Blinatumomab Versus Standard of Care Chemotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)
Sponsor
Amgen (Industry)
Overall Status
Terminated
CT.gov ID
NCT02013167
Collaborator
(none)
405
117
2
38.3
3.5
0.1
Study Details
Study Description
Brief Summary
The primary objective was to evaluate the effect of blinatumomab on overall survival when compared to standard of care (SOC) chemotherapy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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.
Study Design
Study Type:
Interventional
Actual Enrollment
:
405 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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)
Actual Study Start Date
:
Jan 3, 2014
Actual Primary Completion Date
:
Dec 29, 2015
Actual Study Completion Date
:
Mar 14, 2017
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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. |
Drug: Blinatumomab
Blinatumomab is administered as a continuous intravenous infusion (CIV).
Other Names:
|
| 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. |
Drug: 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.
|
Outcome Measures
Primary Outcome Measures
- Overall Survival [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.]
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.
Secondary Outcome Measures
- Percentage of Participants With Complete Remission Within 12 Weeks of Treatment Initiation [12 weeks]
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.
- 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 [12 weeks]
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).
- Event Free Survival (EFS) [6 months]
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.
- Duration of Complete Remission [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.]
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.
- Duration of Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) [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.]
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.
- Percentage of Participants With Minimal Residual Disease (MRD) Within 12 Weeks of Treatment Initiation [12 weeks]
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.
- 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.]
- Number of Participants With Adverse Events [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.]
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?
- 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant [100 days, from the date of allogeneic HSCT until the data cut-off date of 04 January 2016]
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.
- Number of Participants With Anti-blinatumomab Antibodies [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).]
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).
- Time to a 10-point Decrease From Baseline in Global Health Status and Quality of Life or Death [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.]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
-
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Duarte | California | United States | 91010 |
| 2 | Research Site | Los Angeles | California | United States | 90095 |
| 3 | Research Site | San Francisco | California | United States | 94143 |
| 4 | Research Site | Atlanta | Georgia | United States | 30322 |
| 5 | Research Site | Chicago | Illinois | United States | 60637 |
| 6 | Research Site | Baltimore | Maryland | United States | 21201 |
| 7 | Research Site | Boston | Massachusetts | United States | 02111 |
| 8 | Research Site | Boston | Massachusetts | United States | 02215 |
| 9 | Research Site | Rochester | Minnesota | United States | 55905 |
| 10 | Research Site | Saint Louis | Missouri | United States | 63110 |
| 11 | Research Site | New York | New York | United States | 10065 |
| 12 | Research Site | Durham | North Carolina | United States | 27710 |
| 13 | Research Site | Greenville | South Carolina | United States | 29607 |
| 14 | Research Site | Nashville | Tennessee | United States | 37232 |
| 15 | Research Site | Houston | Texas | United States | 77030 |
| 16 | Research Site | Milwaukee | Wisconsin | United States | 53226 |
| 17 | Research Site | St Leonards | New South Wales | Australia | 2065 |
| 18 | Research Site | Herston | Queensland | Australia | 4029 |
| 19 | Research Site | Adelaide | South Australia | Australia | 5000 |
| 20 | Research Site | Parkville | Victoria | Australia | 3050 |
| 21 | Research Site | Prahran | Victoria | Australia | 3181 |
| 22 | Research Site | Murdoch | Western Australia | Australia | 6150 |
| 23 | Research Site | Salzburg | Austria | 5020 | |
| 24 | Research Site | Wels | Austria | 4600 | |
| 25 | Research Site | Wien | Austria | 1090 | |
| 26 | Research Site | Wien | Austria | 1140 | |
| 27 | Research Site | Antwerpen | Belgium | 2060 | |
| 28 | Research Site | Brugge | Belgium | 8000 | |
| 29 | Research Site | Bruxelles | Belgium | 1200 | |
| 30 | Research Site | Ghent | Belgium | 9000 | |
| 31 | Research Site | Leuven | Belgium | 3000 | |
| 32 | Research Site | Yvoir | Belgium | 5530 | |
| 33 | Research Site | Plovdiv | Bulgaria | 4000 | |
| 34 | Research Site | Sofia | Bulgaria | 1756 | |
