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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02013167




Registration number
NCT02013167
Ethics application status
Date submitted
3/12/2013
Date registered
17/12/2013
Date last updated
5/03/2024

Titles & IDs
Public title
Blinatumomab Versus Standard of Care Chemotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)
Scientific title
A Phase 3, Randomized, Open Label Study Investigating the Efficacy of the BiTE Antibody Blinatumomab Versus Standard of Care Chemotherapy in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (TOWER Study)
Secondary ID [1] 0 0
2013-000536-10
Secondary ID [2] 0 0
00103311
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia 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

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Blinatumomab
Treatment: Drugs - Standard of Care Chemotherapy

Experimental: Blinatumomab - Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh*/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab.
Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period.
The initial dose of blinatumomab was 9 µg/day for the first 7 days of treatment, increased to 28 µg/day starting on day 8 through day 29 and for all subsequent cycles.

Active Comparator: Standard of Care Chemotherapy - Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh*/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy.
Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh*/CRi could continue to receive SOC therapy for an additional 12 months.


Treatment: Drugs: Blinatumomab
Blinatumomab is administered as a continuous intravenous infusion (CIV).

Treatment: Drugs: Standard of Care Chemotherapy
FLAG (fludarabine, cytarabine arabinoside, and granulocyte colony-stimulating factor) ± anthracycline-based regimen (e.g. idarubicin 10 mg/m² days 1 & 3; fludarabine 30 mg/m² days 1-5; cytarabine arabinoside 2 g/m² days 1-5). Patients > 60 years: Idarubicin 5 mg/m² day 1 & 3; fludarabine 20 mg/m² day 1-5; cytarabine arabinoside 1 g/m² day 1-5
HiDAC (high-dose cytarabine arabinoside) - based regimen =1 g/m²/day ± anthracycline and/or in combination with other drugs such as native Escherichia coli asparaginase, polyethylene glycol linked to asparaginase (PEG-asparaginase), vinca alkaloids, steroids, etoposide or alkylating agents
High-dose methotrexate-based regimen (HDMTX; 500 mg/m² to 3 g/m² infused up to 24 hours) in combination with native E. coli asparaginase, PEG-asparaginase, vinca alkaloids, steroids, etoposide or alkylating agents.
Clofarabine as a single agent as recommended in the prescribing information or clofarabine-based regimens with 20 mg/m²/day for up to 5 days.

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

Outcomes
Primary outcome [1] 0 0
Overall Survival
Timepoint [1] 0 0
From randomization until the data cut-off date of 04 January 2016; median observation time was 11.8 months in the SOC group and 11.7 months in the blinatumomab group.
Secondary outcome [1] 0 0
Percentage of Participants With Complete Remission Within 12 Weeks of Treatment Initiation
Timepoint [1] 0 0
12 weeks
Secondary outcome [2] 0 0
Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) Within 12 Weeks of Treatment Initiation
Timepoint [2] 0 0
12 weeks
Secondary outcome [3] 0 0
Event Free Survival (EFS)
Timepoint [3] 0 0
6 months
Secondary outcome [4] 0 0
Duration of Complete Remission
Timepoint [4] 0 0
Up to the data cut-off date of 04 January 2016; median observation time was 10.8 months in the SOC group and 7.0 months in the blinatumomab group.
Secondary outcome [5] 0 0
Duration of Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi)
Timepoint [5] 0 0
Up to the data cut-off date of 04 January 2016; median observation time was 10.8 months in the SOC group and 7.2 months in the blinatumomab group.
Secondary outcome [6] 0 0
Percentage of Participants With Minimal Residual Disease (MRD) Within 12 Weeks of Treatment Initiation
Timepoint [6] 0 0
12 weeks
Secondary outcome [7] 0 0
Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT)
Timepoint [7] 0 0
Up to the data cut-off date of 04 January 2016; maximum time on study was 23 months.
Secondary outcome [8] 0 0
Number of Participants With Adverse Events
Timepoint [8] 0 0
From first dose of protocol-specified therapy until 30 days after the last dose, up to the data cut-off date of 04 January 2016; median duration of treatment was 5 days in the SOC group and 70 days in the blinatumomab group.
Secondary outcome [9] 0 0
100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant
Timepoint [9] 0 0
100 days, from the date of allogeneic HSCT until the data cut-off date of 04 January 2016
Secondary outcome [10] 0 0
Number of Participants With Anti-blinatumomab Antibodies
Timepoint [10] 0 0
Samples were collected on day 29 at the end of cycle 2 and 30 days after the last dose of blinatumomab (median duration of treatment was 70 days).
Secondary outcome [11] 0 0
Time to a 10-point Decrease From Baseline in Global Health Status and Quality of Life or Death
Timepoint [11] 0 0
From randomization until the data cut-off date of 04 January 2016; EORTC QLQ-C30 was assessed on day 1, 8, 15, and 29 during cycle 1; days 1, 15, and 29 in cycle 2 and each consolidation cycle, and 30-days following the last dose of drug treatment.

