Blinatumomab Versus Standard of Care Chemotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02013167
• Other study ID #: 00103311
• Secondary ID: 2013-000536-10
• Status: Terminated
• Phase: Phase 3
• Start date: January 3, 2014
• Est. completion date: March 14, 2017

Study information

• Verified date: March 2024
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 405
• Est. completion date: March 14, 2017
• Est. primary completion date: December 29, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• 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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

Intervention

Drug:
• Blinatumomab
Blinatumomab is administered as a continuous intravenous infusion (CIV).
• 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.

Locations

Country	Name	City	State
Australia	Research Site	Adelaide	South Australia
Australia	Research Site	Herston	Queensland
Australia	Research Site	Murdoch	Western Australia
Australia	Research Site	Parkville	Victoria
Australia	Research Site	Prahran	Victoria
Australia	Research Site	St Leonards	New South Wales
Austria	Research Site	Salzburg
Austria	Research Site	Wels
Austria	Research Site	Wien
Austria	Research Site	Wien
Belgium	Research Site	Antwerpen
Belgium	Research Site	Brugge
Belgium	Research Site	Bruxelles
Belgium	Research Site	Ghent
Belgium	Research Site	Leuven
Belgium	Research Site	Yvoir
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Sofia
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Toronto	Ontario
Czechia	Research Site	Brno
Czechia	Research Site	Hradec Kralove
Czechia	Research Site	Praha 10
Czechia	Research Site	Praha 2
France	Research Site	Creteil Cedex
France	Research Site	Le Chesnay
France	Research Site	Nantes Cedex 1
France	Research Site	Paris Cedex 10
France	Research Site	Pessac Cedex
France	Research Site	Pierre-Benite
France	Research Site	Toulouse cedex 9
Germany	Research Site	Berlin
Germany	Research Site	Essen
Germany	Research Site	Frankfurt am Main
Germany	Research Site	Freiburg
Germany	Research Site	Heidelberg
Germany	Research Site	Kiel
Germany	Research Site	Köln
Germany	Research Site	Leipzig
Germany	Research Site	München
Germany	Research Site	Münster
Germany	Research Site	Tübingen
Germany	Research Site	Ulm
Germany	Research Site	Würzburg
Greece	Research Site	Athens
Greece	Research Site	Athens
Greece	Research Site	Ioannina
Greece	Research Site	Patra
Greece	Research Site	Thessaloniki
Ireland	Research Site	Dublin
Israel	Research Site	Haifa
Israel	Research Site	Jerusalem
Israel	Research Site	Jerusalem
Israel	Research Site	Petah Tikva
Israel	Research Site	Tel Aviv
Israel	Research Site	Tel Hashomer
Italy	Research Site	Bari
Italy	Research Site	Bergamo
Italy	Research Site	Bologna
Italy	Research Site	Firenze
Italy	Research Site	Napoli
Italy	Research Site	Novara
Italy	Research Site	Palermo
Italy	Research Site	Roma
Italy	Research Site	Roma
Italy	Research Site	Torino
Italy	Research Site	Venezia
Italy	Research Site	Verona
Korea, Republic of	Research Site	Busan
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Mexico	Research Site	Mexico City	Distrito Federal
Mexico	Research Site	Monterrey	Nuevo León
Poland	Research Site	Lublin
Poland	Research Site	Warszawa
Poland	Research Site	Warszawa
Poland	Research Site	Wroclaw
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhny Novgorod
Russian Federation	Research Site	Petrozavodsk
Russian Federation	Research Site	Saratov
Spain	Research Site	Badalona	Cataluña
Spain	Research Site	Madrid
Spain	Research Site	Oviedo	Asturias
Spain	Research Site	Salamanca	Castilla León
Spain	Research Site	Valencia	Comunidad Valenciana
Taiwan	Research Site	ChangHua
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Turkey	Research Site	Adana
Turkey	Research Site	Ankara
Turkey	Research Site	Istanbul
Turkey	Research Site	Izmir
United Kingdom	Research Site	Bristol
United Kingdom	Research Site	London
United Kingdom	Research Site	Oxford
United Kingdom	Research Site	Sheffield
United Kingdom	Research Site	Southampton
United Kingdom	Research Site	Sutton
United States	Research Site	Atlanta	Georgia
United States	Research Site	Baltimore	Maryland
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boston	Massachusetts
United States	Research Site	Chicago	Illinois
United States	Research Site	Duarte	California
United States	Research Site	Durham	North Carolina
United States	Research Site	Greenville	South Carolina
United States	Research Site	Houston	Texas
United States	Research Site	Los Angeles	California
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	Nashville	Tennessee
United States	Research Site	New York	New York
United States	Research Site	Rochester	Minnesota
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Greece,  Ireland,  Israel,  Italy,  Korea, Republic of,  Mexico,  Poland,  Russian Federation,  Spain,  Taiwan,  Turkey,  United Kingdom, 

