NCT02393859 · CITED IN SOURCE DOCUMENTS

Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2026-06-26

B-precursor ALL is an aggressive malignant disease. Therapy is usually stratified according to risk characteristics to ensure that appropriate treatment is administered to patients with high-risk of relapse. In general, pediatric treatment regimens are more intense than those employed in adults and include courses of combination chemotherapy. Standard of care chemotherapy is associated with considerable toxicity. There is a lack of novel treatment options for subjects who relapse or are refractory to treatment. Therefore, innovative therapeutic approaches are urgently needed. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against CD19 expressing cells. This study will evaluate the event-free survival (EFS) after treatment with blinatumomab when compared to standard of care (SOC) chemotherapy. The effect of blinatumomab on overall survival and reduction of minimal residual disease compared to SOC chemotherapy will also be investigated.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Kaplan Meier Estimate: Event-Free Survival (EFS; Primary Analysis)

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outcome · POSTED

Kaplan Meier Estimate: EFS (Final Analysis)

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outcome · POSTED

Kaplan Meier Estimate: Overall Survival (OS)

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outcome · POSTED

Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation

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outcome · POSTED

Cumulative Incidence of Relapse (CIR)

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outcome · POSTED

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs)

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outcome · POSTED

Number of Participants With TEAEs of Interest

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outcome · POSTED

Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values

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outcome · POSTED

Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)

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outcome · POSTED

Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only)

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outcome · POSTED

Pharmacokinetics: Concentration at Steady State (Css) (Blinatumomab Arm Only)

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outcome · POSTED

Pharmacokinetics: Clearance (CL) (Blinatumomab Arm Only)

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: * Subjects with Philadelphia chromosome negative (Ph-) high-risk (HR) first relapse B-precursor acute lymphoblastic leukemia (ALL; as defined by International Berlin-Frankfurt-Muenster study group/International study for treatment of childhood relapsed ALL \[I-BFM SG/IntReALL\] criteria) * Subjects with bone marrow blast percentage \< 5% (M1) or bone marrow blast percentage \< 25% and ≥5% (M2) marrow at the time of randomization, * Age \> 28 days and \< 18 years at the time of informed consent/assent * Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated * Availability of the following material from relapse diagnosis for central analysis of minimal residual disease (MRD) by polymerase chain reaction (PCR): clone-specific primers and reference deoxyribonucleic acid (DNA), as well as primer sequences and analyzed sequences of clonal rearrangements (cases with isolated extramedullary relapse or cases with technical and/or logistic hurdles to obtain and process bone marrow material are exempt from providing this material. In these cases, central MRD analysis only by Flow is permitted). Exclusion Criteria: * Clinically relevant central nervous system (CNS) pathology requiring treatment (eg, unstable epilepsy). Evidence of current CNS (CNS 2, CNS 3) involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully treated prior to enrollment * Peripheral neutrophils \< 500/μL prior to start of treatment * Peripheral platelets \< 50,000/μL prior to start of treatment * Currently receiving treatment in another investigational device or drug study or less than 4 weeks since ending treatment on another investigational device or drug study(s), procedures required by IntReALL high-risk (HR) guidelines are allowed * Chemotherapy related toxicities that have not resolved to ≤ grade 2 (except for parameters defined in Exclusion Criteria 202, 203, 204, and 217) * Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol * Abnormal renal or hepatic function prior to start of treatment (day 1) as defined below * Abnormal serum creatinine based on age/gender * Total bilirubin \> 3.0 mg/dL prior to start of treatment (unless related to Gilbert's or Meulengracht disease) * Documented infection with human immunodeficiency virus (HIV) * Known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing (excluding asparaginase) * Post-menarchal female subject who is pregnant or breastfeeding, or is planning to become pregnant or breastfeed while receiving protocol-specified therapy and for at least 12 months after the last dose of chemotherapy * Post-menarchal female subject who is not willing to practice true sexual abstinence or use a highly effective form of contraception while receiving protocol-specified therapy and for at least 12 months after the last dose of chemotherapy * Sexually mature male subject who is not willing to practice true sexual abstinence or use a condom with spermicide while receiving protocol-specified therapy and for at least 6 months after last dose of chemotherapy. In countries where spermicide is not available, a condom without spermicide is acceptable * Sexually mature male subject who is not willing to abstain from sperm donation while receiving protocol-specified therapy and for at least 6 months after last dose of chemotherapy * Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject's and investigator's knowledge * History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion * Placed into an institution due to juridical or regulatory ruling.
healthy Volunteers: false
maximum Age: 17 Years
minimum Age: 0 Years
sex: ALL
std Ages: CHILD

