will maintain a 5-year DFS of greater than 93% when treated with a standard chemotherapy regimen with a treatment duration of 2 years from the start of interim maintenance I (IM1).

SECONDARY OBJECTIVES:

I. To describe the DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of IM1, regardless of sex.

II. To describe the DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen.

III. To determine if patients with DS-High achieve a reduction of treatment-related mortality (TRM) after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of delayed intensification [DI]) with 3 cycles of blinatumomab.

IV. To describe the DFS characterized by the replacement of intensive elements of standard chemotherapy with 3 cycles of blinatumomab in patients with DS-High B ALL.

V. To describe the DFS for patients with localized (Murphy stage I and II) B lymphoblastic lymphoma (B-LLy) receiving standard risk B-ALL therapy.

VI. To compare the change in neurocognitive functioning, as measured by the CogState Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4- < 10 years at the time of diagnosis between children from poor families (defined as presence of household material hardship [HMH], including either food, housing or energy insecurity) and non-poor families (absence of HMH).

VII. To describe the impact of blinatumomab on caregiver burden and patient/proxy-reported symptoms among a subset of children enrolled in the HMH and neurocognitive outcome study.

VII. To evaluate available peripheral blood (PB) samples at EOI using HTS MRD and compare the results against bone marrow (BM) results.

IX. To evaluate available end of Consolidation (EOC) BM samples using HTS in patients who were Day 29 MRD positive by flow cytometry and who have submitted EOC BM flow cytometry results.

EXPLORATORY OBJECTIVES:

I. To explore adaptive and innate immune functions and host genetic factors associated with severe infectious complications in children with DS B-ALL.

II. To explore the impact of acute lymphoblastic leukemia (ALL) and its therapy on neurocognitive, functional, and quality of life outcomes in patients with DS and ALL, as measured by caregiver (parent/legal guardian) questionnaires.

III. To define the prevalence of minimal marrow disease (MMD) in B-LLy and to correlate MMD at diagnosis with outcome in patients with B-LLy.

OUTLINE: All patients are assigned to, and complete an INDUCTION treatment regimen. Patients are then assigned to a CONSOLIDATION treatment regimen. Finally, following CONSOLIDATION, patients are either assigned or randomized to 1 of 7 arms.

NON-DS SR B-ALL INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1, vincristine intravenous (IV) push over 1 minute on days 1, 8, 15, and 22, dexamethasone orally (PO) or IV twice daily (BID) on days 1-28, pegaspargase IV over 1-2 hours or intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29. CNS2 patients also receive cytarabine IT twice weekly except during weeks when days 8 and 29 methotrexate is administered. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.

* After Non-DS SR B-ALL INDUCTION, SR-Fav and SR-Avg patients complete SR CONSOLIDATION, while patients with SR-High complete high-risk (HR) CONSOLIDATION.

DS B-ALL INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1 minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30. Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28, and patients 10 years of age or older receive prednisone or prednisolone PO or IV BID on days 1-28. CNS2 patients also receive cytarabine IT twice weekly except during weeks when days 8 and 29 IT methotrexate is administered. CNS3 patients also receive methotrexate IT on days 15 and 22, and leucovorin PO or IV every 6 hours for 2 doses on days 16 and 23. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.

* After DS B-ALL INDUCTION, patients without high risk features and MRD < 0.01 % complete SR CONSOLIDATION. Patients without high risk features and MRD >= 0.01%, OR with high risk features and any MRD complete HR CONSOLIDATION.

NON-DS B-LLy INDUCTION: Patients receive cytarabine IT on day 1 and twice weekly if CNS2, vincristine IV push over 1 minute on days 1, 8, 15, and 22, dexamethasone PO or IV BID on days 1-28, pegaspargase IV over 1-2 hours or IM on day 4, and methotrexate IT on days 8 and 29. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.

* After NON-DS B-LLy INDUCTION, all B-LLy patients then complete SR CONSOLIDATION.

DS B-LLY INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1 minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30. Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28, and patients 10 years of age or older receive PO or IV prednisone or methylprednisolone on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.

* After DS B-LLy INDUCTION, patients then complete SR CONSOLIDATION.

SR CONSOLIDATION: Patients receive vincristine IV push over 1 minute on day 1, mercaptopurine PO on days 1-28, and methotrexate IT on days 1, 8, and 15. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2, 9, and 16. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.

