Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations
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ClinicalTrials.gov Identifier: NCT02883049 |
Recruitment Status :
Active, not recruiting
First Posted : August 30, 2016
Last Update Posted : January 31, 2023
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
B Acute Lymphoblastic Leukemia B Acute Lymphoblastic Leukemia With BCR-ABL1-Like Features Central Nervous System Leukemia Testicular Leukemia | Drug: Clofarabine Drug: Cyclophosphamide Drug: Cytarabine Drug: Dasatinib Drug: Daunorubicin Hydrochloride Drug: Dexamethasone Drug: Doxorubicin Hydrochloride Drug: Etoposide Drug: Hydrocortisone Sodium Succinate Other: Laboratory Biomarker Analysis Drug: Leucovorin Calcium Drug: Mercaptopurine Drug: Methotrexate Drug: Pegaspargase Drug: Prednisone Radiation: Radiation Therapy Drug: Thioguanine Drug: Vincristine Sulfate | Phase 3 |

Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 5937 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase III Randomized Trial for Newly Diagnosed High Risk B-Lymphoblastic Leukemia (B-ALL) Including a Stratum Evaluating Dasatinib (NSC#732517) in Patients With Ph-like Tyrosine Kinase Inhibitor (TKI) Sensitive Mutations |
Actual Study Start Date : | February 27, 2012 |
Actual Primary Completion Date : | December 31, 2022 |
Estimated Study Completion Date : | January 27, 2024 |

Arm | Intervention/treatment |
---|---|
Experimental: DS HR B-ALL (RER)
Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Dexamethasone PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
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 and IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisone Given PO or IV
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
|
Experimental: DS HR B-ALL (SER)
Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
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 and IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisone Given PO or IV
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
|
Experimental: Group I Arm A (HR B-ALL)
Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
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 and IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisone Given PO or IV
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
|
Experimental: Group I Arm B (HR B-ALL) (CLOSED 03/19/2018)
Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Hydrocortisone Sodium Succinate Given IT
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 and IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisone Given PO or IV
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
|
Active Comparator: Group II Arm A (VHR B-ALL - Control Arm)
Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
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 and IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisone Given PO or IV
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
|
Experimental: Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017)
Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
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 and IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisone Given PO or IV
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
|
Experimental: Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014)
Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. |
Drug: Clofarabine
Given IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
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 and IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisone Given PO or IV
Other Names:
Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
|
Experimental: Group III PH-like predicted TKI-sensitive kinase mutation
Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Dasatinib Given PO
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
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 and IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Drug: Prednisone Given PO or IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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- Comparison of disease-free survival (DFS) of children with high-risk (HR) B-acute lymphoblastic leukemia (ALL) (Completed effective March 19, 2018) [ Time Frame: At 5 years ]DFS of children with HR B-acute ALL receiving post-induction age adjusted intrathecal triple therapy (ITT) on an Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance high-dose methotrexate (IMHDM) backbone will be compared to age adjusted intrathecal (IT) methotrexate (MTX). Compared using 2-sided log rank test, alpha = 5%.
- DFS of children, adolescents, and young adults with very high-risk (VHR) B-ALL between arms (Completed effective February 15, 2017) [ Time Frame: At 4 years ]DFS of children, adolescents, and young adults with VHR B-ALL will be compared in all arms using 1-sided log rank test, alpha 0.025.
- Toxicity and tolerability of post-induction age-adjusted ITT compared to age-adjusted IT MTX in children with HR B-ALL (Completed effective March 19, 2018) [ Time Frame: Up to 10 years ]Graded using the version 5.0 Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI).
- Toxicity and tolerability of Experimental arm and Control arm in patients with VHR B-ALL (Closed effective February 15, 2017) [ Time Frame: Up to 10 years ]Graded using the version 5.0 CTCAE of the NCI.
- Induction mortality in patients with DS and HR B-ALL treated with modified Induction [ Time Frame: At 1 month ]Induction mortality rate will be calculated.
- 5-year DFS in patients with Down syndrome (DS) and HR B-ALL treated with modified Induction and post-Induction therapy regimen with MBFM-IMIDM [ Time Frame: At 5 years ]5-year DFS for patients with DS and HR B-ALL will be estimated using the Kaplan-Meier method.
- DFS for children and young adults with Ph-like B-ALL and a predicted tyrosine kinase inhibitor (TKI)-sensitive mutation treated with dasatinib plus MBFM-IMHDM [ Time Frame: Up to 4 years ]4-year DFS will be estimated using the Kaplan-Meier method.
- Toxicity and tolerability of MBFM-interim maintenance intermediate dose methotrexate (IMIDM) in children with Down syndrome [ Time Frame: Up to 10 years ]Graded using the version 5.0 CTCAE of the NCI.
- Overall survival (OS) rate for HR B-ALL patients [ Time Frame: At 5 years ]5-year OS will be estimated for the two randomized arms using the Kaplan-Meier method.
- OS rate for VHR B-ALL patients [ Time Frame: At 4 years ]4-year OS will be estimated for the two randomized arms using the Kaplan-Meier method.
- Change in the minimal residual disease (MRD) from end-Induction to end-Consolidation (Closed effective Amendment 6) [ Time Frame: Up to 90 days ]Whether the reduction of MRD from end-Induction to end-Consolidation is greater for children, adolescents, and young adults with VHR B-ALL receiving Experimental Arms 1 and/or 2 compared to the Control Arm will be determined.

