Blinatumomab in Adults With Relapsed/Refractory Philadelphia Positive B-precursor Acute Lymphoblastic Leukemia

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02000427
• Collaborator: (none)
• Enrollment: 45
• Locations: 22
• Arm: 1
• Actual Duration (Months): 36.1
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective is to evaluate the rate of complete remission/complete remission with partial hematological recovery (CRh*) in adults with relapsed/refractory Philadelphia chromosome positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who receive blinatumomab.

Condition or Disease	Intervention/Treatment	Phase
Relapsed/Refractory Philadelphia Positive B-precursor ALL	Drug: Blinatumomab	Phase 2

Detailed Description

This is a single-arm Simon II stage design, multicenter study consisting of a screening period, an induction treatment period (2 cycles of blinatumomab), a consolidation treatment period (up to 3 additional cycles of blinatumomab for applicable participants), and a safety follow-up visit 30 days after treatment. Following the safety follow-up visit, participants will be followed for response duration and survival every 3 months for 18 months or death, whichever occurs first.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Single Arm, Multicenter Trial to Evaluate the Efficacy of the BiTE Antibody Blinatumomab in Adult Subjects With Relapsed/Refractory Philadelphia Positive B-precursor Acute Lymphoblastic Leukemia (Alcantara Study)
• Actual Study Start Date: Jan 3, 2014
• Actual Primary Completion Date: May 20, 2015
• Actual Study Completion Date: Jan 6, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Blinatumomab Participants will receive blinatumomab by continuous intravenous (CIVI) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieve a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose will be 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 for all subsequent cycles of treatment.

Drug: Blinatumomab; Blinatumomab is administered as a continuous intravenous infusion (CIV). A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks of blinatumomab followed by a 2-week treatment-free interval.; Other Names: Blincyto® AMG 103

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery (CR/CRh*) During the First Two Treatment Cycles [Approximately 12 weeks, as of the data cut-off date of 20 May 2015]

   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 meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl. Complete remission with partial hematological recovery (CRh*) was defined as meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow no evidence of disease partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Participants without a post-baseline disease assessment were considered non-responders.

Secondary Outcome Measures

1. Percentage of Participants With Minimal Residual Disease (MRD) Remission During the First 2 Cycles of Treatment [Approximately 12 weeks]

   Bone marrow samples were evaluated for MRD remission by a central laboratory using bcr-abl fusion gene reverse transcription polymerase chain reaction (RT-PCR). An MRD response was defined as MRD < 10^-4 measured by PCR. Participants with no post-baseline MRD assessment were considered non-responders.

2. Duration of CR or CRh* Response [Up to the data cut-off date of 20 May 2015; median observation time was 7.0 months]

   Duration of response was measured for participants in remission (CR/CRh*), and was measured from the time the participant first achieved remission until first documented relapse or death from disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of the last bone marrow assessment or the last survival follow-up visit to confirm remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death.

3. Percentage of Participants With Complete Remission (CR) During the First Two Treatment Cycles [Approximately 12 weeks, as of the data cut-off date of 20 May 2015]

   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 meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl. Participants without a post-baseline disease assessment were considered non-responders.

4. Percentage of Participants With Complete Remission With Partial Hematological Recovery (CRh*) During the First Two Treatment Cycles [Approximately 12 weeks, as of the data cut-off date of 20 May 2015]

   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 with partial hematological recovery (CRh*) was defined as meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Participants without a post-baseline disease assessment were considered non-responders.

5. Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) During the First Two Treatment Cycles [Approximately 12 weeks, as of the data cut-off date of 20 May 2015]

   Efficacy was evaluated via a central bone marrow aspiration and local peripheral blood counts. Complete remission was defined as meeting the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl. Complete remission with partial hematological recovery was defined as meeting the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Complete remission with incomplete hematologic recovery was defined as meeting all of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; incomplete recovery of peripheral blood counts: platelets > 100,000/μl or ANC > 1000/μl. Participants without a post-baseline disease assessment were considered non-responders.

6. Overall Survival [From first dose of blinatumomab until the data cut-off date; median observation time was 8.8 months.]

   Overall survival was assessed from the date the participant received the first infusion of blinatumomab until death from any cause or the date of the last follow-up. Participants still alive at the data cut-off date were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive.

7. Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission [Up to the data cut-of date of 20 May 2015; Maximum duration on study was 14.5 months.]

   Participants who achieved remission (CR/CRh*) during the first 2 cycles of treatment and received an allogeneic HSCT.

8. 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant [From the date of allogeneic HSCT until the data cut-off date of 20 May 2015; median observation time was 3.2 months.]

   The analysis of 100-day mortality after allogeneic HSCT was assessed for participants who received an allogeneic HSCT while in remission (CR/CRh*) after 2 cycles of blinatumomab treatment and did not receive any additional antileukemic treatment. 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.

9. Number of Participants With Adverse Events [From the first dose of blinatumomab until 30 days after the last dose, up to the cut-off date of 20 May 2015; the median duration of treatment was 53.8 days.]

   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?

