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Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT03007147
Recruitment Status : Recruiting
First Posted : January 2, 2017
Last Update Posted : September 24, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
University of Milano Bicocca
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date  ICMJE December 28, 2016
First Posted Date  ICMJE January 2, 2017
Last Update Posted Date September 24, 2019
Actual Study Start Date  ICMJE July 28, 2017
Estimated Primary Completion Date June 30, 2028   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 3, 2018)
Disease free survival (DFS) [ Time Frame: From randomization to first event (relapse, second malignancy, or death in complete remission) or time to last follow-up for patients without events, assessed up to 3 years ]
Will compare the DFS of standard risk Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) patients treated continuous imatinib mesylate with high risk Children's Oncology Group (COG)-ALL chemotherapy backbone or more intensive European (Es)PhALL chemotherapy backbone.
Original Primary Outcome Measures  ICMJE
 (submitted: December 28, 2016)
DFS [ Time Frame: Up to 3 years ]
Will compare the DFS of standard risk Ph+ ALL patients treated continuous imatinib mesylate with high risk COG/BFM ALL chemotherapy backbone or more intensive EsPhALL chemotherapy backbone.
Change History Complete list of historical versions of study NCT03007147 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 3, 2018)
  • Imatinib mesylate administration after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk Ph+ ALL patients [ Time Frame: Up to 2 years ]
    Feasibility of post-HSCT imatinib mesylate is determined based on the proportion of patients who receive at least 75% of intended doses.
  • Event free survival (EFS) of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate [ Time Frame: From the date of bone marrow for minimal residual disease (MRD) assessment at end-IB to first event or time to last follow-up for patients without events, assessed up to 3 years ]
    Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood.
  • Incidence of grade 3 or higher infections in standard risk Ph+ ALL patients in the two randomized arms evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 3 years ]
    The rate of infections during the post IB/pre-maintenance phases of treatment will be compared accounting for follow-up time.
  • EFS of all enrolled patients [ Time Frame: From enrollment until the first occurrence of: M3 marrow at the end of Induction IA, relapse, second malignancy, or death as a first event, assessed up to 3 years ]
    Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood.
  • Overall survival (OS) of all enrolled patients [ Time Frame: From study enrollment to death from any cause, assessed up to 3 years ]
    Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood. Will be estimated with a maximum standard error of 1.9%.
  • OS of standard risk patients [ Time Frame: From randomization to death from any cause, assessed up to 3 years ]
    Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood. Estimates will also be calculated for each of the randomization groups.
  • OS of high risk patients [ Time Frame: From the date of MRD assessment at end-IB to death from any cause, assessed up to 3 years ]
    Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood. Estimates will also be calculated for each of the randomization groups.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 28, 2016)
  • DFS of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate [ Time Frame: Up to 3 years ]
    The 3-year DFS for these patients will be estimated with a maximum standard error of 0.053.
  • Imatinib mesylate administration after allogeneic HSCT in high risk Ph+ ALL patients [ Time Frame: Up to 2 years ]
    Feasibility of post-HSCT imatinib mesylate is determined based on the proportion of patients who receive at least 75% of intended doses.
  • Incidence of grade 3 or higher infections in standard risk Ph+ ALL patients in the two randomized arms evaluated according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 3 years ]
    The rate of infections during the post IB/pre-maintenance phases of treatment will be compared accounting for follow-up time.
Current Other Pre-specified Outcome Measures
 (submitted: August 3, 2018)
  • Incidence of toxicities associated with post-HSCT administration of imatinib mesylate evaluated according to NCI CTCAE version 4.0 [ Time Frame: Up to 1 year post-HSCT ]
    Frequencies of target toxicities in high risk patients after the initiation of post-HSCT imatinib mesylate will be described. For the high risk patients, the specific targeted toxicities will include grade 4 neutropenia, grade 4 thrombocytopenia, grade 3 or higher bilirubin, grade 4 or higher transaminitis, and grade 3 or higher infection.