Eligibility
Key inclusion criteria
- Subjects with Philadelphia negative B-precursor ALL, with any of the following:

- refractory to primary induction therapy or refractory to salvage therapy,

- in untreated first relapse with first remission duration <12 months

- in untreated second or greater relapse

- relapse at any time after allogeneic HSCT

- Subject has received intensive combination chemotherapy for the treatment of ALL for
initial treatment or subsequent salvage therapy.

- Greater than 5% blasts in the bone marrow

- Eastern Cooperative Oncology Group (ECOG) performance status = 2
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

- Malignancy other than ALL within 5 years before blinatumomab treatment, except for
adequately treated selected cancers without evidence of disease

- Diagnosis of Burkitt's leukemia according to World Health Organization classification,
or human immunodeficiency virus (HIV), Hepatitis B or C, or other clinically
significant disorder

- Current relevant central nervous system (CNS) pathology or known or suspected CNS
involvement

- Isolated extramedullary disease

- Current autoimmune disease or history of autoimmune disease with potential CNS
involvement

- Autologous HSCT within 6 weeks or allogeneic HSCT within 12 weeks before blinatumomab
treatment, or eligibility for allogeneic HSCT at the time of enrollment

- Active acute grade 2 to 4 graft versus host disease (GvHD) according to Glucksberg et
al (1974) criteria that required systemic treatment to prevent or treat GvHD 2 weeks
before blinatumomab treatment

- Known exclusion criteria to investigator choice of SOC chemotherapy (per package
insert)

- Cancer chemotherapy or radiotherapy with 2 weeks, or immunotherapy (included CD19
therapy) within 4 weeks of protocol-specified therapy

- Abnormal laboratory values (alanine or aspartate transaminase [ALT or AST] or alkaline
phosphatase [ALP] = 5 × upper limit of normal [ULN]; total bilirubin or creatinine =
1.5 × ULN), or calculated creatinine clearance < 60 mL/min.

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
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Research Site - St Leonards
Recruitment hospital [2] 0 0
Research Site - Herston
Recruitment hospital [3] 0 0
Research Site - Adelaide
Recruitment hospital [4] 0 0
Research Site - Parkville
Recruitment hospital [5] 0 0
Research Site - Prahran
Recruitment hospital [6] 0 0
Research Site - Murdoch
Recruitment postcode(s) [1] 0 0
2065 - St Leonards
Recruitment postcode(s) [2] 0 0
4029 - Herston
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment postcode(s) [4] 0 0
3050 - Parkville
Recruitment postcode(s) [5] 0 0
3181 - Prahran
Recruitment postcode(s) [6] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
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United States of America
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Georgia
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Illinois
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Maryland
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Massachusetts
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Minnesota
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Missouri
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New York
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North Carolina
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South Carolina
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Tennessee
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Texas
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United States of America
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Wisconsin
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Austria
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Salzburg
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Austria
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Wels
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Austria
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Wien
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Belgium
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Antwerpen
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Belgium
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Brugge
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Belgium
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Bruxelles
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Belgium
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Ghent
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Belgium
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Leuven
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Belgium
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Yvoir
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Bulgaria
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Plovdiv
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Bulgaria
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Sofia
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Canada
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Ontario
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Quebec
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Czechia
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Brno
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Czechia
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Hradec Kralove
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Czechia
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Praha 10
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Czechia
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Praha 2
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France
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Creteil Cedex
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France
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Le Chesnay
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Nantes Cedex 1
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France
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Paris Cedex 10
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France
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Pessac Cedex
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France
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Pierre-Benite
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France
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Toulouse cedex 9
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Germany
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Berlin
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Germany
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Essen
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Germany
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Frankfurt am Main
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Freiburg
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Heidelberg
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Kiel
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Köln
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Leipzig
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Germany
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Münster
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Germany
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Tübingen
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Germany
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Ulm
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Germany
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Würzburg
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Greece
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Athens
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Greece
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Ioannina
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Patra
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Israel
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Tel Hashomer
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Bari
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Firenze
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Napoli
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Novara
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Italy
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Palermo
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Italy
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Roma
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Italy
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Torino
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Italy
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Venezia
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Italy
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Verona
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Korea, Republic of
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Busan
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Distrito Federal
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Mexico
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Poland
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Lublin
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Poland
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Warszawa
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Wroclaw
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Russian Federation
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Moscow
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Russian Federation
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Nizhny Novgorod
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Russian Federation
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Petrozavodsk
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Russian Federation
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Saratov
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Spain
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Asturias
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Spain
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Castilla León
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Spain
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Cataluña
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Spain
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Comunidad Valenciana
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Spain
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Madrid
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Taiwan
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ChangHua
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Taiwan
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Taichung
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Taiwan
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Tainan
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Taiwan
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Taipei
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Turkey
State/province [92] 0 0
Adana
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Turkey
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Ankara
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Turkey
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Istanbul
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Turkey
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Izmir
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United Kingdom
State/province [96] 0 0
Bristol
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United Kingdom
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London
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United Kingdom
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Oxford
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United Kingdom
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Sheffield
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United Kingdom
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Southampton
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United Kingdom
State/province [101] 0 0
Sutton