10. Number of Participants Who Developed Anti-blinatumomab Antibodies [Day 29 of each treatment period and 30 days after the last dose]

    Anti-blinatumomab binding antibodies were evaluated with a validated blinatumomab anti-drug antibody assay with the electrochemiluminescence detection technology.

11. Steady State Concentration of Blinatumomab [Cycle 1, day 8, 6 to 8 hours after the dose step to 28 μg/day, and Cycle 2, day 1, 6 to 8 hours after blinatumomab infusion]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Patients with Ph+ B-precursor ALL, with any of the following:

• Relapsed or refractory to at least one second generation tyrosine kinase inhibitor (TKI) (dasatinib, nilotinib, bosutinib, ponatinib)

• OR intolerant to second generation TKI and intolerant or refractory to imatinib mesylate

• Greater than 5% blasts in bone marrow

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Age ≥ 18 years of age, at the time of informed consent.

• Subject has provided informed consent or subject's legally acceptable representative has provided informed consent when the subject has any kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent.

Exclusion Criteria

• History of malignancy other than ALL within 5 years prior to start of protocol-required therapy, except for adequately treated selected cancers without evidence of disease

• History or presence of clinically relevant central nervous system (CNS) pathology as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis

• Active ALL in the CNS or testes

• Isolated extramedullary disease

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

• Allogeneic hematopoietic stem cell transplantation (HSCT) within 12 weeks before blinatumomab treatment

• Active acute or extensive chronic graft-versus-host disease (GvHD) which included the administration of immunosuppressive agents to prevent or treat GvHD within 2 weeks before blinatumomab treatment

• immediately previous cancer chemotherapy, radiotherapy, or immunotherapy; and eligibility for allogeneic HSCT at the time of enrollment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Duarte	California	United States	91010
2	Research Site	La Jolla	California	United States	92093-0960
3	Research Site	Atlanta	Georgia	United States	30322
4	Research Site	Rochester	Minnesota	United States	55905
5	Research Site	Saint Louis	Missouri	United States	63110
6	Research Site	New York	New York	United States	10065
7	Research Site	Durham	North Carolina	United States	27710
8	Research Site	Houston	Texas	United States	77030
9	Research Site	Nantes Cedex 1		France	44093
10	Research Site	Paris Cedex 10		France	75475
11	Research Site	Toulouse cedex 9		France	31059
12	Research Site	Berlin		Germany	12200
13	Research Site	Essen		Germany	45122
14	Research Site	Frankfurt am Main		Germany	60590
15	Research Site	Würzburg		Germany	97080
16	Research Site	Bergamo		Italy	24127
17	Research Site	Bologna		Italy	40138
18	Research Site	Roma		Italy	00161
19	Research Site	Venezia		Italy	30174
20	Research Site	Verona		Italy	37134
21	Research Site	London		United Kingdom	NW3 2PF
22	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:

• AmgenTrials clinical trials website

Publications

• 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.
• Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, Fielding AK, Rambaldi A, Ritchie EK, Papayannidis C, Sterling LR, Benjamin J, Stein A. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol. 2017 Jun 1;35(16):1795-1802. doi: 10.1200/JCO.2016.69.3531. Epub 2017 Mar 29. Erratum in: J Clin Oncol. 2017 Aug 10;35(23):2722. J Clin Oncol. 2017 Aug 20;35(24):2856.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT02000427
• Other Study ID Numbers: 20120216; 2006-006520-19
• First Posted: Dec 4, 2013
• Last Update Posted: Jan 5, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Amgen: Relapsed; Refractory; Philadelphia Positive; B-precursor; Acute Lymphoblastic Leukemia; ALL; Blinatumomab; Leukemia;
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Blinatumomab

Study Results

Participant Flow

Recruitment Details	This study was conducted at 19 centers in 4 European countries and the United States: 3 centers in France, 3 in Germany, 5 in Italy, 1 in the United Kingdom, and 7 in the United States. The first participant enrolled on 03 January 2014 and the last participant enrolled on 12 January 2015.
Pre-assignment Detail	Results are reported as of the data cut-off date of 20 May 2015.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Period Title: Overall Study
STARTED	45
COMPLETED	23
NOT COMPLETED	22