* After SR CONSOLIDATION, patients with MRD undetectable are assigned to ARM A, and patients with MRD detectable/indeterminate/unavailable are randomized to ARM A or B. Patients with SR-Fav and all B-LLy patients are assigned to treatments identical to that in ARM A.

HR CONSOLIDATION: 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, vincristine IV push over 1 minute on days 15, 22, 43, and 50, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 , and pegaspargase IV over 1-2 hours or IM on days 15 and 43. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2, 9, 16, and 23 (on days 2 and 9 only for DS CNS3 patients). Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. Patients with continued clinical evidence of DS or testicular leukemia (from diagnosis through the end of Induction) undergo testicular radiation therapy over 12 fractions once daily (QD).

* After HR CONSOLIDATION, patients are randomized to ARM C or D. DS B-ALL patients with MRD < 1% are assigned to an arm including three blocks of blinatumomab.

ARM A:

  • INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on 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, and methotrexate IT on day 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and 15, doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 29-32 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on 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, and methotrexate IT on days 1 and 31. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • MAINTENANCE: Non-DS patients receive methotrexate IT on day 1, vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients receive vincristine IV push over 1 minute on day 1, methotrexate IT on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78, and leucovorin IV or PO on day 2 if DS. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of INTERIM MAINTENANCE I is reached in the absence of disease progression or unacceptable toxicity.

ARM B:

  • BLINATUMOMAB BLOCK I: Patients receive dexamethasone IV or PO on day 1, methotrexate IT on day 1, and blinatumomab IV continuously on days 1-28. DS patients also receive leucovorin IV or PO every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
  • INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on 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, and methotrexate IT on day 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • BLINATUMOMAB BLOCK II: Patients receive methotrexate IT on day 1, and blinatumomab IV continuously on days 1-28. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
  • DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone PO or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and 15, doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on 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, and methotrexate IT on days 1 and 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • MAINTENANCE: Non-DS patients receive methotrexate IT on day 1 (omit on final 2 cycles), vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 1 on final 2 cycles). DS patients receive methotrexate IT on day 1 (omit on final 2 cycles), dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 1 except for final 2 cycles), for DS patients and leucovorin IV or PO every 6 hours for 2 doses on day 2 (omit on final 2 cycles). Treatment repeats every 84 days until a total duration of therapy of 2 years from start of INTERIM MAINTENANCE I is reached in the absence of disease progression or unacceptable toxicity.

ARM C:

  • INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on day 1 and 29, and leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21, 31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 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 or IM on days 2 and 22. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • MAINTENANCE: Patients receive vincristine IV over 1 minute on day 1, prednisone or prednisolone or methylprednisolone PO or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on days 1 and 29 of cycles 1-2 and on day 1 of subsequent cycles, methotrexate PO on days 8, 15, 22, 29 (for cycle 3 and later only), 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity.

ARM D:

  • BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, methotrexate IT on day 1, and blinatumomab IV continuously on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
  • INTERIM MAINTENANCE I: Patients receive vincristine IV over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on days 1 and 29, and leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28 and methotrexate IT on day 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
  • DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21, 31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 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 or IM on days 2 and 22. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • MAINTENANCE: Patients receive methotrexate IT on day 1, vincristine IV over 1 minute on day 1, prednisone, prednisolone or methylprednisolone PO or IV on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity.

DS-HIGH B-ALL:

  • BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, blinatumomab IV continuously on days 1-28, methotrexate IT on day 1 (or on day 56 of Consolidation), and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
  • INTERIM MAINTENANCE: Patients receive vincristine IV push over 1 minute on days 1, 15, 29, and 43, intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-46, methotrexate IT on days 1 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 2-4, 16-18, 30-32, and 44-46. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity.
  • BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28, methotrexate IT on day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
  • DELAYED INTENSIFICATION: Patients receive vincristine IV over 1 minute on days 1, 8, and 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on days 1-7 and 15-21, methotrexate IT on day 1, leucovorin PO or IV every 6 hours for 2 doses on day 2, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
  • BLINATUMOMAB BLOCK III: Patients receive blinatumomab IV on days 1-28, methotrexate IT on day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
  • MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, prednisone, prednisolone or methylprednisolone PO or IV BID on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on day 1, methotrexate PO on days 8, 15, 22, 29 (omit day 29 for first 3 cycles for patients who do not receive cranial radiotherapy), 36, 43, 50, 57, 64, 71, and 78, and leucovorin PO on days 2 and 30 (day 30 dose is for cycles 1-3 and for patients who do not receive cranial radiotherapy). CNS3 patients receive cranial radiotherapy during first 4 weeks of cycle 1. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity.