Treatment arms and interventions

arm Groups

description
One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day intravenous \[IV\] on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or intramuscularly \[IM\] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).
intervention Names
Drug: Dexamethasone
Drug: Vincrisitne
Drug: Daunorubicin
Drug: Methotrexate
Drug: Ifosfamide
Drug: PEG-asparaginase
Drug: Erwinia-asparaginase
label
High Risk Consolidation 3 (HC3) Chemotherapy
type
ACTIVE_COMPARATOR
description
15 μg/m\^2/day as a continuous intravenous infusion (CIVI) for 4 weeks
intervention Names
Drug: Blinatumomab
label
Blinatumomab
type
EXPERIMENTAL

interventions

arm Group Labels
Blinatumomab
description
15 μg/m\^2/day as a continuous intravenous infusion (CIVI) for 4 weeks
name
Blinatumomab
other Names
Blincyto, AMG103
type
DRUG
arm Group Labels
High Risk Consolidation 3 (HC3) Chemotherapy
description
10 mg/m\^2/day intravenous (IV) on Days 1-6
name
Dexamethasone
type
DRUG
arm Group Labels
High Risk Consolidation 3 (HC3) Chemotherapy
description
1.5 mg/m\^2/day IV on Days 1 and 6
name
Vincrisitne
type
DRUG
arm Group Labels
High Risk Consolidation 3 (HC3) Chemotherapy
description
30 mg/m\^2 IV over 24 hours on Day 5
name
Daunorubicin
type
DRUG
arm Group Labels
High Risk Consolidation 3 (HC3) Chemotherapy
description
1 g/m\^2 IV over 36 hours on Day 1
name
Methotrexate
type
DRUG
arm Group Labels
High Risk Consolidation 3 (HC3) Chemotherapy
description
800 mg/m\^2 IV for 1 hour on Days 2-4
name
Ifosfamide
type
DRUG
arm Group Labels
High Risk Consolidation 3 (HC3) Chemotherapy
description
1000 U/m\^2 IV for 2 hours or intramuscularly (IM) on Day 6
name
PEG-asparaginase
type
DRUG
arm Group Labels
High Risk Consolidation 3 (HC3) Chemotherapy
description
In case of allergic reaction to PEG-asparaginase, participants could change to erwinia-asparaginase, 20,000 units/m2 every 48 hours for a total of 6 doses
name
Erwinia-asparaginase
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 111
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
EFS is calculated from the time of randomization until the date of relapse or M2 marrow (representative bone marrow aspirate or biopsy with ≥ 5% and \< 25% blasts) after having achieved a complete remission (CR), failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with investigational product (IP) or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date. Participants were said to be in CR when they had the following: * M1 marrow * Peripheral blood without blasts * Absence of extramedullary leukemic involvement Months are calculated as days from randomization date to event/censor date, divided by 30.5.
measure
Kaplan Meier Estimate: Event-Free Survival (EFS; Primary Analysis)
time Frame
As of the primary analysis data cutoff date (17 July 2019), overall median follow-up time for EFS was 22.4 months.
description
EFS is calculated from the time of randomization until the date of relapse or M2 marrow after having achieved a CR, failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with IP or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date. Participants were said to be in CR when they had the following: * M1 marrow * Peripheral blood without blasts * Absence of extramedullary leukemic involvement Months are calculated as days from randomization date to event/censor date, divided by 30.5.
measure
Kaplan Meier Estimate: EFS (Final Analysis)
time Frame
At final analysis, overall median follow-up time for EFS was 51.9 months.

