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 |
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Recruitment Status :
Recruiting
First Posted : January 2, 2017
Last Update Posted : April 11, 2024
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Sponsor:
Children's Oncology Group
Collaborators:
EsPhALL Network/ BFM Study Group
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
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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: Calaspargase Pegol 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 detailed description
| 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 : | August 8, 2017 |
| Estimated Primary Completion Date : | September 30, 2027 |
| Estimated Study Completion Date : | September 30, 2027 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
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Drug: Calaspargase Pegol
Given IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IV, SC, or IT
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Dexrazoxane Hydrochloride Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Biological: Filgrastim Given IV
Other Names:
Drug: Ifosfamide Given IV
Other Names:
Drug: Imatinib Mesylate Given PO
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Leucovorin Calcium Given PO or IV
Other Names:
Drug: Mercaptopurine Given PO
Other Names:
Drug: Mercaptopurine Given PO
Other Names:
Drug: Methotrexate Given IT
Other Names:
Drug: Methylprednisolone Given IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisolone Given PO
Other Names:
Other: Questionnaire Administration Ancillary studies Drug: Therapeutic Hydrocortisone Given IT
Other Names:
Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
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Drug: Calaspargase Pegol
Given IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IV, SC, or IT
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Dexrazoxane Hydrochloride Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Imatinib Mesylate Given PO
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Leucovorin Calcium Given PO or IV
Other Names:
Drug: Mercaptopurine Given PO
Other Names:
Drug: Methotrexate Given IT
Other Names:
Drug: Methylprednisolone Given IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisolone Given PO
Other Names:
Other: Questionnaire Administration Ancillary studies Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
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Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo HSCT
Other Names:
Drug: Calaspargase Pegol Given IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IV, SC, or IT
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Dexrazoxane Hydrochloride Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Biological: Filgrastim Given IV
Other Names:
Drug: Ifosfamide Given IV
Other Names:
Drug: Imatinib Mesylate Given PO
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Leucovorin Calcium Given PO or IV
Other Names:
Drug: Mercaptopurine Given PO
Other Names:
Drug: Mercaptopurine Given PO
Other Names:
Drug: Methotrexate Given IT
Other Names:
Drug: Methylprednisolone Given IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisolone Given PO
Other Names:
Other: Questionnaire Administration Ancillary studies Drug: Therapeutic Hydrocortisone Given IT
Other Names:
Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Primary Outcome Measures :
- 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 :
- 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.
- 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.
- 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 ]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.
- 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.
- 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.
- 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.
- 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
- 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.
- 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.
- 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.
- 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:
- Incidence of toxicities associated with post-HSCT administration of imatinib mesylate [ Time Frame: Up to 2 years ]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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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| Ages Eligible for Study: | 1 Year to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
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For patients enrolled on APEC14B1 prior to enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled
- For patients who have not previously enrolled on APEC14B1 prior to enrollment on AALL1631, a baseline diagnostic sample (or peripheral blood sample with blasts if marrow sample unavailable) must be available to develop an MRD probe
- In addition, laboratory reports detailing evidence of BCR-ABL1 fusion or ABL-class fusion must be submitted for rapid central review within 72 hours of study enrollment
- >= 1 year (365 days) and =< 21 years at ALL diagnosis
- Ph+ (BCR-ABL1 fusion): newly diagnosed de novo 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 molecular methodologies
- ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions. ABL-class fusions are defined as those involving the following genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA. 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 (e.g. TruSight RNA Pan-Cancer Panel; Illumina, San Diego, CA, USA or similar)
- Ph+ patients must have previously started Induction therapy, which includes vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or other standard cytotoxic chemotherapy
- Ph+ patients have not received more than 14 days of multiagent Induction therapy beginning with the first dose of vinCRIStine
- Ph+ 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 (Induction IA phase)
- 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
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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
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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
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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 other than imatinib
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 227 study locations
Sponsors and Collaborators
Children's Oncology Group
EsPhALL Network/ BFM Study Group
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Lewis B Silverman | Children's Oncology Group | |
| Principal Investigator: | Prof. Andrea Biondi | EsPhALL Network/ BFM Study Group |
| 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 2017-000705-20 ( EudraCT Number ) 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: | April 11, 2024 |
| Last Verified: | April 2024 |
| 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 Hematologic Diseases Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Translocation, Genetic Chromosome Aberrations Pathologic Processes |
Calcium, Dietary Leucovorin Folic Acid Cytarabine Dexamethasone Dexamethasone acetate Methylprednisolone Methylprednisolone Acetate Methylprednisolone Hemisuccinate Prednisolone Prednisolone acetate Hydrocortisone Hydrocortisone 17-butyrate 21-propionate Hydrocortisone acetate Hydrocortisone hemisuccinate |