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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03007147
Recruitment Status : Recruiting
First Posted : January 2, 2017
Last Update Posted : June 22, 2022
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief Summary:
This randomized phase III trial studies how well imatinib mesylate works in combination with two different chemotherapy regimens in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Imatinib mesylate has been shown to improve outcomes in children and adolescents with Philadelphia chromosome positive (Ph+) ALL when given with strong chemotherapy, but the combination has many side effects. This trial is testing whether a different chemotherapy regimen may work as well as the stronger one but have fewer side effects when given with imatinib. The trial is also testing how well the combination of chemotherapy and imatinib works in another group of patients with a type of ALL that is similar to Ph+ ALL. This type of ALL is called "ABL-class fusion positive ALL", and because it is similar to Ph+ ALL, is thought it will respond well to the combination of agents used to treat Ph+ ALL.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia B Acute Lymphoblastic Leukemia Mixed Phenotype Acute Leukemia T Acute Lymphoblastic Leukemia 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: Methotrexate Drug: Methylprednisolone Drug: Pegaspargase Drug: Prednisolone Other: Questionnaire Administration Drug: Therapeutic Hydrocortisone Drug: Thioguanine Drug: Vincristine Sulfate Phase 3

Show Show detailed description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 475 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: International Phase 3 Trial in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Testing Imatinib in Combination With Two Different Cytotoxic Chemotherapy Backbones
Actual Study Start Date : July 28, 2017
Estimated Primary Completion Date : March 31, 2028
Estimated Study Completion Date : March 31, 2028


Arm Intervention/treatment
Experimental: Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
Drug: Cyclophosphamide
Given IV

Drug: Cytarabine
Given IV, SC, or IT

Drug: Daunorubicin Hydrochloride
Given IV

Drug: Dexamethasone
Given PO or IV

Drug: Dexrazoxane Hydrochloride
Given IV

Drug: Doxorubicin
Given IV

Drug: Etoposide
Given IV

Biological: Filgrastim
Given IV

Drug: Ifosfamide
Given IV

Drug: Imatinib Mesylate
Given PO

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Leucovorin Calcium
Given PO or IV

Drug: Mercaptopurine
Given PO

Drug: Mercaptopurine
Given PO

Drug: Methotrexate
Given IT

Drug: Methylprednisolone
Given IV

Drug: Pegaspargase
Given IV

Drug: Prednisolone
Given PO

Other: Questionnaire Administration
Ancillary studies

Drug: Therapeutic Hydrocortisone
Given IT

Drug: Thioguanine
Given PO

Drug: Vincristine Sulfate
Given IV

Experimental: Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
Drug: Cyclophosphamide
Given IV

Drug: Cytarabine
Given IV, SC, or IT

Drug: Dexamethasone
Given PO or IV

Drug: Dexrazoxane Hydrochloride
Given IV

Drug: Doxorubicin
Given IV

Drug: Imatinib Mesylate
Given PO

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Leucovorin Calcium
Given PO or IV

Drug: Mercaptopurine
Given PO

Drug: Methotrexate
Given IT

Drug: Methylprednisolone
Given IV

Drug: Pegaspargase
Given IV

Drug: Prednisolone
Given PO

Other: Questionnaire Administration
Ancillary studies

Drug: Thioguanine
Given PO

Drug: Vincristine Sulfate
Given IV

Experimental: Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo HSCT

Drug: Cyclophosphamide
Given IV

Drug: Cytarabine
Given IV, SC, or IT

Drug: Daunorubicin Hydrochloride
Given IV

Drug: Dexamethasone
Given PO or IV

Drug: Dexrazoxane Hydrochloride
Given IV

Drug: Doxorubicin
Given IV

Drug: Etoposide
Given IV

Biological: Filgrastim
Given IV

Drug: Ifosfamide
Given IV

Drug: Imatinib Mesylate
Given PO

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Leucovorin Calcium
Given PO or IV