All B-LLy patients:

  • INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • DELAYED INTENSIFICATION: Patients receive vincristine IV push over 1 minute on days 1, 8 and 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on days 1-7 and 15-21, methotrexate IT on days 1 and 29, pegaspargase IV over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. DS patients additionally receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on 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, and methotrexate IT on days 1 and 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
  • MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on day 1, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 weeks until complete blood count(CBC)/differential/platelet count recovery, then every 3 months for the first 2 years, then every 4-6 months for the 3rd year, and every 6-12 months for the 4th and 5th years.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • B Acute Lymphoblastic Leukemia
  • B Lymphoblastic Lymphoma
  • Down Syndrome
Intervention  ICMJE
  • Drug: Asparaginase Erwinia chrysanthemi
    Given IV or IM
    Other Names:
    • Crisantaspase
    • Crisantaspasum
    • Erwinase
    • Erwinaze
    • L-asparginase (Erwinia )
  • Biological: Blinatumomab
    Given IV
    Other Names:
    • Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody
    • Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103
    • Blincyto
    • MEDI-538
    • MT-103
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamide Monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
  • Drug: Cytarabine
    Given IT or IV
    Other Names:
    • .beta.-Cytosine arabinoside
    • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
    • 1-.beta.-D-Arabinofuranosylcytosine
    • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
    • 1-Beta-D-arabinofuranosylcytosine
    • 1.beta.-D-Arabinofuranosylcytosine
    • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
    • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
    • Alexan
    • Ara-C
    • ARA-cell
    • Arabine
    • Arabinofuranosylcytosine
    • Arabinosylcytosine
    • Aracytidine
    • Aracytin
    • Aracytine
    • Beta-Cytosine Arabinoside
    • CHX-3311
    • Cytarabinum
    • Cytarbel
    • Cytosar
    • Cytosine Arabinoside
    • Cytosine-.beta.-arabinoside
    • Cytosine-beta-arabinoside
    • Erpalfa
    • Starasid
    • Tarabine PFS
    • U 19920
    • U-19920
    • Udicil
    • WR-28453
  • Drug: Dexamethasone
    Given PO or IV
    Other Names:
    • Aacidexam
    • Adexone
    • Aknichthol Dexa
    • Alba-Dex
    • Alin
    • Alin Depot
    • Alin Oftalmico
    • Amplidermis
    • Anemul mono
    • Auricularum
    • Auxiloson
    • Baycadron
    • Baycuten
    • Baycuten N
    • Cortidexason
    • Cortisumman
    • Decacort
    • Decadrol
    • Decadron
    • Decadron DP
    • Decalix
    • Decameth
    • Decasone R.p.
    • Dectancyl
    • Dekacort
    • Deltafluorene
    • Deronil
    • Desamethasone
    • Desameton
    • Dexa-Mamallet
    • Dexa-Rhinosan
    • Dexa-Scheroson
    • Dexa-sine
    • Dexacortal
    • Dexacortin
    • Dexafarma
    • Dexafluorene
    • Dexalocal
    • Dexamecortin
    • Dexameth
    • Dexamethasone Intensol
    • Dexamethasonum
    • Dexamonozon
    • Dexapos
    • Dexinoral
    • Dexone
    • Dinormon
    • Dxevo
    • Fluorodelta
    • Fortecortin
    • Gammacorten
    • Hemady
    • Hexadecadrol
    • Hexadrol
    • Lokalison-F
    • Loverine
    • Methylfluorprednisolone
    • Millicorten
    • Mymethasone
    • Orgadrone
    • Spersadex
    • TaperDex
    • Visumetazone
    • ZoDex
  • Drug: Doxorubicin Hydrochloride
    Given IV
    Other Names:
    • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
    • ADM
    • Adriacin
    • Adriamycin
    • Adriamycin Hydrochloride
    • Adriamycin PFS
    • Adriamycin RDF
    • ADRIAMYCIN, HYDROCHLORIDE
    • Adriamycine
    • Adriblastina
    • Adriblastine
    • Adrimedac
    • Chloridrato de Doxorrubicina
    • DOX
    • DOXO-CELL
    • Doxolem
    • Doxorubicin HCl
    • Doxorubicin.HCl
    • Doxorubin
    • Farmiblastina
    • FI 106
    • FI-106
    • hydroxydaunorubicin
    • Rubex
  • Drug: Leucovorin Calcium
    Given PO or IV
    Other Names:
    • Adinepar
    • Calcifolin
    • Calcium (6S)-Folinate
    • Calcium Folinate
    • Calcium Leucovorin
    • Calfolex
    • Calinat
    • Cehafolin
    • Citofolin
    • Citrec
    • Citrovorum Factor
    • Cromatonbic Folinico
    • Dalisol
    • Disintox
    • Divical
    • Ecofol
    • Emovis
    • Factor, Citrovorum
    • Flynoken A