  • Incidence of long-term toxicities in patients treated with chemotherapy plus imatinib mesylate (no transplant) in both arms evaluated according to NCI CTCAE version 4.0 [ Time Frame: Up to 3 years ]
    Frequencies of long-term toxicities will be described and differences between randomized arms will be explored. Specific long-term toxicities to be explored include cardiac (echocardiographic abnormalities, including decreased left ventricular (LV) function and decreased LV wall thickness), growth (linear height, bone age), and second malignant neoplasm.
  • MRD measured by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) and next generation sequencing (NGS) assay [ Time Frame: At the end of induction IB ]
    For all patients, frequencies and prognostic significance (DFS, EFS, OS) will be explored for MRD levels (i.e., MRD negative, detectable at < 5 x 10^-4, and dectectable at >= 5 x 10^-4) at end of Induction IB.
  • MRD in high risk patients measured by IGH-TCR PCR and NGS assay [ Time Frame: Up to 12 months post-HSCT ]
    The outcome of high risk patients will be described, including proportion of patients who achieve MRD-negativity just prior to HSCT, and at regular intervals post-HSCT. Associations between these findings and long-term outcomes (e.g., OS, DFS) will be explored.
  • MRD assessments made by IGH-TCR PCR assay and NGS assay [ Time Frame: Up to 2 years ]
    Concordance of MRD assessments made by IGH-TCR PCR assay and NGS assay will be described and evaluated. Scatter plots and diagrams will be used to examine agreements and patterns of agreement or any differences found. Concordance will be explored both for the overall cohort, as well as by risk group. The increased sensitivity of the NGS will be closely examined to find cases where the MRD levels are detectable by NGS but undetectable by PCR, as well as cases in which one test yields results and the other does not (test failure). Prognostic relationships on outcomes for these subjects will be inspected.
  • IKZF1 gene aberrations and deletions [ Time Frame: Up to 2 years ]
    For both standard risk and high risk groups, frequencies and prognostic significance (OS, DFS) will be explored for IKZF1 gene aberrations and deletions.
  • Frequency of p190 and p210 BCR-ABL1 fusion variants [ Time Frame: Up to 2 years ]
    For both standard risk and high risk groups, frequencies and prognostic significance (OS, DFS) will be explored for p190 and p210 BCR-ABL1 fusion variants in pediatric Ph+ ALL.
  • Adherence to oral chemotherapeutic agents in standard risk Ph+ ALL patients [ Time Frame: Up to 2 years during maintenance phase ]
    Adherence to imatinib mesylate, 6-mercaptopurine, and methotrexate will be evaluated in COG-enrolled participants using an electronic monitoring device. Adherence rate will be computed for each month of adherence monitoring. Longitudinal binomial regression will be conducted using generalized estimating equation methods by modeling monthly adherence rate as an unstructured mean model using five indicator variables of time for the study months. Time in months will also be treated as a continuous variable to explore temporal trends in adherence rate. Compound symmetry will be assumed as the working correlation matrix over time. Covariates that will be considered for adjustment include those hypothesized to be predictors of adherence, annual household income, parental education, time since start of maintenance, risk classification for ALL, and imatinib, 6-mercaptopurine (6MP), and methotrexate dose-intensity.
  • Adherence to imatinib mesylate after allogeneic HSCT in high risk Ph+ ALL patients [ Time Frame: Up to 12 months post-HSCT ]
    Longitudinal binomial regression will be conducted using generalized estimating equation methods by modeling monthly adherence rate as an unstructured mean model using five indicator variables of time for the study months. Time in months will also be treated as a continuous variable to explore temporal trends in adherence rate. Compound symmetry will be assumed as the working correlation matrix over time. Covariates that will be considered for adjustment include those hypothesized to be predictors of adherence, annual household income, parental education, time since start of maintenance, risk classification for ALL, and imatinib, 6MP, and methotrexate dose-intensity.
Original Other Pre-specified Outcome Measures
 (submitted: December 28, 2016)
  • Adherence to imatinib mesylate after allogeneic HSCT in high risk Ph+ ALL patients [ Time Frame: Up to 12 months post-HSCT ]