| 35 | Research Site | Toronto | Ontario | Canada | M5G 2M9 |
| 36 | Research Site | Montreal | Quebec | Canada | H1T 2M4 |
| 37 | Research Site | Brno | Czechia | 625 00 | |
| 38 | Research Site | Hradec Kralove | Czechia | 500 05 | |
| 39 | Research Site | Praha 10 | Czechia | 100 34 | |
| 40 | Research Site | Praha 2 | Czechia | 128 20 | |
| 41 | Research Site | Creteil Cedex | France | 94010 | |
| 42 | Research Site | Le Chesnay | France | 78157 | |
| 43 | Research Site | Nantes Cedex 1 | France | 44093 | |
| 44 | Research Site | Paris Cedex 10 | France | 75475 | |
| 45 | Research Site | Pessac Cedex | France | 33604 | |
| 46 | Research Site | Pierre-Benite | France | 69495 | |
| 47 | Research Site | Toulouse cedex 9 | France | 31059 | |
| 48 | Research Site | Berlin | Germany | 12200 | |
| 49 | Research Site | Essen | Germany | 45147 | |
| 50 | Research Site | Frankfurt am Main | Germany | 60590 | |
| 51 | Research Site | Freiburg | Germany | 79106 | |
| 52 | Research Site | Heidelberg | Germany | 69120 | |
| 53 | Research Site | Kiel | Germany | 24116 | |
| 54 | Research Site | Köln | Germany | 50937 | |
| 55 | Research Site | Leipzig | Germany | 04103 | |
| 56 | Research Site | München | Germany | 81377 | |
| 57 | Research Site | Münster | Germany | 48149 | |
| 58 | Research Site | Tübingen | Germany | 72076 | |
| 59 | Research Site | Ulm | Germany | 89081 | |
| 60 | Research Site | Würzburg | Germany | 97080 | |
| 61 | Research Site | Athens | Greece | 10676 | |
| 62 | Research Site | Athens | Greece | 11527 | |
| 63 | Research Site | Ioannina | Greece | 45110 | |
| 64 | Research Site | Patra | Greece | 26500 | |
| 65 | Research Site | Thessaloniki | Greece | 57010 | |
| 66 | Research Site | Dublin | Ireland | 8 | |
| 67 | Research Site | Haifa | Israel | 31096 | |
| 68 | Research Site | Jerusalem | Israel | 91031 | |
| 69 | Research Site | Jerusalem | Israel | 91120 | |
| 70 | Research Site | Petah Tikva | Israel | 49100 | |
| 71 | Research Site | Tel Aviv | Israel | 64239 | |
| 72 | Research Site | Tel Hashomer | Israel | 52621 | |
| 73 | Research Site | Bari | Italy | 70124 | |
| 74 | Research Site | Bergamo | Italy | 24127 | |
| 75 | Research Site | Bologna | Italy | 40138 | |
| 76 | Research Site | Firenze | Italy | 50134 | |
| 77 | Research Site | Napoli | Italy | 80131 | |
| 78 | Research Site | Novara | Italy | 28100 | |
| 79 | Research Site | Palermo | Italy | 90146 | |
| 80 | Research Site | Roma | Italy | 00133 | |
| 81 | Research Site | Roma | Italy | 00161 | |
| 82 | Research Site | Torino | Italy | 10126 | |
| 83 | Research Site | Venezia | Italy | 30174 | |
| 84 | Research Site | Verona | Italy | 37134 | |
| 85 | Research Site | Busan | Korea, Republic of | 614-735 | |
| 86 | Research Site | Seoul | Korea, Republic of | 110-744 | |
| 87 | Research Site | Seoul | Korea, Republic of | 135-710 | |
| 88 | Research Site | Seoul | Korea, Republic of | 138-736 | |
| 89 | Research Site | Mexico City | Distrito Federal | Mexico | 07760 |
| 90 | Research Site | Monterrey | Nuevo León | Mexico | 64460 |
| 91 | Research Site | Lublin | Poland | 20-081 | |
| 92 | Research Site | Warszawa | Poland | 02-776 | |
| 93 | Research Site | Warszawa | Poland | 04-141 | |
| 94 | Research Site | Wroclaw | Poland | 50-367 | |
| 95 | Research Site | Moscow | Russian Federation | 125167 | |
| 96 | Research Site | Nizhny Novgorod | Russian Federation | 603126 | |
| 97 | Research Site | Petrozavodsk | Russian Federation | 185019 | |
| 98 | Research Site | Saratov | Russian Federation | 410012 | |
| 99 | Research Site | Oviedo | Asturias | Spain | 33011 |
| 100 | Research Site | Salamanca | Castilla León | Spain | 37007 |
| 101 | Research Site | Badalona | Cataluña | Spain | 08916 |
| 102 | Research Site | Valencia | Comunidad Valenciana | Spain | 46026 |
| 103 | Research Site | Madrid | Spain | 28041 | |
| 104 | Research Site | ChangHua | Taiwan | 50006 | |
| 105 | Research Site | Taichung | Taiwan | 40447 | |
| 106 | Research Site | Tainan | Taiwan | 70403 | |
| 107 | Research Site | Taipei | Taiwan | 10002 | |
| 108 | Research Site | Adana | Turkey | 01330 | |
| 109 | Research Site | Ankara | Turkey | 06100 | |
| 110 | Research Site | Istanbul | Turkey | 34093 | |
| 111 | Research Site | Izmir | Turkey | 35340 | |
| 112 | Research Site | Bristol | United Kingdom | BS2 8ED | |
| 113 | Research Site | London | United Kingdom | NW3 2PF | |
| 114 | Research Site | Oxford | United Kingdom | OX3 7LJ | |
| 115 | Research Site | Sheffield | United Kingdom | S10 2JF | |
| 116 | Research Site | Southampton | United Kingdom | SO16 6YD | |
| 117 | Research Site | Sutton | United Kingdom | SM2 5PT |
Sponsors and Collaborators
- Amgen
Investigators
- Study Director: MD, Amgen
Study Documents (Full-Text)
None provided.More Information
Additional Information:
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.
- 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.
- Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Brüggemann 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.
- Kantarjian HM, Zugmaier G, Brüggemann 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). pii: 5607. doi: 10.3390/cancers13225607.
- 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.
