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 : March 28, 2022
|
Sponsor:
Children's Oncology Group
Collaborators:
National Cancer Institute (NCI)
EsPhALL network I-BFM Study Group
Information provided by (Responsible Party):
Children's Oncology Group
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
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.
| 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 detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 700 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 : | June 30, 2028 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Arm A (imatinib mesylate, EsPhALL chemotherapy)
See Detailed Description
|
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:
|
|
Experimental: Arm B (imatinib mesylate, COG/BFM chemotherapy)
See Detailed Description.
|
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:
|
|
Experimental: Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)
See Detailed Description
|
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo HSCT
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:
|
Primary Outcome Measures :
- 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.
Secondary Outcome Measures :
- 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 [ 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 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.
Other Outcome Measures:
- 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.
- 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: 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.
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.
| Ages Eligible for Study: | 2 Years to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
-
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 must be submitted for rapid central review within 72 hours of study enrollment
- 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 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 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
- 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
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 219 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
EsPhALL network I-BFM Study Group
Investigators
| Principal Investigator: | Lewis B Silverman, MD | Children's Oncology Group | |
| Principal Investigator: | Prof. Andrea Biondi | EsPhALL network I-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 AALL1631 ( Other Identifier: Childrens Oncology Group ) AALL1631 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) 2017-000705-20 ( EudraCT Number ) |
| First Posted: | January 2, 2017 Key Record Dates |
| Last Update Posted: | March 28, 2022 |
| Last Verified: | July 2021 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
|
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 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 Cyclophosphamide |