    Longitudinal binomial regression will be conducted using generalized estimating equation methods by modeling monthly adherence rate as an unstructured mean model using five indicator variables of time for the study months. Time in months will also be treated as a continuous variable to explore temporal trends in adherence rate. Compound symmetry will be assumed as the working correlation matrix over time. Covariates that will be considered for adjustment include those hypothesized to be predictors of adherence, annual household income, parental education, time since start of maintenance, risk
  • Adherence to oral chemotherapeutic agents in standard risk Ph+ ALL patients [ Time Frame: Up to day 168 of maintenance phase ]
    Adherence to imatinib mesylate, 6-mercaptopurine, and methotrexate will be evaluated in COG-enrolled participants using an electronic monitoring device. Adherence rate will be computed for each month of adherence monitoring. Longitudinal binomial regression will be conducted using generalized estimating equation methods by modeling monthly adherence rate as an unstructured mean model using five indicator variables of time for the study months. Time in months will also be treated as a continuous variable to explore temporal trends in adherence rate. Compound symmetry will be assumed as the work
  • Frequency of p210 BCR-ABL1 fusion variants [ Time Frame: Up to 2 years ]
    For both SR and HR risk groups, frequencies and prognostic significance (OS, DFS) will be explored for p210 BCR-ABL1 fusion variants in pediatric Ph+ ALL.
  • IKZF1 gene aberrations and deletions [ Time Frame: Up to 2 years ]
    For both SR and HR risk groups, frequencies and prognostic significance (OS, DFS) will be explored for IKZF1 gene aberrations and deletions.
  • Incidence of long-term toxicities in patients treated with chemotherapy plus imatinib mesylate (no transplant) in both arms evaluated according to NCI CTCAE version 4.0 [ Time Frame: Up to 3 years ]
    Frequencies of long-term toxicities will be described and differences between randomized arms will be explored. Specific long-term toxicities to be explored include cardiac (echocardiographic abnormalities, including decreased left ventricular (LV) function and decreased LV wall thickness), growth (linear height, bone age), and second malignant neoplasm.
  • Incidence of toxicities associated with post-HSCT administration of imatinib mesylate evaluated according to NCI CTCAE version 4.0 [ Time Frame: Up to 1 year post-HSCT ]
    Frequencies of target toxicities in HR patients after the initiation of post-HSCT imatinib mesylate will be described. For the HR patients, the specific targeted toxicities will include grade 4 neutropenia, grade 4 thrombocytopenia, grade 3 or higher bilirubin, grade 4 or higher transaminitis, and grade 3 or higher infection.
  • MRD assessments made by IGH-TCR PCR assay and NGS assay [ Time Frame: Up to 2 years ]
    Concordance of MRD assessments made by IGH-TCR PCR assay and NGS assay will be described and evaluated. Scatter plots and diagrams will be used to examine agreements and patterns of agreement or any differences found. Concordance will be explored both for the overall cohort, as well as by risk group. The increased sensitivity of the NGS will be closely examined to find cases where the MRD levels are detectable by NGS but undetectable by PCR, as well as cases in which one test yields results and the other does not (test failure). Prognostic relationships on outcomes for these subjects will be i
  • MRD in HR patients measured by IGH-TCR PCR and NGS assay [ Time Frame: Up to 12 months post-HSCT ]
    The outcome of HR patients will be described, including proportion of patients who achieve MRD-negativity just prior to HSCT, and at regular intervals post-HSCT. Associations between these findings and long-term outcomes (e.g., OS, DFS) will be explored.
  • MRD in SR patients measured by IGH-TCR PCR and NGS assay [ Time Frame: Up to 2 years ]
    The proportion of patients with detectable MRD will be described, and association between MRD levels at later time points and long-term outcomes (e.g., DFS and OS) will be explored. The proportion of SR patients in each of the randomized arms at each of the time points who are not MRD-negative (i.e., MRD non-detectable), or who revert to MRD-positive (i.e., MRD value >= 5 x 10^-4) after previously attaining MRD-negative status will also be explored. Odds ratio estimates comparing the rates of not being MRD-negative at start of delayed intensification phase or MRD-positive at any subsequent mon
  • MRD measured by IGH-TCR PCR and NGS assay [ Time Frame: At the end of induction IA ]
    For both SR and HR risk groups, frequencies and prognostic significance (overall survival [OS], DFS) will be explored for MRD negativity (< 5 x 10^-4) at end of Induction IA.
 