References & Publications (8)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Overall survival (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.	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	Percentage of Participants With Complete Remission Within 12 Weeks of Treatment Initiation	Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts.; Complete Remission (CR) was defined as having = 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl, and absolute neutrophil count (ANC) > 1,000/µl. CR must have occurred within 12 weeks of the first dose of therapy.	12 weeks
Secondary	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	Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts.; Complete remission was defined as having = 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl, and ANC > 1,000/µl.; Complete Remission with partial hematological recovery (CRh*) was defined as = 5% blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts: platelets > 50,000/µl, and ANC > 500/µl.; Complete remission with incomplete hematological recovery (CRi) was defined as = 5% blasts in the bone marrow, no evidence of disease and incomplete recovery of peripheral blood counts: platelets > 100,000/µl or ANC > 1000 (but not both).	12 weeks
Secondary	Event Free Survival (EFS)	Event free survival was defined as the time from randomization until a documented relapse after achieving CR/CRh*/CRi or death, whichever occurred first. Participants who failed to achieve a CR/CRh*/CRi within 12 weeks of treatment initiation were considered as non-responders and assigned an EFS duration of 1 day. Participants still alive and relapse-free were censored on their last disease assessment date.; A relapse event was any one of the following: Hematological relapse: proportion of blasts in bone marrow >5% or blasts in peripheral blood after documented CR or CRh* or CRi; Progressive disease: An increase from baseline of at least 25% of bone marrow blasts or an absolute increase of at least 5,000 cells/µL in the number of circulating leukemia cells; Extramedullary relapse: extramedullary lesion that is new or increased by 50% from nadir as assessed by Cheson criteria.; The Kaplan-Meier estimate of EFS at 6 months is reported.	6 months
Secondary	Duration of Complete Remission	Duration of complete remission, calculated only for participants who achieved a CR, was calculated from the date a CR was first achieved until the earliest date of a disease assessment indicating a relapse event or death, whichever occurred first. Participants who did not have a relapse event were censored on their last disease assessment date.	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	Duration of Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi)	Duration of CR/CRh*/CRi, calculated only for participants who achieved a CR/CRh*/CRi, was calculated from the date a CR/CRh*/CRi was first achieved until the earliest date of a disease assessment indicating a relapse event or death, whichever occurred first. Participants who did not have a relapse event were censored on their last disease assessment date.	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	Percentage of Participants With Minimal Residual Disease (MRD) Within 12 Weeks of Treatment Initiation	Bone marrow samples were evaluated for MRD remission by a central laboratory. MRD remission was defined as the occurrence of an MRD level below 10^-4 measured by quantitative reverse transcription polymerase chain reaction (PCR) or flow cytometry.	12 weeks
Secondary	Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT)		Up to the data cut-off date of 04 January 2016; maximum time on study was 23 months.
Secondary	Number of Participants With Adverse Events	Adverse events (AEs) were graded for severity according to the CTCAE version 4.0, where Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living.; Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living.; Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. Treatment-related adverse events (TRAEs) were those assessed by the investigator as possibly related to blinatumomab based on response to the question: Is there a reasonable possibility that the event may have been caused by blinatumomab or other protocol-specified therapies/procedures?	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	100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant	The analysis of 100-day mortality after allogeneic HSCT was assessed for participants who achieved a best response of CR/CRh*CTi within 12 weeks of treatment initiation, who received an allogeneic HSCT and did not receive any additional anticancer treatment before the transplant. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT.; The 100-day mortality rate after allogeneic HSCT was defined as the percentage of participants having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive.	100 days, from the date of allogeneic HSCT until the data cut-off date of 04 January 2016
Secondary	Number of Participants With Anti-blinatumomab Antibodies	Anti-blinatumomab binding antibodies were evaluated using a validated electrochemiluminescence (ECL)-based assay (binding assay). Samples positive for binding were analyzed using a cell-based bioassay to determine if the detected antibodies had neutralizing properties (neutralizing assay).	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	Time to a 10-point Decrease From Baseline in Global Health Status and Quality of Life or Death	The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) is a 30-item questionnaire that assesses the health related quality of life of cancer patients. The EORTC QLQ-C30 consists of a global health status/quality of life (QoL) scale, 5 functional scales, 3 symptom scales, and 6 single items.; The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life durig the past week on a scale from 1 (very poor) to 7 (excellent). The scale score was derived as the sum of each score and transformed to a scale from 0 to 100 where higher scores represent a high QoL.; Time to a =10-point decrease from baseline GHS/QoL or death, whichever came first, was calculated from baseline. Participants still alive and without a 10-point decrease in GHS/QoL EORTC QLQ-C30 were censored on their last EORTC QLQ-C30 assessment date.	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.

External Links

•   AmgenTrials clinical trials website