    • Folaren
    • Folaxin
    • FOLI-cell
    • Foliben
    • Folidan
    • Folidar
    • Folinac
    • Folinate Calcium
    • folinic acid
    • Folinic Acid Calcium Salt Pentahydrate
    • Folinoral
    • Folinvit
    • Foliplus
    • Folix
    • Imo
    • Lederfolat
    • Lederfolin
    • Leucosar
    • leucovorin
    • Rescufolin
    • Rescuvolin
    • Tonofolin
    • Wellcovorin
  • Drug: Mercaptopurine
    Given PO
    Other Names:
    • 3H-Purine-6-thiol
    • 6 MP
    • 6 Thiohypoxanthine
    • 6 Thiopurine
    • 6-Mercaptopurine
    • 6-Mercaptopurine Monohydrate
    • 6-MP
    • 6-Purinethiol
    • 6-Thiopurine
    • 6-Thioxopurine
    • 6H-Purine-6-thione, 1,7-dihydro- (9CI)
    • 7-Mercapto-1,3,4,6-tetrazaindene
    • Alti-Mercaptopurine
    • Azathiopurine
    • Bw 57-323H
    • Flocofil
    • Ismipur
    • Leukerin
    • Leupurin
    • Mercaleukim
    • Mercaleukin
    • Mercaptina
    • Mercaptopurinum
    • Mercapurin
    • Mern
    • NCI-C04886
    • Puri-Nethol
    • Purimethol
    • Purine, 6-mercapto-
    • Purine-6-thiol (8CI)
    • Purine-6-thiol, monohydrate
    • Purinethiol
    • Purinethol
    • U-4748
    • WR-2785
  • Drug: Mercaptopurine Oral Suspension
    Given PO
    Other Names:
    • 6-MP Oral Suspension
    • Purixan
    • Xaluprine
  • Drug: Methotrexate
    Given IT or IV
    Other Names:
    • Abitrexate
    • Alpha-Methopterin
    • Amethopterin
    • Brimexate
    • CL 14377
    • CL-14377
    • Emtexate
    • Emthexat
    • Emthexate
    • Farmitrexat
    • Fauldexato
    • Folex
    • Folex PFS
    • Lantarel
    • Ledertrexate
    • Lumexon
    • Maxtrex
    • Medsatrexate
    • Metex
    • Methoblastin
    • Methotrexate LPF
    • Methotrexate Methylaminopterin
    • Methotrexatum
    • Metotrexato
    • Metrotex
    • Mexate
    • Mexate-AQ
    • MTX
    • Novatrex
    • Rheumatrex
    • Texate
    • Tremetex
    • Trexeron
    • Trixilem
    • WR-19039
  • Drug: Pegaspargase
    Given IV or IM
    Other Names:
    • L-Asparaginase with Polyethylene Glycol
    • Oncaspar
    • Oncaspar-IV
    • PEG-Asparaginase
    • PEG-L-Asparaginase
    • PEG-L-Asparaginase (Enzon - Kyowa Hakko)
    • PEGLA
    • Polyethylene Glycol L-Asparaginase
    • Polyethylene Glycol-L-Asparaginase
  • Drug: Prednisolone
    Given PO or IV
    Other Names:
    • (11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione
    • .delta.1-Hydrocortisone
    • Adnisolone
    • Aprednislon
    • Capsoid
    • Cortalone
    • Cortisolone
    • Dacortin H
    • Decaprednil
    • Decortin H
    • Delta(1)Hydrocortisone
    • Delta- Cortef
    • Delta-Cortef
    • Delta-Diona
    • Delta-F
    • Delta-Phoricol
    • Delta1-dehydro-hydrocortisone
    • Deltacortril
    • Deltahydrocortisone
    • Deltasolone
    • Deltidrosol
    • Dhasolone
    • Di-Adreson-F
    • Dontisolon D
    • Estilsona
    • Fisopred
    • Frisolona
    • Gupisone
    • Hostacortin H
    • Hydeltra
    • Hydeltrasol
    • Klismacort
    • Kuhlprednon
    • Lenisolone
    • Lepi-Cortinolo
    • Linola-H N
    • Linola-H-Fett N
    • Longiprednil
    • Metacortandralone
    • Meti Derm
    • Meticortelone
    • Opredsone
    • Panafcortelone
    • Precortisyl
    • Pred-Clysma
    • Predeltilone
    • Predni-Coelin
    • Predni-Helvacort
    • Prednicortelone
    • Prednisolonum
    • Prelone
    • Prenilone
    • Sterane
  • Drug: Prednisone
    Given PO or IV
    Other Names:
    • .delta.1-Cortisone
    • 1, 2-Dehydrocortisone
    • Adasone
    • Cortancyl
    • Dacortin
    • DeCortin
    • Decortisyl
    • Decorton
    • Delta 1-Cortisone
    • Delta-Dome
    • Deltacortene
    • Deltacortisone
    • Deltadehydrocortisone
    • Deltasone
    • Deltison
    • Deltra
    • Econosone
    • Lisacort
    • Meprosona-F
    • Metacortandracin
    • Meticorten
    • Ofisolona
    • Orasone
    • Panafcort
    • Panasol-S
    • Paracort
    • Perrigo Prednisone
    • PRED
    • Predicor
    • Predicorten
    • Prednicen-M
    • Prednicort
    • Prednidib
    • Prednilonga
    • Predniment
    • Prednisone Intensol
    • Prednisonum
    • Prednitone
    • Promifen
    • Rayos
    • Servisone
    • SK-Prednisone
  • Radiation: Radiation Therapy
    Undergo cranial radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • ENERGY_TYPE
    • Irradiate
    • Irradiated
    • Irradiation
    • Radiation
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
  • Radiation: Radiation Therapy
    Undergo testicular radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • ENERGY_TYPE
    • Irradiate
    • Irradiated
    • Irradiation
    • Radiation