Drug: Mercaptopurine
Given PO

Drug: Mercaptopurine
Given PO

Drug: Methotrexate
Given IT

Drug: Methylprednisolone
Given IV

Drug: Pegaspargase
Given IV

Drug: Prednisolone
Given PO

Other: Questionnaire Administration
Ancillary studies

Drug: Therapeutic Hydrocortisone
Given IT

Drug: Thioguanine
Given PO

Drug: Vincristine Sulfate
Given IV




Primary Outcome Measures :
  1. Disease free survival (DFS) of Randomized Arms (standard risk [SR] Philadelphia chromosome [Ph+] acute lymphoblastic leukemia [ALL] patients) [ Time Frame: Up to 3 years ]
    Three-year DFS and 95% confidence intervals (CI) of SR Ph+ 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.


Secondary Outcome Measures :
  1. DFS on Randomized Arms (SR Ph+ ALL and ABL-class fusion positive patients) [ Time Frame: Up to 3 years ]
    Three-year DFS (time from randomization to relapse, second malignancy, or death in complete remission) and 95% CI of SR pediatric Ph+ and ABL-class fusion positive patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.

  2. Feasibility of post hematopoietic stem cell transplantation (HSCT) imatinib mesylate administration after allogenic HSCT in high risk Ph+ ALL patients [ Time Frame: Up to 2 years ]
    The proportion of patients who receive at least 75% of intended doses.

  3. 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: Up to 3 years ]

    Will be estimated using the Kaplan-Meier method and standard errors estimated by Greenwood.

    Three-year EFS and 95% CI for high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate. EFS is defined as the time from the date of bone marrow for minimal residual disease (MRD) assessment at end-IB to first event (resistant disease [MRD >= 10-2 or morphologic residual disease at end of consolidation block 3], relapse, progressive disease [i.e., MRD >= 10-2 at two post-HSCT time points separated by at least 2 weeks], second malignancy, or death in complete remission), or time to last follow-up for patients without events.


  4. Incidence of grade 3 or higher infections in standard risk Ph+ ALL patients in the two randomized arms [ Time Frame: Up to 3 years ]
    Evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The rate of infections during the post IB/pre-maintenance phases of treatment will be described for each randomization group.

  5. EFS of all Ph+ patients [ Time Frame: Up to 3 years ]
    Three-year EFS and 95% CI for Ph+ ALL patients. EFS here is defined as the time from enrollment until resistant disease, relapse, progressive disease post-HSCT, second malignant, or death, whichever occurs first.

  6. Overall survival (OS) of all Ph+ patients [ Time Frame: Up to 3 years ]
    Three-year OS and 95% CI for Ph+ ALL patients. OS is defined as the time from study enrollment to death from any cause.

  7. OS of SR Ph+ patients [ Time Frame: Up to 3 years ]
    Three-year OS (time from randomization to death from any cause) and 95% CI of SR pediatric Ph+ patients

  8. OS of SR Ph+ patients by randomization group [ Time Frame: Up to 3 years ]
    Three-year OS (time from randomization to death from any cause) and 95% CI of SR pediatric Ph+ patients by randomization group: treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.

  9. OS of high risk Ph+ patients [ Time Frame: Up to 3 years ]
    Three-year OS (time from the date of MRD assessment at end-IB to death from any cause) and 95% CI of HR pediatric Ph+ patients.

  10. EFS of all eligibility ABL-class fusion positive ALL patients [ Time Frame: Up to 3 years ]
    Three-year EFS (time from enrollment until resistant disease, relapse, progressive disease post-HSCT, second malignancy, or death, whichever occurs first) and 95% CI of ABL-class fusion positive patients.

  11. OS of all eligibility ABL-class fusion positive ALL patients [ Time Frame: Up to 3 years ]
    Three-year OS (the time from study enrollment to death from any cause) and 95% CI of ABL-class fusion positive patients.


Other Outcome Measures:
  1. Incidence of toxicities associated with post-HSCT administration of imatinib mesylate [ Time Frame: Up to 1 year post-HSCT ]
    Evaluated according to NCI CTCAE version 5.0. 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.