Descriptive Information
Brief Title  ICMJE Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Official Title  ICMJE International Phase 3 Trial in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Testing Imatinib in Combination With Two Different Cytotoxic Chemotherapy Backbones
Brief Summary This randomized phase III trial studies how well imatinib mesylate and combination chemotherapy work in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia. Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, 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 imatinib mesylate and combination chemotherapy may work better in treating patients with Philadelphia chromosome positive acute lymphoblastic leukemia.
Detailed Description

PRIMARY OBJECTIVES:

I. To compare disease-free survival (DFS) of standard risk pediatric Philadelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or the more intensive European (Es)PhALL chemotherapy backbone.

SECONDARY OBJECTIVES:

I. To determine the feasibility of administration of imatinib after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk Ph+ ALL patients.

II. To determine event-free survival (EFS) of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.

III. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients between the two randomized arms.

IV. To evaluate event free survival (EFS) and overall survival (OS) of all enrolled participants.

V. To evaluate OS in SR patients. VI. To evaluate OS in high risk (HR) patients.

TERTIARY OBJECTIVES:

I. To describe the toxicities associated with post-HSCT administration of imatinib.

II. To evaluate the long-term toxicities in SR patients treated with chemotherapy plus imatinib (no transplant), overall and between both randomized arms.

III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at various time points during therapy.

IV. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals post-HSCT and explore the association of these measurements with long-term outcome.

V. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays.

VI. To determine prognostic significance of IKZF1 gene aberrations and deletions.

VII. To determine frequency and prognostic significance of p190 and p210 BCR-ABL1 fusion variants in pediatric Ph+ ALL.

VIII. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine, and methotrexate) during the maintenance phase in SR Ph+ ALL patients.

IX. To identify factors associated with poor adherence. X. To determine association between relapse risk and adherence to each oral chemotherapeutic agent (separately and combined).

XI. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and identify factors associated with poor adherence.

OUTLINE:

INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days 1-14.

INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or twice daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate intrathecally (IT) on day 29.

INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35, cyclophosphamide IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 15-18, and 22-25, and methotrexate IT on days 8 and 22.

POST-INDUCTION THERAPY: Patients with standard risk are randomized to 1 of 2 arms. Patients with high risk are assigned to Arm C.

ARM A:

CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6, dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4, leucovorin calcium PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and pegaspargase IV over 1-2 hours on day 5, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days 2-4, leucovorin calcium PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 5-15 minutes and daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase IV over 1-2 hours on day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high dose cytarabine IV over 3 hours on days 1-2, dexamethasone PO BID or IV on days 1-5, etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 5, pegaspargase IV over 1-2 hours on day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity.

INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity.

MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate PO once weekly (QW) and IT on days 1 and 43 of courses 1, 2, and 3, and mercaptopurine PO on days 1-84. Courses with imatinib mesylate and mercaptopurine repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity.

ARM B:

INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63, vincristine sulfate IV over 1 minute and 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 on days 1-56, and methotrexate IT on days 1 and 29 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 1, 8, and 15, and pegaspargase IV over 1-2 hours on day 4 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, 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 in the absence of disease progression or unexpected toxicity.

INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD or BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours on days 2 and 22 in the absence of disease progression or unexpected toxicity.

MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV for course 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for course 1 and 2). Courses repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity.

ARM C:

CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone, leucovorin calcium, high dose cytarabine, and pegaspargase as in Arm A Consolidation Block 1, and filgrastim SC on day 7 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate, ifosfamide, leucovorin calcium, dexrazoxane hydrochloride, daunorubicin hydrochloride, pegaspargase, and filgrastim as Arm A Consolidation Block 2 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide, methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase, and filgrastim as in Arm A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence of disease progression or unexpected toxicity.

HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm A.

POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up every year for 3 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
  • BCR-ABL1 Fusion Protein Expression
  • Minimal Residual Disease
  • Philadelphia Chromosome Positive
  • T Acute Lymphoblastic Leukemia
  • Untreated Adult Acute Lymphoblastic Leukemia
  • Untreated Childhood Acute Lymphoblastic Leukemia
Intervention  ICMJE
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    Undergo HSCT
    Other Names:
    • Allogeneic Hematopoietic Cell Transplantation
    • Allogeneic Stem Cell Transplantation
    • HSC
    • HSCT
  • 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
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
  • Drug: Cytarabine
    Given IV, SC, or IT
    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: Daunorubicin Hydrochloride
    Given IV
    Other Names:
    • Cerubidin
    • Cerubidine
    • Cloridrato de Daunorubicina
    • Daunoblastin
    • Daunoblastina
    • Daunoblastine
    • Daunomycin Hydrochloride
    • Daunomycin, hydrochloride
    • Daunorubicin.HCl
    • Daunorubicini Hydrochloridum
    • FI-6339
    • Ondena
    • RP-13057
    • Rubidomycin Hydrochloride
    • Rubilem
  • Drug: Dexamethasone
    Given PO or IV
    Other Names:
    • Aacidexam
    • Adexone
    • Aknichthol Dexa
    • Alba-Dex
    • Alin
    • Alin Depot
    • Alin Oftalmico
    • Amplidermis
    • Anemul mono
    • Auricularum
    • Auxiloson
    • Baycuten
    • Baycuten N
    • Cortidexason
    • Cortisumman
    • Decacort
    • Decadrol
    • Decadron
    • 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
    • Dexamethasonum
    • Dexamonozon
    • Dexapos
    • Dexinoral
    • Dexone
    • Dinormon
    • Fluorodelta
    • Fortecortin
    • Gammacorten
    • Hexadecadrol
    • Hexadrol
    • Lokalison-F
    • Loverine
    • Methylfluorprednisolone
    • Millicorten
    • Mymethasone
    • Orgadrone
    • Spersadex
    • Visumetazone
  • Drug: Dexrazoxane Hydrochloride
    Given IV
    Other Names:
    • Cardioxane
    • Totect
    • Zinecard
  • Drug: Doxorubicin
    Given IV
    Other Names:
    • Adriablastin
    • Hydroxyl Daunorubicin
    • Hydroxyldaunorubicin
  • Drug: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16-213
    • VP-16
    • VP-16-213
  • Biological: Filgrastim
    Given IV
    Other Names:
    • FILGRASTIM, LICENSE HOLDER UNSPECIFIED
    • G-CSF
    • Neupogen
    • r-metHuG-CSF
    • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
    • rG-CSF
    • Tevagrastim
  • Drug: Ifosfamide
    Given IV
    Other Names:
    • Asta Z 4942
    • Asta Z-4942
    • Cyfos
    • Holoxan
    • Holoxane
    • Ifex
    • IFO
    • IFO-Cell
    • Ifolem
    • Ifomida
    • Ifomide
    • Ifosfamidum
    • Ifoxan
    • IFX
    • Iphosphamid
    • Iphosphamide
    • Iso-Endoxan
    • Isoendoxan
    • Isophosphamide
    • Mitoxana
    • MJF 9325
    • MJF-9325
    • Naxamide
    • Seromida
    • Tronoxal
    • Z 4942
    • Z-4942
  • Drug: Imatinib Mesylate
    Given PO
    Other Names:
    • CGP 57148
    • CGP57148B
    • Gleevec
    • Glivec
    • STI 571
    • STI-571
    • STI571
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • 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: Methotrexate
    Given IT
    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: Methylprednisolone
    Given IV
    Other Names:
    • Adlone
    • Caberdelta M
    • DepMedalone
    • Depo Moderin
    • Depo-Nisolone
    • Duralone
    • Emmetipi
    • Esametone
    • Firmacort
    • Medlone 21
    • Medrate
    • Medrol
    • Medrol Veriderm
    • Medrone
    • Mega-Star
    • Meprolone
    • Methylprednisolonum
    • Metilbetasone Solubile
    • Metrocort
    • Metypresol
    • Metysolon
    • Predni-M-Tablinen
    • Prednilen
    • Radilem
    • Sieropresol
    • Solpredone
    • Summicort
    • Urbason
    • Veriderm Medrol
    • Wyacort
  • Drug: Pegaspargase
    Given IV
    Other Names:
    • L-Asparaginase with Polyethylene Glycol
    • Oncaspar
    • PEG-Asparaginase
    • PEG-L-Asparaginase
    • PEG-L-Asparaginase (Enzon - Kyowa Hakko)
    • PEGLA
    • Polyethylene Glycol L-Asparaginase
    • Polyethylene Glycol-L-Asparaginase
  • Drug: Prednisolone
    Given PO
    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
  • Other: Questionnaire Administration
    Ancillary studies
  • Drug: Therapeutic Hydrocortisone
    Given IT
    Other Names:
    • Aeroseb-HC
    • Barseb HC
    • Barseb-HC
    • Cetacort
    • Cort-Dome
    • Cortef
    • Cortenema
    • Cortifan
    • Cortisol
    • Cortispray
    • Cortril
    • Dermacort
    • Domolene
    • Eldecort
    • Hautosone
    • Heb-Cort
    • HYDROCORTISONE
    • Hydrocortone
    • Hytone
    • Komed-HC
    • Nutracort
    • Proctocort
    • Rectoid
  • 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-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
    • 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
  • Experimental: Arm A (imatinib mesylate, EsPhALL chemotherapy)
    See Detailed Description
    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Dexamethasone
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Doxorubicin
    • Drug: Etoposide
    • Biological: Filgrastim
    • Drug: Ifosfamide
    • Drug: Imatinib Mesylate
    • Other: Laboratory Biomarker Analysis
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Mercaptopurine
    • Drug: Methotrexate
    • Drug: Methylprednisolone
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Other: Questionnaire Administration
    • Drug: Therapeutic Hydrocortisone
    • Drug: Thioguanine
    • Drug: Vincristine Sulfate
  • Experimental: Arm B (imatinib mesylate, COG/BFM chemotherapy)
    See Detailed Description.
    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Dexamethasone
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Doxorubicin
    • Drug: Imatinib Mesylate
    • Other: Laboratory Biomarker Analysis
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Methotrexate
    • Drug: Methylprednisolone
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Other: Questionnaire Administration
    • Drug: Thioguanine
    • Drug: Vincristine Sulfate
  • Experimental: Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
    See Detailed Description
    Interventions:
    • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin Hydrochloride
    • Drug: Dexamethasone
    • Drug: Dexrazoxane Hydrochloride
    • Drug: Doxorubicin
    • Drug: Etoposide
    • Biological: Filgrastim
    • Drug: Ifosfamide
    • Drug: Imatinib Mesylate
    • Other: Laboratory Biomarker Analysis
    • Drug: Leucovorin Calcium
    • Drug: Mercaptopurine
    • Drug: Mercaptopurine
    • Drug: Methotrexate
    • Drug: Methylprednisolone
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Other: Questionnaire Administration
    • Drug: Therapeutic Hydrocortisone
    • Drug: Thioguanine
    • Drug: Vincristine Sulfate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 28, 2016)
700
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2028
Estimated Primary Completion Date June 30, 2028   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • For patients enrolled on AALL08B1 or APEC14B1 (if open for ALL patients) prior to enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled

    • For patients who have not previously enrolled on AALL08B1 or APEC14B1 (if open for ALL patients) prior to enrollment on AALL1631, a baseline diagnostic sample must be available to develop an MRD probe
    • In addition, laboratory reports detailing evidence of BCR-ABL1 fusion must be submitted for rapid central review within 72 hours of study enrollment
  • Newly diagnosed de novo ALL (B-ALL or T-ALL) with definitive evidence of BCR-ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or reverse transcriptase (RT)-PCR
  • Patient must have previously started induction therapy, which includes vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or other standard cytotoxic chemotherapy
  • Patient has not received more than 14 days of multiagent induction therapy beginning with the first dose of vinCRIStine
  • Patient may have started imatinib prior to study entry but has not received more than 14 days of imatinib
  • Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2
  • Direct bilirubin =< 2.0 mg/dL
  • Shortening fraction of >= 27% by echocardiogram
  • Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
  • Corrected QT interval, QTc < 480 msec

    • Note: Repeat echocardiogram is not required if echocardiogram was obtained within 21 days of study enrollment
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2
  • Serum creatinine within normal limits based on age/gender, as follows:

    • 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
    • 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
    • 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
    • 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
    • 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
    • >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)

Exclusion Criteria:

  • Known history of chronic myelogenous leukemia (CML)
  • ALL developing after a previous cancer treated with cytotoxic chemotherapy
  • Active, uncontrolled infection, or active systemic illness that requires ongoing vasopressor support or mechanical ventilation
  • Down syndrome
  • Pregnancy and breast feeding

    • Female patients who are pregnant; 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
  • Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block
  • Prior treatment with dasatinib, or any BCR-ABL1 inhibitor other than imatinib
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   Saudi Arabia,   United States
Removed Location Countries Austria,   Chile,   China,   Czechia,   France,   Germany,   Italy,   Netherlands,   Sweden,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT03007147
Other Study ID Numbers  ICMJE AALL1631
NCI-2016-01588 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AALL1631
AALL1631 ( Other Identifier: Childrens Oncology Group )
AALL1631 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
2017-000705-20 ( EudraCT Number )
EsPhALL2017 ( Other Identifier: EsPhALL )
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 Not Provided
Responsible Party Children's Oncology Group
Study Sponsor  ICMJE Children's Oncology Group
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • University of Milano Bicocca
Investigators  ICMJE
Principal Investigator: Lewis Silverman Children's Oncology Group
Principal Investigator: Andrea Biondi EsPhALL
PRS Account Children's Oncology Group
Verification Date February 2019

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