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
  • Drug: Thioguanine
    Given PO
    Other Names:
    • 2-Amino 6MP
    • 2-Amino-1,7-dihydro-6H-purine-6-thione
    • 2-Amino-6-mercaptopurine
    • 2-Amino-6-purinethiol
    • 2-Aminopurin-6-thiol
    • 2-Aminopurine-6(1H)-thione
    • 2-Aminopurine-6-thiol
    • 2-Aminopurine-6-thiol Hemihydrate
    • 2-Mercapto-6-aminopurine
    • 6-Amino-2-mercaptopurine
    • 6-Mercapto-2-aminopurine
    • 6-Mercaptoguanine
    • 6-TG
    • 6H-Purine-6-thione, 2-amino-1,7-dihydro- (9CI)
    • BW 5071
    • Lanvis
    • Tabloid
    • Thioguanine Hemihydrate
    • Thioguanine Hydrate
    • Tioguanin
    • Tioguanine
    • Wellcome U3B
    • WR-1141
    • X 27
  • Drug: Vincristine Sulfate
    Given IV
    Other Names:
    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate
Study Arms  ICMJE
  • Active Comparator: Arm A (SR-Avg control)
    Arm A: See detailed description.
    Interventions:
    • Drug: Asparaginase Erwinia chrysanthemi
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Doxorubicin Hydrochloride
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Mercaptopurine Oral Suspension
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisone
    • Drug: Thioguanine
    • Drug: Vincristine Sulfate
  • Experimental: Arm B (SR-Avg experimental)
    Arm B: See detailed description.
    Interventions:
    • Drug: Asparaginase Erwinia chrysanthemi
    • Biological: Blinatumomab
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Doxorubicin Hydrochloride
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Mercaptopurine Oral Suspension
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Thioguanine
    • Drug: Vincristine Sulfate
  • Active Comparator: Arm C (SR-High Control)
    Arm C: See detailed description.
    Interventions:
    • Drug: Asparaginase Erwinia chrysanthemi
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Doxorubicin Hydrochloride
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Mercaptopurine Oral Suspension
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Prednisone
    • Drug: Thioguanine
    • Drug: Vincristine Sulfate
  • Experimental: Arm D (SR-High experimental)
    Arm D See detailed description.
    Interventions:
    • Drug: Asparaginase Erwinia chrysanthemi
    • Biological: Blinatumomab
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Doxorubicin Hydrochloride
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Mercaptopurine Oral Suspension
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Prednisone
    • Drug: Thioguanine
    • Drug: Vincristine Sulfate
  • Experimental: B-LLy
    See detailed description.
    Interventions:
    • Drug: Asparaginase Erwinia chrysanthemi
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Doxorubicin Hydrochloride
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Mercaptopurine Oral Suspension
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Prednisone
    • Drug: Thioguanine
    • Drug: Vincristine Sulfate
  • Experimental: DS B-ALL
    See detailed description.
    Interventions:
    • Drug: Asparaginase Erwinia chrysanthemi
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Doxorubicin Hydrochloride
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Mercaptopurine Oral Suspension
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Radiation: Radiation Therapy
    • Radiation: Radiation Therapy
    • Drug: Thioguanine
    • Drug: Vincristine Sulfate
  • Experimental: NCI SR or HR DS B-ALL
    See detailed description.
    Interventions:
    • Drug: Asparaginase Erwinia chrysanthemi
    • Biological: Blinatumomab
    • Drug: Dexamethasone
    • Drug: Doxorubicin Hydrochloride
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Mercaptopurine Oral Suspension
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Prednisone
    • Drug: Vincristine Sulfate
Publications * Sora F, Annunziata M, Laurenti L, Giammarco S, Chiusolo P, Innocenti I, Autore F, Metafuni E, Galli E, Bacigalupo A, Ferrara F, Sica S. Blinatumomab as a successful and safe therapy in Down syndrome patients with relapsed/refractory b-precursor acute lymphoblastic leukaemia: Case reports and literature review. Pediatr Blood Cancer. 2021 Jul;68(7):e29044. doi: 10.1002/pbc.29044. Epub 2021 Apr 12. No abstract available.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: April 12, 2019)		 6720
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2029
Estimated Primary Completion Date September 30, 2029   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement for B-LLy patients. B-LLy patients may directly enroll on AALL1731.

