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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02393859




Registration number
NCT02393859
Ethics application status
Date submitted
16/03/2015
Date registered
20/03/2015
Date last updated
29/05/2024

Titles & IDs
Public title
Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)
Scientific title
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
Secondary ID [1] 0 0
2014-002476-92
Secondary ID [2] 0 0
20120215
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Leukemia, Acute Lymphoblastic 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Blinatumomab
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Vincrisitne
Treatment: Drugs - Daunorubicin
Treatment: Drugs - Methotrexate
Treatment: Drugs - Ifosfamide
Treatment: Drugs - PEG-asparaginase
Treatment: Drugs - Erwinia-asparaginase

Active comparator: High Risk Consolidation 3 (HC3) Chemotherapy - 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).

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


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

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

Treatment: Drugs: Vincrisitne
1.5 mg/m\^2/day IV on Days 1 and 6

Treatment: Drugs: Daunorubicin
30 mg/m\^2 IV over 24 hours on Day 5

Treatment: Drugs: Methotrexate
1 g/m\^2 IV over 36 hours on Day 1

Treatment: Drugs: Ifosfamide
800 mg/m\^2 IV for 1 hour on Days 2-4

Treatment: Drugs: PEG-asparaginase
1000 U/m\^2 IV for 2 hours or intramuscularly (IM) on Day 6

Treatment: Drugs: Erwinia-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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Kaplan Meier Estimate: Event-Free Survival (EFS; Primary Analysis)
Timepoint [1] 0 0
As of the primary analysis data cutoff date (17 July 2019), overall median follow-up time for EFS was 22.4 months.
Primary outcome [2] 0 0
Kaplan Meier Estimate: EFS (Final Analysis)
Timepoint [2] 0 0
At final analysis, overall median follow-up time for EFS was 51.9 months.
Secondary outcome [1] 0 0
Kaplan Meier Estimate: Overall Survival (OS)
Timepoint [1] 0 0
At final analysis, overall median follow-up time for OS was 55.2 months.
Secondary outcome [2] 0 0
Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation
Timepoint [2] 0 0
Up to End of Treatment (Cycle 1, Day 29)
Secondary outcome [3] 0 0
Cumulative Incidence of Relapse (CIR)
Timepoint [3] 0 0
At final analysis, the overall maximum follow-up time was 82.0 months.
Secondary outcome [4] 0 0
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs)
Timepoint [4] 0 0
From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
Secondary outcome [5] 0 0
Number of Participants With TEAEs of Interest
Timepoint [5] 0 0
From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.
Secondary outcome [6] 0 0
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values
Timepoint [6] 0 0
Up to Day 29 (± 2 days).
Secondary outcome [7] 0 0
Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)
Timepoint [7] 0 0
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.
Secondary outcome [8] 0 0
Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only)
Timepoint [8] 0 0
Day 1 to Day 29.
Secondary outcome [9] 0 0
Pharmacokinetics: Concentration at Steady State (Css) (Blinatumomab Arm Only)
Timepoint [9] 0 0
Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15
Secondary outcome [10] 0 0
Pharmacokinetics: Clearance (CL) (Blinatumomab Arm Only)
Timepoint [10] 0 0
Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15