Responsible Party:
Amgen
ClinicalTrials.gov Identifier:
NCT02013167
Other Study ID Numbers:
- 00103311
- 2013-000536-10
First Posted:
Dec 17, 2013
Last Update Posted:
Jan 5, 2022
Last Verified:
Jan 1, 2022
Keywords provided by Amgen
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | This study was conducted at 101 centers in 21 countries in Asia, Australia, Europe, and Latin and North America. The first participant was enrolled on 03 January 2014 and treated on 06 January 2014. The last participant enrolled on 25 September 2015 and the data cutoff date for this report was 04 January 2016. |
|---|---|
| Pre-assignment Detail | Participants were randomized in a 2:1 ratio to either blinatumomab or standard of care (SOC) chemotherapy regimens. Randomization was stratified by age (< 35 years vs ≥ 35 years), prior salvage therapy (yes vs no), and prior allogeneic hematopoietic stem cell transplantation (HSCT) (yes vs no) as assessed at the time of consent. |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Period Title: Overall Study | ||
| STARTED | 134 | 271 |
| Received Treatment | 109 | 267 |
| COMPLETED | 33 | 93 |
| NOT COMPLETED | 101 | 178 |
Baseline Characteristics
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab | Total |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | Total of all reporting groups |
| Overall Participants | 134 | 271 | 405 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
41.1
(17.3)
|
40.8
(17.1)
|
40.9
(17.2)
|
| Age, Customized (participants) [Number] | |||
| < 35 years |
60
44.8%
|
124
45.8%
|
184
45.4%
|
| 35 to 54 years |
33
24.6%
|
80
29.5%
|
113
27.9%
|
| 55 to 64 years |
26
19.4%
|
34
12.5%
|
60
14.8%
|
| ≥ 65 years |
15
11.2%
|
33
12.2%
|
48
11.9%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
57
42.5%
|
109
40.2%
|
166
41%
|
| Male |
77
57.5%
|
162
59.8%
|
239
59%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
11
8.2%
|
26
9.6%
|
37
9.1%
|
| Not Hispanic or Latino |
122
91%
|
243
89.7%
|
365
90.1%
|
| Unknown or Not Reported |
1
0.7%
|
2
0.7%
|
3
0.7%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| American Indian or Alaska Native |
1
0.7%
|
4
1.5%
|
5
1.2%
|
| Asian |
9
6.7%
|
19
7%
|
28
6.9%
|
| Native Hawaiian or Other Pacific Islander |
1
0.7%
|
1
0.4%
|
2
0.5%
|
| Black or African American |
3
2.2%
|
5
1.8%
|
8
2%
|
| White |
112
83.6%
|
228
84.1%
|
340
84%
|
| Multiple |
0
0%
|
2
0.7%
|
2
0.5%
|
| Other |
8
6%
|
12
4.4%
|
20
4.9%
|
| Age Stratification at Randomization (participants) [Number] | |||
| < 35 years |
60
44.8%
|
123
45.4%
|
183
45.2%
|
| ≥ 35 years |
74
55.2%
|
148
54.6%
|
222
54.8%
|
| Prior Salvage Therapy Stratification at Randomization (participants) [Number] | |||
| Yes |
80
59.7%
|
164
60.5%
|
244
60.2%
|
| No |
54
40.3%
|
107
39.5%
|
161
39.8%
|
| Prior Allogeneic Hematopoietic Stem Cell Transplant (HCST) (participants) [Number] | |||
| Yes |
46
34.3%
|
94
34.7%
|
140
34.6%
|
| No |
88
65.7%
|
177
65.3%
|
265
65.4%
|
| Standard of Care Chemotherapy Regimen Received (participants) [Number] | |||
| FLAG ± anthracycline |
56
41.8%
|
0
0%
|
56
13.8%
|
| High-dose methotrexate |
30
22.4%
|
0
0%
|
30
7.4%
|
| Clofarabine |
26
19.4%
|
0
0%
|
26
6.4%
|
| HIDAC |
22
16.4%
|
0
0%
|
22
5.4%
|
Outcome Measures
| Title | Overall Survival |
|---|---|
| Description | 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. |
| Time Frame | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 134 | 271 |
| Median (95% Confidence Interval) [months] |
4.0
|
7.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Standard of Care Chemotherapy, Blinatumomab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.012 |
| Comments | ||
| Method | Stratified Log Rank | |
| Comments | Stratified by age (< 35 years; ≥ 35 years), prior salvage therapy (yes vs. no), and prior allogeneic HSCT (yes vs. no). | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.71 | |
| Confidence Interval |
(2-Sided) 95% 0.55 to 0.93 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio obtained from the Cox Proportional Hazard Model. A hazard ratio < 1.0 indicated a lower average event rate and longer survival time for blinatumomab relative to SOC chemotherapy. | |
| Title | Percentage of Participants With Complete Remission Within 12 Weeks of Treatment Initiation |
|---|---|
| Description | 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. |
| Time Frame | 12 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 134 | 271 |
| Number (95% Confidence Interval) [percentage of participants] |
15.7
11.7%
|
33.6
12.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Standard of Care Chemotherapy, Blinatumomab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | < 0.001 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | Adjusted for the stratification factors: age (< 35 vs. ≥ 35), prior salvage therapy (yes vs. no), and prior allogeneic HSCT (yes vs. no). | |
| Method of Estimation | Estimation Parameter | Treatment difference |
| Estimated Value | 17.9 | |
| Confidence Interval |
(2-Sided) 95% 9.6 to 26.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | 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 |
|---|---|
| Description | 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). |
| Time Frame | 12 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 134 | 271 |
| Number (95% Confidence Interval) [percentage of participants] |
24.6
18.4%
|
43.9
16.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Standard of Care Chemotherapy, Blinatumomab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | < 0.001 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | Adjusted for the stratification factors: age (< 35 vs. ≥ 35), prior salvage therapy (yes vs. no), and prior allogeneic HSCT (yes vs. no). | |
| Method of Estimation | Estimation Parameter | Treatment difference |
| Estimated Value | 19.3 | |
| Confidence Interval |
(2-Sided) 95% 9.9 to 28.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Event Free Survival (EFS) |
|---|---|
| Description | 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. |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 134 | 271 |
| Number (95% Confidence Interval) [percentage of participants] |
12.5
9.3%
|
30.7
11.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Standard of Care Chemotherapy, Blinatumomab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other (legacy) | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.55 | |
| Confidence Interval |
(2-Sided) 95% 0.43 to 0.71 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The hazard ratio estimates were obtained from the Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average event rate and a longer survival for Blinatumomab relative to SOC Chemotherapy. | |
| Title | Duration of Complete Remission |
|---|---|
| Description | 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. |
| Time Frame | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Randomized participants with a best response of complete remission within 12 weeks of treatment initiation. |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 21 | 91 |
| Median (95% Confidence Interval) [months] |
7.8
|
8.3
|
| Title | Duration of Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) |
|---|---|
| Description | 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. |
| Time Frame | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Randomized participants with a best response of CR/CRh*/CRi within 12 weeks of treatment initiation. |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 33 | 119 |
| Median (95% Confidence Interval) [months] |
4.6
|
7.3
|
| Title | Percentage of Participants With Minimal Residual Disease (MRD) Within 12 Weeks of Treatment Initiation |
|---|---|
| Description | 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. |
| Time Frame | 12 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 134 | 271 |
| Number (95% Confidence Interval) [percentage of participants] |
14.2
10.6%
|
29.9
11%
|
| Title | Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) |
|---|---|
| Description | |
| Time Frame | Up to the data cut-off date of 04 January 2016; maximum time on study was 23 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 134 | 271 |
| Number (95% Confidence Interval) [percentage of participants] |
23.9
17.8%
|
24.0
8.9%
|
| Title | Number of Participants With Adverse Events |
|---|---|
| Description | 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? |
| Time Frame | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants who received protocol-specified therapy analyzed according to the treatment they received. |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 109 | 267 |
| Any adverse event |
108
80.6%
|
263
97%
|
| AE grade ≥ 2 |
106
79.1%
|
256
94.5%
|
| AE grade ≥ 3 |
100
74.6%
|
231
85.2%
|
| AE grade ≥ 4 |
67
50%
|
133
49.1%
|
| Serious adverse events |
49
36.6%
|
165
60.9%
|
| AEs leading to interruption of study drug |
6
4.5%
|
86
31.7%
|
| AEs leading to discontinuation of study drug |
9
6.7%
|
33
12.2%
|
| Life-threatening adverse events |
26
19.4%
|
55
20.3%
|
| Fatal adverse events |
19
14.2%
|
51
18.8%
|
| Treatment-related adverse events |
92
68.7%
|
214
79%
|
| Treatment-related AE grade ≥ 2 |
89
66.4%
|
195
72%
|
| Treatment-related AE grade ≥ 3 |
78
58.2%
|
143
52.8%
|
| Treatment-related AE grade ≥ 4 |
51
38.1%
|
57
21%
|
| Serious treatment-related adverse events |
34
25.4%
|
74
27.3%
|
| TRAEs leading to interruption of study drug |
6
4.5%
|
58
21.4%
|
| TRAEs leading to discontinuation of study drug |
8
6%
|
19
7%
|
| Treatment-related life-threatening adverse events |
17
12.7%
|
21
7.7%
|
| Treatment-related fatal adverse events |
8
6%
|
8
3%
|
| Title | 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant |
|---|---|
| Description | 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. |
| Time Frame | 100 days, from the date of allogeneic HSCT until the data cut-off date of 04 January 2016 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Randomized participants with a best response of CR/CRh*/CRi within 12 weeks of treatment initiation and who received an allogeneic HSC without anti-cancer therapy prior to allogeneic HSCT. |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 12 | 38 |
| Number (95% Confidence Interval) [percentage of participants] |
0.0
0%
|
12.4
4.6%
|
| Title | Number of Participants With Anti-blinatumomab Antibodies |
|---|---|
| Description | 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). |
| Time Frame | 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). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants who received blinatumomab with available post-baseline antibody data. |
| Arm/Group Title | Blinatumomab |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 171 |
| Binding antibody positive |
5
3.7%
|
| Neutralizing antibody positive |
3
2.2%
|
| Title | Time to a 10-point Decrease From Baseline in Global Health Status and Quality of Life or Death |
|---|---|
| Description | 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. |
| Time Frame | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| EORTC QLQ-C30 analysis set included all randomized participants with a non-missing baseline and at least 1 non-missing postbaseline result of any EORTC QLQ-C30 scales/item. |
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 95 | 247 |
| Median (95% Confidence Interval) [months] |
1.0
|
1.7
|
Adverse Events
| Time Frame | 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. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold. | |||
| Arm/Group Title | Standard of Care Chemotherapy | Blinatumomab | ||
| Arm/Group Description | 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. | 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. | ||
All Cause Mortality |
||||
| Standard of Care Chemotherapy | Blinatumomab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Standard of Care Chemotherapy | Blinatumomab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 49/109 (45%) | 165/267 (61.8%) | ||
| Blood and lymphatic system disorders | ||||
| Agranulocytosis | 1/109 (0.9%) | 0/267 (0%) | ||
| Anaemia | 0/109 (0%) | 1/267 (0.4%) | ||
| Febrile bone marrow aplasia | 0/109 (0%) | 1/267 (0.4%) | ||
| Febrile neutropenia | 12/109 (11%) | 23/267 (8.6%) | ||
| Histiocytosis haematophagic | 0/109 (0%) | 3/267 (1.1%) | ||
| Leukocytosis | 0/109 (0%) | 3/267 (1.1%) | ||
| Leukopenia | 1/109 (0.9%) | 0/267 (0%) | ||
| Lymphadenopathy | 0/109 (0%) | 1/267 (0.4%) | ||
| Neutropenia | 2/109 (1.8%) | 2/267 (0.7%) | ||
| Pancytopenia | 1/109 (0.9%) | 3/267 (1.1%) | ||
| Thrombocytopenia | 1/109 (0.9%) | 0/267 (0%) | ||
| Cardiac disorders | ||||
| Acute myocardial infarction | 0/109 (0%) | 1/267 (0.4%) | ||
| Atrial fibrillation | 0/109 (0%) | 1/267 (0.4%) | ||
| Atrial flutter | 0/109 (0%) | 1/267 (0.4%) | ||
| Cardiac arrest | 1/109 (0.9%) | 1/267 (0.4%) | ||
| Cardiac failure congestive | 0/109 (0%) | 1/267 (0.4%) | ||
| Cardiac tamponade | 1/109 (0.9%) | 0/267 (0%) | ||
| Cardiopulmonary failure | 0/109 (0%) | 1/267 (0.4%) | ||
| Pericardial effusion | 0/109 (0%) | 1/267 (0.4%) | ||
| Supraventricular tachycardia | 1/109 (0.9%) | 0/267 (0%) | ||
| Congenital, familial and genetic disorders | ||||
| Aplasia | 0/109 (0%) | 1/267 (0.4%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 0/109 (0%) | 2/267 (0.7%) | ||
| Gastric haemorrhage | 0/109 (0%) | 1/267 (0.4%) | ||
| Gastrointestinal inflammation | 1/109 (0.9%) | 0/267 (0%) | ||
| Gastrointestinal necrosis | 0/109 (0%) | 1/267 (0.4%) | ||
| Haematemesis | 0/109 (0%) | 1/267 (0.4%) | ||
| Mouth haemorrhage | 1/109 (0.9%) | 0/267 (0%) | ||
| Nausea | 0/109 (0%) | 1/267 (0.4%) | ||
| Pancreatitis | 1/109 (0.9%) | 0/267 (0%) | ||
| Stomatitis | 0/109 (0%) | 1/267 (0.4%) | ||
| Vomiting | 0/109 (0%) | 2/267 (0.7%) | ||
| General disorders | ||||
| Asthenia | 0/109 (0%) | 2/267 (0.7%) | ||
| Chest pain | 0/109 (0%) | 1/267 (0.4%) | ||
| Death | 0/109 (0%) | 1/267 (0.4%) | ||
| Discomfort | 0/109 (0%) | 1/267 (0.4%) | ||
| General physical health deterioration | 0/109 (0%) | 2/267 (0.7%) | ||
| Hyperthermia | 0/109 (0%) | 1/267 (0.4%) | ||
| Medical device complication | 0/109 (0%) | 1/267 (0.4%) | ||
| Multi-organ failure | 1/109 (0.9%) | 4/267 (1.5%) | ||
| Oedema peripheral | 0/109 (0%) | 1/267 (0.4%) | ||
| Pyrexia | 1/109 (0.9%) | 16/267 (6%) | ||
| Systemic inflammatory response syndrome | 0/109 (0%) | 1/267 (0.4%) | ||
| Hepatobiliary disorders | ||||
| Acute hepatic failure | 1/109 (0.9%) | 0/267 (0%) | ||
| Cholelithiasis | 0/109 (0%) | 1/267 (0.4%) | ||
| Cholestasis | 1/109 (0.9%) | 0/267 (0%) | ||
| Hepatitis | 0/109 (0%) | 1/267 (0.4%) | ||
| Immune system disorders | ||||
| Acute graft versus host disease in skin | 0/109 (0%) | 1/267 (0.4%) | ||
| Anaphylactic shock | 0/109 (0%) | 1/267 (0.4%) | ||
| Cytokine release syndrome | 0/109 (0%) | 7/267 (2.6%) | ||
| Graft versus host disease | 0/109 (0%) | 1/267 (0.4%) | ||
| Graft versus host disease in liver | 0/109 (0%) | 1/267 (0.4%) | ||
| Infections and infestations | ||||
| Abscess fungal | 1/109 (0.9%) | 0/267 (0%) | ||
| Bacteraemia | 3/109 (2.8%) | 2/267 (0.7%) | ||
| Bacterial infection | 0/109 (0%) | 2/267 (0.7%) | ||
| Bacterial sepsis | 2/109 (1.8%) | 6/267 (2.2%) | ||
| Brain abscess | 1/109 (0.9%) | 0/267 (0%) | ||
| Bronchitis | 0/109 (0%) | 1/267 (0.4%) | ||
| Bronchopulmonary aspergillosis | 1/109 (0.9%) | 4/267 (1.5%) | ||
| Catheter site infection | 0/109 (0%) | 2/267 (0.7%) | ||
| Cellulitis | 0/109 (0%) | 1/267 (0.4%) | ||
| Central nervous system abscess | 1/109 (0.9%) | 0/267 (0%) | ||
| Citrobacter infection | 0/109 (0%) | 1/267 (0.4%) | ||
| Citrobacter sepsis | 1/109 (0.9%) | 0/267 (0%) | ||
| Device related infection | 1/109 (0.9%) | 6/267 (2.2%) | ||
| Device related sepsis | 2/109 (1.8%) | 1/267 (0.4%) | ||
| Encephalitis enteroviral | 0/109 (0%) | 1/267 (0.4%) | ||
| Enterococcal bacteraemia | 1/109 (0.9%) | 0/267 (0%) | ||
| Enterococcal infection | 1/109 (0.9%) | 0/267 (0%) | ||
| Escherichia infection | 0/109 (0%) | 2/267 (0.7%) | ||
| Fungaemia | 0/109 (0%) | 1/267 (0.4%) | ||
| Fungal infection | 1/109 (0.9%) | 0/267 (0%) | ||
| Fungal sepsis | 0/109 (0%) | 2/267 (0.7%) | ||
| Fusarium infection | 1/109 (0.9%) | 0/267 (0%) | ||
| Gastroenteritis | 0/109 (0%) | 2/267 (0.7%) | ||
| Hepatosplenic candidiasis | 1/109 (0.9%) | 0/267 (0%) | ||
| Infection | 0/109 (0%) | 1/267 (0.4%) | ||
| Infection in an immunocompromised host | 0/109 (0%) | 1/267 (0.4%) | ||
| Influenza | 0/109 (0%) | 1/267 (0.4%) | ||
| Lower respiratory tract infection | 0/109 (0%) | 1/267 (0.4%) | ||
| Lower respiratory tract infection fungal | 0/109 (0%) | 1/267 (0.4%) | ||
| Lung infection | 1/109 (0.9%) | 1/267 (0.4%) | ||
| Mastoiditis | 0/109 (0%) | 1/267 (0.4%) | ||
| Meningitis bacterial | 0/109 (0%) | 1/267 (0.4%) | ||
| Mucormycosis | 0/109 (0%) | 1/267 (0.4%) | ||
| Muscle abscess | 0/109 (0%) | 1/267 (0.4%) | ||
| Neutropenic sepsis | 1/109 (0.9%) | 3/267 (1.1%) | ||
| Osteomyelitis | 0/109 (0%) | 1/267 (0.4%) | ||
| Otitis media acute | 0/109 (0%) | 1/267 (0.4%) | ||
| Pneumonia | 2/109 (1.8%) | 10/267 (3.7%) | ||
| Pneumonia bacterial | 0/109 (0%) | 1/267 (0.4%) | ||
| Pneumonia fungal | 2/109 (1.8%) | 1/267 (0.4%) | ||
| Pneumonia pseudomonal | 0/109 (0%) | 1/267 (0.4%) | ||
| Pneumonia respiratory syncytial viral | 0/109 (0%) | 1/267 (0.4%) | ||
| Progressive multifocal leukoencephalopathy | 0/109 (0%) | 1/267 (0.4%) | ||
| Pseudomonal sepsis | 1/109 (0.9%) | 3/267 (1.1%) | ||
| Pseudomonas infection | 1/109 (0.9%) | 3/267 (1.1%) | ||
| Pulmonary mycosis | 0/109 (0%) | 1/267 (0.4%) | ||
| Respiratory syncytial virus bronchiolitis | 0/109 (0%) | 1/267 (0.4%) | ||
| Rhinovirus infection | 1/109 (0.9%) | 0/267 (0%) | ||
| Sepsis | 7/109 (6.4%) | 13/267 (4.9%) | ||
| Sepsis syndrome | 0/109 (0%) | 1/267 (0.4%) | ||
| Septic shock | 3/109 (2.8%) | 8/267 (3%) | ||
| Sinusitis | 0/109 (0%) | 1/267 (0.4%) | ||
| Skin infection | 0/109 (0%) | 1/267 (0.4%) | ||
| Soft tissue infection | 1/109 (0.9%) | 0/267 (0%) | ||
| Staphylococcal infection | 1/109 (0.9%) | 2/267 (0.7%) | ||
| Staphylococcal sepsis | 0/109 (0%) | 1/267 (0.4%) | ||
| Streptococcal sepsis | 1/109 (0.9%) | 0/267 (0%) | ||
| Systemic candida | 1/109 (0.9%) | 0/267 (0%) | ||
| Tooth infection | 0/109 (0%) | 1/267 (0.4%) | ||
| Injury, poisoning and procedural complications | ||||
| Accidental overdose | 0/109 (0%) | 3/267 (1.1%) | ||
| Ankle fracture | 1/109 (0.9%) | 0/267 (0%) | ||
| Fall | 0/109 (0%) | 1/267 (0.4%) | ||
| Medication error | 0/109 (0%) | 1/267 (0.4%) | ||
| Overdose | 0/109 (0%) | 8/267 (3%) | ||
| Subdural haematoma | 0/109 (0%) | 1/267 (0.4%) | ||
| Subdural haemorrhage | 0/109 (0%) | 1/267 (0.4%) | ||
| Investigations | ||||
| Blood bilirubin increased | 0/109 (0%) | 2/267 (0.7%) | ||
| Blood lactate dehydrogenase increased | 0/109 (0%) | 1/267 (0.4%) | ||
| CSF cell count abnormal | 0/109 (0%) | 1/267 (0.4%) | ||
| Platelet count decreased | 0/109 (0%) | 1/267 (0.4%) | ||
| Transaminases increased | 0/109 (0%) | 1/267 (0.4%) | ||
| Weight increased | 0/109 (0%) | 1/267 (0.4%) | ||
| White blood cell count decreased | 0/109 (0%) | 1/267 (0.4%) | ||
| White blood cell count increased | 0/109 (0%) | 1/267 (0.4%) | ||
| Metabolism and nutrition disorders | ||||
| Hypercalcaemia | 0/109 (0%) | 1/267 (0.4%) | ||
| Hyperkalaemia | 1/109 (0.9%) | 0/267 (0%) | ||
| Hyperuricaemia | 0/109 (0%) | 2/267 (0.7%) | ||
| Hypoglycaemia | 1/109 (0.9%) | 0/267 (0%) | ||
| Hypokalaemia | 0/109 (0%) | 1/267 (0.4%) | ||
| Hypomagnesaemia | 0/109 (0%) | 1/267 (0.4%) | ||
| Hypophosphataemia | 0/109 (0%) | 2/267 (0.7%) | ||
| Lactic acidosis | 1/109 (0.9%) | 1/267 (0.4%) | ||
| Metabolic acidosis | 1/109 (0.9%) | 0/267 (0%) | ||
| Tumour lysis syndrome | 0/109 (0%) | 3/267 (1.1%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 0/109 (0%) | 2/267 (0.7%) | ||
| Bone pain | 0/109 (0%) | 3/267 (1.1%) | ||
| Osteitis | 1/109 (0.9%) | 0/267 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Acute lymphocytic leukaemia | 0/109 (0%) | 1/267 (0.4%) | ||
| Leukaemic infiltration extramedullary | 0/109 (0%) | 1/267 (0.4%) | ||
| Leukaemic infiltration pulmonary | 0/109 (0%) | 1/267 (0.4%) | ||
| Tumour associated fever | 0/109 (0%) | 1/267 (0.4%) | ||
| Nervous system disorders | ||||
| Aphasia | 0/109 (0%) | 3/267 (1.1%) | ||
| Cerebral haemorrhage | 0/109 (0%) | 1/267 (0.4%) | ||
| Cognitive disorder | 0/109 (0%) | 1/267 (0.4%) | ||
| Depressed level of consciousness | 0/109 (0%) | 1/267 (0.4%) | ||
| Encephalopathy | 0/109 (0%) | 4/267 (1.5%) | ||
| Generalised tonic-clonic seizure | 1/109 (0.9%) | 0/267 (0%) | ||
| Haemorrhage intracranial | 2/109 (1.8%) | 1/267 (0.4%) | ||
| Haemorrhagic stroke | 0/109 (0%) | 1/267 (0.4%) | ||
| Hemianopia | 0/109 (0%) | 1/267 (0.4%) | ||
| Hemiparesis | 0/109 (0%) | 1/267 (0.4%) | ||
| Hemiplegia | 1/109 (0.9%) | 0/267 (0%) | ||
| Hypoaesthesia | 0/109 (0%) | 1/267 (0.4%) | ||
| Intention tremor | 0/109 (0%) | 1/267 (0.4%) | ||
| Leukoencephalopathy | 0/109 (0%) | 1/267 (0.4%) | ||
| Neurological symptom | 0/109 (0%) | 1/267 (0.4%) | ||
| Paraesthesia | 0/109 (0%) | 1/267 (0.4%) | ||
| Seizure | 1/109 (0.9%) | 1/267 (0.4%) | ||
| Somnolence | 0/109 (0%) | 1/267 (0.4%) | ||
| Status epilepticus | 0/109 (0%) | 1/267 (0.4%) | ||
| Tremor | 0/109 (0%) | 1/267 (0.4%) | ||
| Psychiatric disorders | ||||
| Completed suicide | 0/109 (0%) | 1/267 (0.4%) | ||
| Mental status changes | 0/109 (0%) | 1/267 (0.4%) | ||
| Renal and urinary disorders | ||||
| Acute kidney injury | 2/109 (1.8%) | 3/267 (1.1%) | ||
| Calculus ureteric | 0/109 (0%) | 1/267 (0.4%) | ||
| Urinary bladder haemorrhage | 1/109 (0.9%) | 0/267 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Acute respiratory failure | 0/109 (0%) | 2/267 (0.7%) | ||
| Dyspnoea | 0/109 (0%) | 2/267 (0.7%) | ||
| Epistaxis | 0/109 (0%) | 2/267 (0.7%) | ||
| Haemoptysis | 0/109 (0%) | 2/267 (0.7%) | ||
| Hypoxia | 0/109 (0%) | 1/267 (0.4%) | ||
| Lung infiltration | 1/109 (0.9%) | 1/267 (0.4%) | ||
| Pleural effusion | 1/109 (0.9%) | 1/267 (0.4%) | ||
| Pneumonitis | 0/109 (0%) | 1/267 (0.4%) | ||
| Pneumothorax | 1/109 (0.9%) | 0/267 (0%) | ||
| Pulmonary oedema | 0/109 (0%) | 1/267 (0.4%) | ||
| Respiratory arrest | 0/109 (0%) | 1/267 (0.4%) | ||
| Respiratory failure | 2/109 (1.8%) | 1/267 (0.4%) | ||
| Stridor | 0/109 (0%) | 1/267 (0.4%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 0/109 (0%) | 1/267 (0.4%) | ||
| Skin ulcer | 0/109 (0%) | 1/267 (0.4%) | ||
| Surgical and medical procedures | ||||
| Catheter placement | 0/109 (0%) | 1/267 (0.4%) | ||
| Vascular disorders | ||||
| Aortic occlusion | 0/109 (0%) | 1/267 (0.4%) | ||
| Hypotension | 2/109 (1.8%) | 0/267 (0%) | ||
| Peripheral artery thrombosis | 1/109 (0.9%) | 0/267 (0%) | ||
| Shock | 1/109 (0.9%) | 0/267 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Standard of Care Chemotherapy | Blinatumomab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 105/109 (96.3%) | 250/267 (93.6%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 46/109 (42.2%) | 69/267 (25.8%) | ||
| Febrile neutropenia | 36/109 (33%) | 48/267 (18%) | ||
| Neutropenia | 31/109 (28.4%) | 51/267 (19.1%) | ||
| Thrombocytopenia | 32/109 (29.4%) | 47/267 (17.6%) | ||
| Cardiac disorders | ||||
| Sinus tachycardia | 6/109 (5.5%) | 15/267 (5.6%) | ||
| Tachycardia | 10/109 (9.2%) | 18/267 (6.7%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 19/109 (17.4%) | 15/267 (5.6%) | ||
| Constipation | 28/109 (25.7%) | 34/267 (12.7%) | ||
| Diarrhoea | 38/109 (34.9%) | 58/267 (21.7%) | ||
| Dyspepsia | 7/109 (6.4%) | 10/267 (3.7%) | ||
| Haemorrhoids | 6/109 (5.5%) | 7/267 (2.6%) | ||
| Nausea | 46/109 (42.2%) | 51/267 (19.1%) | ||
| Proctalgia | 7/109 (6.4%) | 2/267 (0.7%) | ||
| Stomatitis | 14/109 (12.8%) | 17/267 (6.4%) | ||
| Vomiting | 26/109 (23.9%) | 31/267 (11.6%) | ||
| General disorders | ||||
| Asthenia | 11/109 (10.1%) | 19/267 (7.1%) | ||
| Chest pain | 6/109 (5.5%) | 6/267 (2.2%) | ||
| Chills | 12/109 (11%) | 19/267 (7.1%) | ||
| Fatigue | 14/109 (12.8%) | 34/267 (12.7%) | ||
| Mucosal inflammation | 14/109 (12.8%) | 9/267 (3.4%) | ||
| Oedema peripheral | 16/109 (14.7%) | 38/267 (14.2%) | ||
| Pain | 6/109 (5.5%) | 16/267 (6%) | ||
| Pyrexia | 48/109 (44%) | 153/267 (57.3%) | ||
| Immune system disorders | ||||
| Cytokine release syndrome | 0/109 (0%) | 35/267 (13.1%) | ||
| Hypogammaglobulinaemia | 1/109 (0.9%) | 16/267 (6%) | ||
| Infections and infestations | ||||
| Bacteraemia | 6/109 (5.5%) | 3/267 (1.1%) | ||
| Oral herpes | 9/109 (8.3%) | 15/267 (5.6%) | ||
| Pneumonia | 14/109 (12.8%) | 7/267 (2.6%) | ||
| Sinusitis | 6/109 (5.5%) | 5/267 (1.9%) | ||
| Upper respiratory tract infection | 1/109 (0.9%) | 19/267 (7.1%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 11/109 (10.1%) | 24/267 (9%) | ||
| Aspartate aminotransferase increased | 10/109 (9.2%) | 15/267 (5.6%) | ||
| Blood bilirubin increased | 9/109 (8.3%) | 10/267 (3.7%) | ||
| Neutrophil count decreased | 11/109 (10.1%) | 10/267 (3.7%) | ||
| Platelet count decreased | 13/109 (11.9%) | 17/267 (6.4%) | ||
| White blood cell count decreased | 6/109 (5.5%) | 13/267 (4.9%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 15/109 (13.8%) | 18/267 (6.7%) | ||
| Hyperglycaemia | 9/109 (8.3%) | 20/267 (7.5%) | ||
| Hypoalbuminaemia | 11/109 (10.1%) | 13/267 (4.9%) | ||
| Hypocalcaemia | 9/109 (8.3%) | 10/267 (3.7%) | ||
| Hypokalaemia | 30/109 (27.5%) | 45/267 (16.9%) | ||
| Hypomagnesaemia | 18/109 (16.5%) | 28/267 (10.5%) | ||
| Hypophosphataemia | 6/109 (5.5%) | 11/267 (4.1%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 5/109 (4.6%) | 16/267 (6%) | ||
| Back pain | 10/109 (9.2%) | 33/267 (12.4%) | ||
| Bone pain | 8/109 (7.3%) | 29/267 (10.9%) | ||
| Myalgia | 6/109 (5.5%) | 19/267 (7.1%) | ||
| Pain in extremity | 8/109 (7.3%) | 25/267 (9.4%) | ||
| Nervous system disorders | ||||
| Dizziness | 8/109 (7.3%) | 18/267 (6.7%) | ||
| Headache | 32/109 (29.4%) | 77/267 (28.8%) | ||
| Tremor | 0/109 (0%) | 26/267 (9.7%) | ||
| Psychiatric disorders | ||||
| Anxiety | 6/109 (5.5%) | 13/267 (4.9%) | ||
| Insomnia | 10/109 (9.2%) | 28/267 (10.5%) | ||
| Renal and urinary disorders | ||||
| Acute kidney injury | 6/109 (5.5%) | 8/267 (3%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 6/109 (5.5%) | 39/267 (14.6%) | ||
| Dyspnoea | 8/109 (7.3%) | 15/267 (5.6%) | ||
| Epistaxis | 9/109 (8.3%) | 16/267 (6%) | ||
| Oropharyngeal pain | 7/109 (6.4%) | 13/267 (4.9%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Petechiae | 6/109 (5.5%) | 7/267 (2.6%) | ||
| Rash | 13/109 (11.9%) | 19/267 (7.1%) | ||
| Vascular disorders | ||||
| Hypertension | 9/109 (8.3%) | 17/267 (6.4%) | ||
| Hypotension | 11/109 (10.1%) | 32/267 (12%) | ||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Amgen Inc. |
| Phone | 866-572-6436 |
Responsible Party:
Amgen
ClinicalTrials.gov Identifier:
NCT02013167
Other Study ID Numbers:
- 00103311
- 2013-000536-10
First Posted:
Dec 17, 2013
Last Update Posted:
Jan 5, 2022
Last Verified:
Jan 1, 2022