secondary Outcomes

description
OS was calculated from time of randomization until death due to any cause. Participants still alive were censored at the date they were last known to be alive. Months were calculated as days from randomization date to event/censor date, divided by 30.5.
measure
Kaplan Meier Estimate: Overall Survival (OS)
time Frame
At final analysis, overall median follow-up time for OS was 55.2 months.
description
At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory. MRD response was defined as MRD level \< 10\^-4, by polymerase chain reaction (PCR) or flow cytometry, at the end of treatment (Cycle 1 Day 29) with study drug. Participants who were part of the MRD Evaluable Set and were missing the end of treatment (Cycle 1 Day 29) assessment for a respective MRD assessment method were considered not to have achieved a response.
measure
Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation
time Frame
Up to End of Treatment (Cycle 1, Day 29)
description
CIR estimate, presented as median months to relapse, calculated from date of achievement of first CR, using the cumulative incidence method (Fine JP, Gray RJ:1999). Deaths prior to relapse not considered related to an otherwise undocumented relapse were treated as a competing risk. Participants still alive without a date of relapse were censored at the time of last follow-up. Relapse=presence of ≥1 of the following: * isolated bone marrow relapse (M3 marrow \[representative bone marrow aspirate or biopsy with ≥25% blasts\] in the absence of extramedullary involvement) * combined bone marrow relapse (M2 \[representative bone marrow aspirate or biopsy with ≥5% and \<25% blasts\] or M3 marrow and ≥1 extramedullary manifestation of acute lymphoblastic leukemia) * central nervous system extramedullary relapse * testicular extramedullary relapse * extramedullary relapse at other sites Months were calculated as days from randomization to event/censor date, divided by 30.5.
measure
Cumulative Incidence of Relapse (CIR)
time Frame
At final analysis, the overall maximum follow-up time was 82.0 months.
description
Adverse event (AE): any untoward medical occurrence. Serious AE: an AE meeting at least 1 of the following serious criteria: fatal; life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Severity was graded according to the Common Terminology Criteria for AEs (CTCAE) version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Investigational product (IP) in the HC3 arm refers to dexamethasone, methotrexate, daunorubicin, erwinase, ifosfamide, asparaginase, and vincristine, and in the blinatumomab arm refers to blinatumomab. Treatment-related refers to the assessment of a relationship between IP and the event.
measure
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs)
time Frame
From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
description
TEAEs of interest included capillary leak syndrome (CLS), cytokine release syndrome (CRS), decreased immunoglobulins (DI), elevated liver enzymes (ELE), embolic and thrombotic events (ETE), infections (INF), infusion reactions without considering duration (IRWCD), medication errors (ME), neurologic events (NE), neutropenia and febrile neutropenia (NFN), pancreatitis (PNC), tumor lysis syndrome, leukoencephalopathy, immunogenicity. Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death.
measure
Number of Participants With TEAEs of Interest
time Frame
From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
description
Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Increases (↑) or decreases (↓) in laboratory value grades (Gr) from baseline (BL) to worst postbaseline (→ PB) grade are presented. NA=not available.
measure
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values
time Frame
Up to Day 29 (± 2 days).
description
The analysis of 100-day mortality after alloHSCT was assessed for participants who received an alloHSCT while in remission and did not receive any additional anti-leukemic treatment. 100-day mortality after alloHSCT was calculated relative to the date of alloHSCT. The 100-day mortality rate after alloHSCT was defined as the percentage of participants having died up to 100 days after alloHSCT, estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants still alive were censored at the date they were last known to be alive.
measure
Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)
time Frame
From the date of alloHSCT until death/censor date; median follow up time was 1742.0 days for blinatumomab and 1619.0 days for HC3.
description
Participants receiving blinatumomab had blood samples analyzed for binding antibodies. Samples testing positive for binding antibodies were also tested for neutralizing antibodies. Participants who were binding antibody-positive or neutralizing antibody-positive post-baseline with a negative or no result at baseline are presented.
measure
Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only)
time Frame
Day 1 to Day 29.
measure
Pharmacokinetics: Concentration at Steady State (Css) (Blinatumomab Arm Only)
time Frame
Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15
measure
Pharmacokinetics: Clearance (CL) (Blinatumomab Arm Only)
time Frame
Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15