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Ages Eligible for Study: | 1 Year to 31 Years (Child, Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients must be enrolled on APEC14B1 and consented to Eligibility Screening on the Part A consent form prior to enrollment on AALL1131
-
White Blood Cell Count (WBC) Criteria
- Age 1-9.99 years: WBC >= 50 000/uL
- Age 10-30.99 years: Any WBC
-
Age 1-30.99 years: Any WBC with:
- Testicular leukemia
- CNS leukemia (CNS3)
- Steroid pretreatment
- Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health Organization [WHO] classification) (also termed B-precursor acute lymphoblastic leukemia); patients with Down syndrome are also eligible
- Organ function requirements for patients with Ph-like ALL and a predicted TKI-sensitive mutation: patients identified as Ph-like with a TKI-sensitive kinase mutation must have assessment of organ function performed within 3 days of study entry onto the dasatinib arm of AALL1131
-
Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
- Age: Maximum Serum Creatinine (mg/dL)
- 1 to < 6 months: 0.4 (male) 0.4 (female)
- 6 months to < 1 year: 0.5 (male) 0.5 (female)
- 1 to < 2 years: 0.6 (male) 0.6 (female)
- 2 < 6 years: 0.8 (male) 0.8 (female)
- 6 to < 10 years: 1.0 (male) 1.0 (female)
- 10 to < 13 years: 1.2 (male) 1.2 (female)
- 13 to < 16 years: 1.5 (male) 1.4 (female)
- > 16 years: 1.7 (male) 1.4 (female)
- Direct bilirubin =< 3 x upper limit of normal (ULN) for age, and
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 10 x upper limit of normal (ULN) for age
-
Shortening fraction >= 27% by echocardiogram, or ejection fraction >= 50% by gated radionuclide study
- Patients must have an electrocardiogram (EKG) fewer than 6 days prior to enrollment on the dasatinib arm; patients who have had cardiac assessments by echocardiogram or radionuclide scan at the beginning of induction do not need to have these repeated prior to study entry; correct QT interval (QTc) < 450 msec on baseline electrocardiogram as measured by the Friderica or Bazett formula
- No major conduction abnormality (unless a cardiac pacemaker is present)
- No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% at sea level if there is clinical indication for determination
- Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled; however, drugs that induce CYP3A4/5 (carbamazepine, oxcarbazepine, phenytoin, primidone, phenobarbital) should be avoided
-
Eligibility criteria for the Longitudinal, Computerized Assessment of Neurocognitive Functioning study
- Patients must be aged 6 to 13 years at time of B-ALL diagnosis, enrolled on AALL1131
- Patients must be English-, French- or Spanish-speaking (languages in which the assessment is available)
- Patients must have no known history of neurodevelopmental disorder prior to diagnosis of B-ALL (e.g., Down syndrome, Fragile X, William's Syndrome, mental retardation)
- Patients must have no significant visual impairment that would prevent computer use and recognition of the visual test stimuli
- Eligibility criteria for the National Cancer Institute (NCI) standard risk patients from AALL0932 enrolling on this study at the end of Induction
-
Effective March 19, 2018, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the HR B-ALL stratum of this study at the end of Induction:
- Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with day 8 peripheral blood (PB) minimal residual disease (MRD) >= 1% and day 29 bone marrow (BM) MRD < 0.01%
- With favorable cytogenetics (ETV6-RUNX1 or double trisomies 4+10), with any day 8 PB MRD and day 29 BM MRD >= 0.01%
- Both NCI standard risk (SR) and HR patients without Down syndrome and with testicular disease at diagnosis, who do not meet other VHR criteria
-
Effective Amendment 6, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the VHR stratum of AALL1131:
- Intrachromosomal amplification of chromosome 21 (iAMP21)
- Mixed-lineage leukemia (MLL) rearrangement
- Hypodiploidy (n < 44 chromosomes and/or a deoxyribonucleic acid [DNA] index < 0.81)
- Induction failure (M3 BM at day 29)
- Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with day 29 BM MRD >= 0.01%
-
Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS HR B-ALL stratum of this study at the end of Induction:
- Day 29 MRD >= 0.01%
- MLL rearrangement
- Hypodiploidy (n < 45 chromosomes and/or DNA index < 0.81)
- DS HR B-ALL patients initially enrolled on AALL0932 or this study who have Induction failure (M3 BM day 29) or Philadelphia chromosome (BCR-ABL1) will not be eligible for post-Induction therapy on either trial (AALL0932 or AALL1131)
- All patients and/or their parents or legal guardians must sign a written informed consent
- All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met
Exclusion Criteria:
- With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B-ALL or any cancer diagnosed prior to the initiation of protocol therapy on AALL1131; patients cannot have secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy; patients receiving prior steroid therapy may be eligible for AALL1131
- Patients with BCR-ABL1 fusion are not eligible for post-induction therapy on this study but may be eligible to enroll in a successor Children's Oncology Group (COG) Philadelphia positive (Ph+) ALL trial by day 15 Induction
- DS HR B-ALL patients with Induction failure or BCR-ABL1
- Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs
- Lactating females are not eligible unless they have agreed not to breastfeed their infant
- Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
- Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation

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): NCT02883049

Principal Investigator: | Michael J Burke | Children's Oncology Group |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | National Cancer Institute (NCI) |
ClinicalTrials.gov Identifier: | NCT02883049 |
Obsolete Identifiers: | NCT01406756 |
Other Study ID Numbers: |
NCI-2011-03797 NCI-2011-03797 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) S12-01254 CDR0000706370 COG-AALL1131 AALL1131 ( Other Identifier: Children's Oncology Group ) AALL1131 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) U10CA098543 ( U.S. NIH Grant/Contract ) |
First Posted: | August 30, 2016 Key Record Dates |
Last Update Posted: | January 31, 2023 |
Last Verified: | January 2023 |
Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Calcium, Dietary Leucovorin Folic Acid Cytarabine Dexamethasone Dexamethasone acetate |
Prednisone Hydrocortisone Hydrocortisone 17-butyrate 21-propionate Hydrocortisone acetate Hydrocortisone hemisuccinate Cortisone Cyclophosphamide Doxorubicin Liposomal doxorubicin Methotrexate Etoposide Vincristine Etoposide phosphate Daunorubicin Asparaginase |