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

Ethics approval
Ethics application status

Summary
Brief summary
The primary objective was to evaluate the effect of blinatumomab on overall survival when
compared to standard of care (SOC) chemotherapy.
Trial website
https://clinicaltrials.gov/ct2/show/NCT02013167
Trial related presentations / publications
Delea TE, Amdahl J, Boyko D, Hagiwara M, Zimmerman ZF, Franklin JL, Cong Z, Hechmati G, Stein A. Cost-effectiveness of blinatumomab versus salvage chemotherapy in relapsed or refractory Philadelphia-chromosome-negative B-precursor acute lymphoblastic leukemia from a US payer perspective. J Med Econ. 2017 Sep;20(9):911-922. doi: 10.1080/13696998.2017.1344127. Epub 2017 Jul 11.
Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foa R, Bassan R, Arslan O, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Bruggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017 Mar 2;376(9):836-847. doi: 10.1056/NEJMoa1609783.
Dombret H, Topp MS, Schuh AC, Wei AH, Durrant S, Bacon CL, Tran Q, Zimmerman Z, Kantarjian H. Blinatumomab versus chemotherapy in first salvage or in later salvage for B-cell precursor acute lymphoblastic leukemia. Leuk Lymphoma. 2019 Sep;60(9):2214-2222. doi: 10.1080/10428194.2019.1576872. Epub 2019 Apr 5.
Kuchimanchi M, Zhu M, Clements JD, Doshi S. Exposure-response analysis of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukaemia and comparison with standard of care chemotherapy. Br J Clin Pharmacol. 2019 Apr;85(4):807-817. doi: 10.1111/bcp.13864. Epub 2019 Feb 18.
Stein AS, Larson RA, Schuh AC, Stevenson W, Lech-Maranda E, Tran Q, Zimmerman Z, Kormany W, Topp MS. Exposure-adjusted adverse events comparing blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia. Blood Adv. 2018 Jul 10;2(13):1522-1531. doi: 10.1182/bloodadvances.2018019034.
Topp MS, Zimmerman Z, Cannell P, Dombret H, Maertens J, Stein A, Franklin J, Tran Q, Cong Z, Schuh AC. Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab. Blood. 2018 Jun 28;131(26):2906-2914. doi: 10.1182/blood-2017-09-804658. Epub 2018 May 8.
Kantarjian HM, Zugmaier G, Bruggemann M, Wood BL, Horst HA, Zeng Y, Martinelli G. Impact of Blinatumomab Treatment on Bone Marrow Function in Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia. Cancers (Basel). 2021 Nov 9;13(22):5607. doi: 10.3390/cancers13225607.
Horst HA, Zugmaier G, Martinelli G, Mergen N, Velasco K, Zaman F, Kantarjian H. CD19-negative relapse in adult patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia following treatment with blinatumomab-a post hoc analysis. Am J Hematol. 2023 Aug;98(8):E222-E225. doi: 10.1002/ajh.26988. Epub 2023 Jun 22. No abstract available.
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/ct2/show/NCT02013167