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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).

15 μg/m\^2/day as a continuous intravenous infusion (CIVI) for 4 weeks

10 mg/m\^2/day intravenous (IV) on Days 1-6

Vincrisitne

1000 U/m\^2 IV for 2 hours or intramuscularly (IM) on Day 6

PEG-asparaginase

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

Erwinia-asparaginase

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.

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.

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

Phase 3 Trial to Investigate the Efficacy, Safety, and Tolerability of Blinatumomab as Consolidation Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects With HR First Relapse B-precursor ALL

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Amgen

All-cause mortality is reported for all participants enrolled/randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.

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 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 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).

HC3 Chemotherapy

One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Stratification Factor: Age Category

M1 Marrow + MRD level ≥ 10^-3

M1 Marrow + MRD level < 10^-3

M2 Marrow

M1: representative bone marrow aspirate or biopsy with blasts \< 5%, with satisfactory cellularity and with regenerating hematopoiesis; M2: representative bone marrow aspirate or biopsy with ≥ 5% and \< 25% blasts; MRD=minimal residual disease levels ≥ 10\^-3 or \< 10\^-3, by polymerase chain reaction (PCR) or flow cytometry.

Stratification Factor: Marrow/Minimal Residual Disease (MRD)

The FAS included all randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received.

Study Director

Full Analysis Set: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received (primary analysis population).

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

FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received (final analysis population).

Kaplan Meier Estimate: EFS (Final Analysis)

FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received.

Kaplan Meier Estimate: Overall Survival (OS)

MRD Response by PCR

MRD Response by Flow Cytometry

MRD Evaluable Set: participants for whom an evaluable baseline MRD marker can be found with either of the MRD assessment methods of PCR or flow cytometry.

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

Cumulative Incidence of Relapse (CIR)

TEAEs

TEAEs Grade ≥ 3

Serious TEAEs

Fatal TEAEs

TEAEs Leading to Discontinuation of IP

TEAEs Leading to Interruption of IP

TRAEs

TRAEs Grade ≥ 3

Serious TRAEs

Fatal TRAEs

TRAEs Leading to Discontinuation of IP

TRAEs Leading to Interruption of IP

Safety Analysis Set: participants who received protocol-specified therapy analyzed according to the treatment they received.

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

CLS Events

CLS Events Grade ≥ 3

Serious CLS Events

Fatal CLS Events

CLS Events Leading to Discontinuation of IP

CLS Events Leading to Interruption of IP

CRS Events

CRS Events Grade ≥ 3

Serious CRS Events

Fatal CRS Events

CRS Events Leading to Discontinuation of IP

CRS Events Leading to Interruption of IP

DI Events

DI Events Grade ≥ 3

Serious DI Events

Fatal DI Events

DI Events Leading to Discontinuation of IP

DI Events Leading to Interruption of IP

ELE Events

ELE Events Grade ≥ 3

Serious ELE Events

Fatal ELE Events

ELE Events Leading to Discontinuation of IP

ELE Events Leading to Interruption of IP

ETE Events

ETE Events Grade ≥ 3

Serious ETE Events

Fatal ETE Events

ETE Events Leading to Discontinuation of IP

ETE Events Leading to Interruption of IP

INF Events

INF Events Grade ≥ 3

Serious INF Events

Fatal INF Events

IFN Events Leading to Discontinuation of IP

IFN Events Leading to Interruption of IP

IRWCD Events

IRWCD Events Grade ≥ 3

Serious IRWCD Events

Fatal IRWCD Events

IRWCD Events Leading to Discontinuation of IP

IRWCD Events Leading to Interruption of IP

ME Events

ME Events Grade ≥ 3

Serious ME Events

Fatal ME Events

ME Events Leading to Discontinuation of IP

ME Events Leading to Interruption of IP

NE Events

NE Events Grade ≥ 3

Serious NE Events

Fatal NE Events

NE Events Leading to Discontinuation of IP

NE Events Leading to Interruption of IP

NFN Events

NFN Events Grade ≥ 3

Serious NFN Events

Fatal NFN Events

NFN Events Leading to Discontinuation of IP

NFN Events Leading to Interruption of IP

PNC Events

PNC Events Grade ≥ 3

Serious PNC Events

Fatal PNC Events

PNC Events Leading to Discontinuation of IP

PNC Events Leading to Interruption of IP

Tumour Lysis Syndrome Events

Leukoencephalopathy Events

Immunogenicity Events

Safety Analysis Set: who received protocol-specified therapy analyzed according to the treatment they received.

Number of Participants With TEAEs of Interest

Potassium ↑ BL Gr 0 → PB Gr 3

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

Spots Global Cancer Trial Database for vincrisitne

Every month we try and update this database with for vincrisitne cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for vincrisitne

Every month we try and update this database with for vincrisitne cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for vincrisitne cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.