Full study description

brief Summary: B-precursor ALL is an aggressive malignant disease. Therapy is usually stratified according to risk characteristics to ensure that appropriate treatment is administered to patients with high-risk of relapse. In general, pediatric treatment regimens are more intense than those employed in adults and include courses of combination chemotherapy. Standard of care chemotherapy is associated with considerable toxicity. There is a lack of novel treatment options for subjects who relapse or are refractory to treatment. Therefore, innovative therapeutic approaches are urgently needed. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against CD19 expressing cells. This study will evaluate the event-free survival (EFS) after treatment with blinatumomab when compared to standard of care (SOC) chemotherapy. The effect of blinatumomab on overall survival and reduction of minimal residual disease compared to SOC chemotherapy will also be investigated.
detailed Description: Patients will be randomized in a 1:1 ratio to receive either one cycle of blinatumomab or one block of standard high-risk consolidation chemotherapy. Blinatumomab is administered as a continuous intravenous infusion (CIVI). One cycle of blinatumomab treatment includes 4 weeks of CIVI of blinatumomab. After completing consolidation therapy, the patients should undergo alloHSCT depending on their bone marrow status. The patients will be followed up until the last subject on study is 36 months following alloHSCT or has died, whichever is first.

Source references

references

citation
Locatelli F, Eckert C, Hrusak O, Buldini B, Sartor M, Zugmaier G, Zeng Y, Pilankar D, Morris J, von Stackelberg A. Blinatumomab overcomes poor prognostic impact of measurable residual disease in pediatric high-risk first relapse B-cell precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2022 Aug;69(8):e29715. doi: 10.1002/pbc.29715. Epub 2022 Apr 28.
pmid
35482538
type
BACKGROUND
citation
Blinatumomabe em pacientes pediátricos com leucemia linfoblástica aguda B em primeira recidiva de alto risco: um estudo de custo-efetividade. van Beurden-Tan CHY, Ribeiro RA, Seber A, de Martino Lee ML, Marçola M, Schuetz R, Loggetto SR, Maiolino A. Jornal Brasileiro de Economia da Saúde 14(1): 41-50. 10.21115/JBES.v14.n1.p41-50
type
BACKGROUND
citation
Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, Moricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):843-854. doi: 10.1001/jama.2021.0987.
pmid
33651091
type
BACKGROUND
citation
Caillon M, Brethon B, van Beurden-Tan C, Supiot R, Le Mezo A, Chauny JV, Majer I, Petit A. Cost-Effectiveness of Blinatumomab in Pediatric Patients with High-Risk First-Relapse B-Cell Precursor Acute Lymphoblastic Leukemia in France. Pharmacoecon Open. 2023 Jul;7(4):639-653. doi: 10.1007/s41669-023-00411-4. Epub 2023 Apr 18.
pmid
37071263
type
BACKGROUND
citation
Peters C, Bruno A, Rizzari C, Brescianini A, Von Stackelberg A, Linderkamp C, Zeng Y, Zugmaier G, Locatelli F. Blinatumomab is associated with better post-transplant outcome than chemotherapy in children with high-risk, first-relapse B-cell acute lymphoblastic leukemia irrespective of the conditioning regimen. Haematologica. 2025 Jan 1;110(1):234-238. doi: 10.3324/haematol.2024.285837. No abstract available.
pmid
39234873
type
BACKGROUND
citation
Locatelli F, Rizzari C, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Eckert C, Moricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, Desai R, Henry M, Zugmaier G, von Stackelberg A. Blinatumomab consolidation in children with high-risk first-relapse B-cell precursor acute lymphoblastic leukemia: final 5-year follow-up analysis of a randomized multicenter phase 3 study. Leukemia. 2026 Jan;40(1):230-234. doi: 10.1038/s41375-025-02800-6. Epub 2025 Nov 13. No abstract available.
pmid
41233549
type
BACKGROUND
citation
Diaz Martinez JP, de Maraumont TA, Camacho LM, Garcia L. Cost-effectiveness of blinatumomab for the treatment of B-precursor acute lymphoblastic leukemia pediatric patients with high-risk first-relapse in Mexico. Leuk Res. 2024 Oct;145:107560. doi: 10.1016/j.leukres.2024.107560. Epub 2024 Aug 22.
pmid
39214018
type
DERIVED