  • Age at diagnosis:

    • Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).
    • Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).
    • Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or without DS).
  • B-ALL patients without DS must have an initial white blood cell count < 50,000/uL (performed within 7 days prior to enrollment).
  • B-ALL patients with DS are eligible regardless of the presenting white blood cell count (WBC) (performed within 7 days prior to enrollment).

  • Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on a bone marrow (BM) aspirate;

    • OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
    • OR a complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells;
    • OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without Down syndrome.
    • Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted (diagnostic biopsy for B-LLy must be performed within 14 days prior to enrollment).
  • 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.

Exclusion Criteria:

  • Patient must not have secondary ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior history of transient myeloproliferative disease (TMD) are not considered to have had a prior malignancy. They would therefore be eligible whether or not the TMD was treated with cytarabine.
  • 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 B LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1731.

  • For patients receiving steroid pretreatment, the following additional exclusion criteria apply:

    • Non-DS B-ALL patients must not have received steroids for more than 24 hours in the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to initiation of the steroids.
    • DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV steroids within 4 weeks of diagnosis.
  • Patients who have received > 72 hours of hydroxyurea within 1 week (7 days) prior to the start of systemic protocol therapy.
  • B-ALL patients who do not have sufficient diagnostic bone marrow submitted for APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.
  • Patient must not have acute undifferentiated leukemia (AUL).

  • Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be known prior to enrollment).

    • Note: DS patients with CNS3 disease are eligible but will be assigned to the DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment.
  • Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular disease are eligible but will be assigned to the DS-High B-ALL arm).

  • For LLy patients, the following additional exclusion criteria apply:

    • T-Lymphoblastic Lymphoma.
    • Morphologically unclassifiable lymphoma.
    • Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma.
    • CNS positive disease or testicular involvement.
    • M2 (5% - 25% blasts) or M3 (> 25% blasts) marrow.
  • Patients with known Charcot-Marie-Tooth disease.
  • Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype.
  • Patients requiring radiation at diagnosis.
  • Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
  • Lactating females who plan to breastfeed their infants.
  • Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 365 Days to 31 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03914625
Other Study ID Numbers  ICMJE NCI-2019-02187
NCI-2019-02187 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AALL1731 ( Other Identifier: Children's Oncology Group )
AALL1731 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm
Current Responsible Party National Cancer Institute (NCI)
Original Responsible Party Same as current
Current Study Sponsor  ICMJE National Cancer Institute (NCI)
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sumit Gupta Children's Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date December 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP