Clinical trial NCT02013167: Blinatumomab Versus Standard of Care Chemotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)
Official 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia
Keywords: Relapsed; Refractory; B-precursor; Acute Lymphoblastic Leukemia; Philadelphia Negative; ALL; Blinatumomab; Leukemia; Standard of Care; SOC
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2013-12-17
Enrollment: 405
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective was to evaluate the effect of blinatumomab on overall survival when compared to standard of care (SOC) chemotherapy.

Detailed description: Adults with relapsed/refractory B-cell precursor ALL were randomized in a 2:1 ratio to receive blinatumomab or 1 of 4 pre-specified, investigator-chosen, SOC chemotherapy regimens. Randomization was stratified by age (\< 35 years vs ≥ 35 years of age), prior salvage therapy (yes vs no), and prior allogeneic HSCT (yes vs no) as assessed at the time of consent.

The study consisted of up to a 3-week screening and pre-phase period, a treatment period consisting of induction with 2 cycles of either blinatumomab or SOC chemotherapy, a consolidation phase of up to 3 additional cycles of protocol-specified therapy, and a maintenance phase for up to an additional 12 months with protocol-specified therapy. A safety follow-up visit 30 days after the last dose of protocol-specified therapy and a long-term follow-up period were included. The long-term follow-up part of the study was discontinued prematurely based on a recommendation from the data monitoring committee (DMC) that the study be stopped for benefit.

Eligibility 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

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.

Primary outcomes:
measure: Overall Survival
timeFrame: 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 outcomes:
measure: Percentage of Participants With Complete Remission Within 12 Weeks of Treatment Initiation
timeFrame: 12 weeks
measure: 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
timeFrame: 12 weeks
measure: Event Free Survival (EFS)
timeFrame: 6 months
measure: Duration of Complete Remission
timeFrame: 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.
measure: Duration of Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi)
timeFrame: 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.
measure: Percentage of Participants With Minimal Residual Disease (MRD) Within 12 Weeks of Treatment Initiation
timeFrame: 12 weeks
measure: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: Up to the data cut-off date of 04 January 2016; maximum time on study was 23 months.
measure: Number of Participants With Adverse Events
timeFrame: 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.
measure: 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant
timeFrame: 100 days, from the date of allogeneic HSCT until the data cut-off date of 04 January 2016
measure: Number of Participants With Anti-blinatumomab Antibodies
timeFrame: 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).
measure: Time to a 10-point Decrease From Baseline in Global Health Status and Quality of Life or Death
timeFrame: 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.
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
facility: Research Site
state: California
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Boston
country: United States
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state: Massachusetts
city: Rochester
country: United States
facility: Research Site
state: Minnesota
city: Saint Louis
country: United States
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state: Missouri
city: New York
country: United States
facility: Research Site
state: New York
city: Durham
country: United States
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state: North Carolina
city: Greenville
country: United States
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state: South Carolina
city: Nashville
country: United States
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state: Tennessee
city: Houston
country: United States
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state: Texas
city: Milwaukee
country: United States
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state: Wisconsin
city: St Leonards
country: Australia
facility: Research Site
state: New South Wales
city: Herston
country: Australia
facility: Research Site
state: Queensland
city: Adelaide
country: Australia
facility: Research Site
state: South Australia
city: Parkville
country: Australia
facility: Research Site
state: Victoria
city: Prahran
country: Australia
facility: Research Site
state: Victoria
city: Murdoch
country: Australia
facility: Research Site
state: Western Australia
city: Salzburg
country: Austria
facility: Research Site
city: Wels
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Antwerpen
country: Belgium
facility: Research Site
city: Brugge
country: Belgium
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Ghent
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Yvoir
country: Belgium
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Toronto
country: Canada
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state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Brno
country: Czechia
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Praha 10
country: Czechia
facility: Research Site
city: Praha 2
country: Czechia
facility: Research Site
city: Creteil Cedex
country: France
facility: Research Site
city: Le Chesnay
country: France
facility: Research Site
city: Nantes Cedex 1
country: France
facility: Research Site
city: Paris Cedex 10
country: France
facility: Research Site
city: Pessac Cedex
country: France
facility: Research Site
city: Pierre-Benite
country: France
facility: Research Site
city: Toulouse cedex 9
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Frankfurt am Main
country: Germany
facility: Research Site
city: Freiburg
country: Germany
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city: Heidelberg
country: Germany
facility: Research Site
city: Kiel
country: Germany
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: Leipzig
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Münster
country: Germany
facility: Research Site
city: Tübingen
country: Germany
facility: Research Site
city: Ulm
country: Germany
facility: Research Site
city: Würzburg
country: Germany
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Ioannina
country: Greece
facility: Research Site
city: Patra
country: Greece
facility: Research Site
city: Thessaloniki
country: Greece
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Petah Tikva
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
facility: Research Site
city: Tel Hashomer
country: Israel
facility: Research Site
city: Bari
country: Italy
facility: Research Site
city: Bergamo
country: Italy
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Novara
country: Italy
facility: Research Site
city: Palermo
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Venezia
country: Italy
facility: Research Site
city: Verona
country: Italy
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Mexico City
country: Mexico
facility: Research Site
state: Distrito Federal
city: Monterrey
country: Mexico
facility: Research Site
state: Nuevo León
city: Lublin
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Nizhny Novgorod
country: Russian Federation
facility: Research Site
city: Petrozavodsk
country: Russian Federation
facility: Research Site
city: Saratov
country: Russian Federation
facility: Research Site
city: Oviedo
country: Spain
facility: Research Site
state: Asturias
city: Salamanca
country: Spain
facility: Research Site
state: Castilla León
city: Badalona
country: Spain
facility: Research Site
state: Cataluña
city: Valencia
country: Spain
facility: Research Site
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: Research Site
city: ChangHua
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Adana
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Bristol
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
city: Southampton
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Shi Z, Zhu Y, Zhang J, Chen B. Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia. Hematology. 2022 Dec;27(1):642-652. doi: 10.1080/16078454.2022.2074704.
citation: Jabbour E, Patel K, Jain N, Duose D, Luthra R, Short NJ, Zugmaier G, San Lucas A, Velasco K, Tran Q, Zaman F, Konopleva M, Kantarjian H. Impact of Philadelphia chromosome-like alterations on efficacy and safety of blinatumomab in adults with relapsed/refractory acute lymphoblastic leukemia: A post hoc analysis from the phase 3 TOWER study. Am J Hematol. 2021 Oct 1;96(10):E379-E383. doi: 10.1002/ajh.26281. Epub 2021 Jul 7. No abstract available.
citation: Wei AH, Ribera JM, Larson RA, Ritchie D, Ghobadi A, Chen Y, Anderson A, Dos Santos CE, Franklin J, Kantarjian H. Biomarkers associated with blinatumomab outcomes in acute lymphoblastic leukemia. Leukemia. 2021 Aug;35(8):2220-2231. doi: 10.1038/s41375-020-01089-x. Epub 2021 Feb 4.
citation: Rambaldi A, Huguet F, Zak P, Cannell P, Tran Q, Franklin J, Topp MS. Blinatumomab consolidation and maintenance therapy in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia. Blood Adv. 2020 Apr 14;4(7):1518-1525. doi: 10.1182/bloodadvances.2019000874.