Eligibility
Key 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).
Minimum age
0 Years
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
10/11/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/11/2022
Sample size
Target
Accrual to date
Final
111
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Research Site - Randwick
Recruitment hospital [2] 0 0
Research Site - Westmead
Recruitment hospital [3] 0 0
Research Site - South Brisbane
Recruitment hospital [4] 0 0
Research Site - Parkville
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment postcode(s) [3] 0 0
4101 - South Brisbane
Recruitment postcode(s) [4] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
Argentina
State/province [1] 0 0
Buenos Aires
Country [2] 0 0
Austria
State/province [2] 0 0
Graz
Country [3] 0 0
Austria
State/province [3] 0 0
Innsbruck
Country [4] 0 0
Austria
State/province [4] 0 0
Wien
Country [5] 0 0
Belgium
State/province [5] 0 0
Brussels
Country [6] 0 0
Belgium
State/province [6] 0 0
Gent
Country [7] 0 0
Belgium
State/province [7] 0 0
Leuven
Country [8] 0 0
Belgium
State/province [8] 0 0
Liege
Country [9] 0 0
Brazil
State/province [9] 0 0
Paraná
Country [10] 0 0
Brazil
State/province [10] 0 0
Rio Grande Do Sul
Country [11] 0 0
Brazil
State/province [11] 0 0
São Paulo
Country [12] 0 0
Czechia
State/province [12] 0 0
Praha 5
Country [13] 0 0
Denmark
State/province [13] 0 0
Kobenhavn O
Country [14] 0 0
France
State/province [14] 0 0
Bordeaux Cedex
Country [15] 0 0
France
State/province [15] 0 0
Lille
Country [16] 0 0
France
State/province [16] 0 0
Lyon
Country [17] 0 0
France
State/province [17] 0 0
Marseille cedex 5
Country [18] 0 0
France
State/province [18] 0 0
Montpellier cedex 05
Country [19] 0 0
France
State/province [19] 0 0
Nantes cedex 1
Country [20] 0 0
France
State/province [20] 0 0
Paris
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France
State/province [21] 0 0
Strasbourg Cedex
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France
State/province [22] 0 0
Vandoeuvre les Nancy
Country [23] 0 0
Germany
State/province [23] 0 0
Berlin
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Germany
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Duesseldorf
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Germany
State/province [25] 0 0
Erlangen
Country [26] 0 0
Germany
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Essen
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Germany
State/province [27] 0 0
Frankfurt am Main
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Germany
State/province [28] 0 0
Freiburg
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Germany
State/province [29] 0 0
Giessen
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Germany
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Hamburg
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Germany
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Hannover
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Germany
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Jena
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Germany
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Kiel
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Germany
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München
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Germany
State/province [35] 0 0
Münster
Country [36] 0 0
Germany
State/province [36] 0 0
Tübingen
Country [37] 0 0
Germany
State/province [37] 0 0
Ulm
Country [38] 0 0
Germany
State/province [38] 0 0
Würzburg
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Greece
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Goudi
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Israel
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Haifa
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Israel
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Jerusalem
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Israel
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Petah Tikva
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Israel
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Tel Aviv
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Israel
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Tel Hashomer
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Italy
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Bologna
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Italy
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Genova
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Italy
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Monza (MB)
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Italy
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Napoli
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Italy
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Padova
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Italy
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Pavia
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Italy
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Roma
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Italy
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Torino
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Mexico
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Distrito Federal
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Mexico
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Jalisco
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Mexico
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Nuevo León
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Netherlands
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Rotterdam
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Netherlands
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Utrecht
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Norway
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Oslo
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Poland
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Bydgoszcz
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Poland
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Krakow
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Lublin
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Wroclaw
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Poland
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Zabrze
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Portugal
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Lisboa
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Portugal
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Porto
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Romania
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Bucharest
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Romania
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Cluj-Napoca
Country [68] 0 0
Russian Federation
State/province [68] 0 0
Moscow
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Russian Federation
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Saint Petersburg
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Spain
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Andalucía
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Spain
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Cantabria
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Spain
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Cataluña
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Spain
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Comunidad Valenciana
Country [74] 0 0
Spain
State/province [74] 0 0
Galicia
Country [75] 0 0
Spain
State/province [75] 0 0
Madrid
Country [76] 0 0
Spain
State/province [76] 0 0
Murcia
Country [77] 0 0
Sweden
State/province [77] 0 0
Stockholm
Country [78] 0 0
Switzerland
State/province [78] 0 0
Basel
Country [79] 0 0
Switzerland
State/province [79] 0 0
Zuerich
Country [80] 0 0
Turkey
State/province [80] 0 0
Adana
Country [81] 0 0
Turkey
State/province [81] 0 0
Antalya
Country [82] 0 0
Turkey
State/province [82] 0 0
Izmir
Country [83] 0 0
Turkey
State/province [83] 0 0
Kayseri
Country [84] 0 0
United Kingdom
State/province [84] 0 0
Birmingham
Country [85] 0 0
United Kingdom
State/province [85] 0 0
Bristol
Country [86] 0 0
United Kingdom
State/province [86] 0 0
Glasgow
Country [87] 0 0
United Kingdom
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London
Country [88] 0 0
United Kingdom
State/province [88] 0 0
Manchester
Country [89] 0 0
United Kingdom
State/province [89] 0 0
Newcastle upon Tyne
Country [90] 0 0
United Kingdom
State/province [90] 0 0
Sheffield
Country [91] 0 0
United Kingdom
State/province [91] 0 0
Sutton

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Amgen
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT02393859
Trial related presentations / publications
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.
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
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
MD
Address 0 0
Amgen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02393859