  2. Incidence of long-term toxicities in patients treated with chemotherapy plus imatinib mesylate (no transplant) in both arms [ Time Frame: Up to 3 years ]
    Evaluated according to NCI CTCAE version 5.0. 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.

  3. MRD measured by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) and next generation sequencing (NGS) assay [ Time Frame: Up to 6 months ]
    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.

  4. MRD in high risk Ph+ patients measured by IGH-TCR PCR and NGS assay [ Time Frame: Up to 3 years ]
    The outcome of high risk Ph+ 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.

  5. MRD assessments made by IGH-TCR PCR assay and NGS assay [ Time Frame: Up to 3 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.

  6. IKZF1 gene aberrations and deletions [ Time Frame: Up to 3 years ]
    For both standard risk and high risk groups, frequencies and prognostic significance (OS, DFS) will be explored for IKZF1 gene aberrations and deletions.

  7. Frequency of p190 and p210 BCR-ABL1 fusion variants [ Time Frame: Up to 3 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.

  8. Adherence to oral chemotherapeutic agents in standard risk Ph+ ALL patients [ Time Frame: Up to 2 years ]
    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.

  9. Adherence to imatinib mesylate after allogeneic HSCT in high risk Ph+ ALL patients [ Time Frame: Up to 2 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnostic samples will be collected and analyzed according to the procedures of the National front-line protocol

    • Patients should be enrolled on National ALL protocol prior to enrollment on EsPhALL2017/COGAALL1631. Regardless of initial front-line protocol baseline diagnostic samples must be available to develop an MRD probe
  • BCR-ABL1 fusion (Ph+): newly diagnosed ALL (B-ALL or T-ALL) or mixed phenotypic acute leukemia (MPAL meeting 2016 World Health Organization [WHO] definition) with definitive evidence of BCR-ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or reverse transcriptase (RT)-PCR
  • ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions identified according to National/Center procedures of each participating country. ABL-class fusions are defined as those involving the following genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA, LYN. Methods of detection include fluorescence in-situ hybridization (FISH, e.g. using break-apart or colocalization signals probes), multiplex or singleplex reverse-transcription polymerase chain reaction (RT-PCR), whole transcriptome or panel-based ribonucleic acid (RNA)-sequencing

    • Regardless of initial front-line protocol, laboratory reports detailing evidence of BCR-ABL1 or ABL-class fusion must be available for the National Trial Unit
  • Ph+ ALL patients must have previously started induction therapy, which includes vincristine, a corticosteroid, usually PEG-L-asparaginase, with or without anthracycline, and/or other standard cytotoxic chemotherapy
  • Ph+ ALL patients have not received more than 14 days of multiagent induction therapy beginning with the first dose of vincristine
  • Ph+ ALL patients may have started imatinib prior to study entry but have not received more than 14 days of imatinib
  • ABL-class fusion patients must have previously completed the 4 or 5 weeks of multiagent Induction chemotherapy
  • ABL-class fusion patients may have started imatinib during Induction IA, at the same time of or after the first vincristine dose
  • 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 and electrocardiogram are not required if they were performed at or after initial ALL diagnosis, before study enrollment
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or 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 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 treatment according to protocol
  • Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block
  • Prior treatment with dasatinib, or any TKI inhibitor other than imatinib
  • All patients and/or their parents or legal guardians must sign a written informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03007147


Locations
Show Show 219 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Lewis B Silverman Children's Oncology Group
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Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT03007147    
Other Study ID Numbers: AALL1631
NCI-2016-01588 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AALL1631
AALL1631 ( Other Identifier: Children's Oncology Group )
AALL1631 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: January 2, 2017    Key Record Dates
Last Update Posted: June 22, 2022
Last Verified: September 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Leucovorin
Cytarabine
Dexamethasone
Methylprednisolone
Prednisolone
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Cyclophosphamide
Ifosfamide
Doxorubicin
Methotrexate
Etoposide
Vincristine
Imatinib Mesylate