Baseline Characteristics

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Overall Participants	45
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.8 (15.0)
Age, Customized (participants) [Number]
18 to < 35 years	5 11.1%
35 to < 55 years	17 37.8%
55 to < 65 years	11 24.4%
≥ 65 years	12 26.7%
Sex: Female, Male (Count of Participants)
Female	21 46.7%
Male	24 53.3%
Race/Ethnicity, Customized (participants) [Number]
White	39 86.7%
Asian	1 2.2%
Black (or African American)	3 6.7%
Other	2 4.4%
Race/Ethnicity, Customized (participants) [Number]
Hispanic/Latino	2 4.4%
Not Hispanic/Latino	43 95.6%
Prior Tyrosine Kinase Inhibitor (TKI) Treatment (participants) [Number]
1 TKI	7 15.6%
2 TKIs	21 46.7%
3 TKIs	13 28.9%
4 TKIs	4 8.9%
Number of Prior Relapses (participants) [Number]
No relapses	3 6.7%
1 relapse	25 55.6%
2 relapses	13 28.9%
≥ 3 relapses	4 8.9%
Number of Prior Salvage Regimens (participants) [Number]
0 regimens	14 31.1%
1 regimen	12 26.7%
2 regimens	11 24.4%
≥ 3 regimens	8 17.8%
Prior Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) (participants) [Number]
Yes	20 44.4%
No	25 55.6%
Time From Initial Diagnosis (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	27.3 (26.1)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery (CR/CRh*) During the First Two Treatment Cycles
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 meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl. Complete remission with partial hematological recovery (CRh*) was defined as meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow no evidence of disease partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Participants without a post-baseline disease assessment were considered non-responders.
Time Frame	Approximately 12 weeks, as of the data cut-off date of 20 May 2015

Outcome Measure Data

Analysis Population Description

All participants who received an infusion of blinatumomab.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	35.6 79.1%

2. Secondary Outcome

Title	Percentage of Participants With Minimal Residual Disease (MRD) Remission During the First 2 Cycles of Treatment
Description	Bone marrow samples were evaluated for MRD remission by a central laboratory using bcr-abl fusion gene reverse transcription polymerase chain reaction (RT-PCR). An MRD response was defined as MRD < 10^-4 measured by PCR. Participants with no post-baseline MRD assessment were considered non-responders.
Time Frame	Approximately 12 weeks

Outcome Measure Data

Analysis Population Description

All participants who received an infusion of blinatumomab.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	40.0 88.9%

3. Secondary Outcome

Title	Duration of CR or CRh* Response
Description	Duration of response was measured for participants in remission (CR/CRh*), and was measured from the time the participant first achieved remission until first documented relapse or death from disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of the last bone marrow assessment or the last survival follow-up visit to confirm remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death.
Time Frame	Up to the data cut-off date of 20 May 2015; median observation time was 7.0 months

Outcome Measure Data

Analysis Population Description

Participants who received an infusion of blinatumomab and with a CR or CRh* response during the first 2 treatment cycles.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	16
Median (95% Confidence Interval) [months]	6.7

4. Secondary Outcome

Title	Percentage of Participants With Complete Remission (CR) During the First Two Treatment Cycles
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 meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl. Participants without a post-baseline disease assessment were considered non-responders.
Time Frame	Approximately 12 weeks, as of the data cut-off date of 20 May 2015

Outcome Measure Data

Analysis Population Description

All participants who received an infusion of blinatumomab

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	31.1 69.1%

5. Secondary Outcome

Title	Percentage of Participants With Complete Remission With Partial Hematological Recovery (CRh*) During the First Two Treatment Cycles
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 with partial hematological recovery (CRh*) was defined as meeting all 3 of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Participants without a post-baseline disease assessment were considered non-responders.
Time Frame	Approximately 12 weeks, as of the data cut-off date of 20 May 2015

Outcome Measure Data

Analysis Population Description

All participants who received an infusion of blinatumomab

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	4.4 9.8%

6. Secondary Outcome

Title	Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) During the First Two Treatment Cycles
Description	Efficacy was evaluated via a central bone marrow aspiration and local peripheral blood counts. Complete remission was defined as meeting the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; full recovery of peripheral blood counts: platelets > 100,000/μl, and absolute neutrophil count (ANC) > 1000/μl. Complete remission with partial hematological recovery was defined as meeting the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. Complete remission with incomplete hematologic recovery was defined as meeting all of the following criteria: less than or equal to 5% blasts in the bone marrow; no evidence of disease; incomplete recovery of peripheral blood counts: platelets > 100,000/μl or ANC > 1000/μl. Participants without a post-baseline disease assessment were considered non-responders.
Time Frame	Approximately 12 weeks, as of the data cut-off date of 20 May 2015

Outcome Measure Data

Analysis Population Description

All participants who received an infusion of blinatumomab

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	40.0 88.9%

7. Secondary Outcome

Title	Overall Survival
Description	Overall survival was assessed from the date the participant received the first infusion of blinatumomab until death from any cause or the date of the last follow-up. Participants still alive at the data cut-off date were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive.
Time Frame	From first dose of blinatumomab until the data cut-off date; median observation time was 8.8 months.

Outcome Measure Data

Analysis Population Description

All participants who received an infusion of blinatumomab

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	45
Median (95% Confidence Interval) [months]	7.1

8. Secondary Outcome

Title	Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission
Description	Participants who achieved remission (CR/CRh*) during the first 2 cycles of treatment and received an allogeneic HSCT.
Time Frame	Up to the data cut-of date of 20 May 2015; Maximum duration on study was 14.5 months.

Outcome Measure Data

Analysis Population Description

Participants who received an infusion of blinatumomab and had a CR/CRh* response during the first 2 cycles of treatment.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	16
Number (95% Confidence Interval) [percentage of participants]	43.8 97.3%

9. Secondary Outcome

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 received an allogeneic HSCT while in remission (CR/CRh*) after 2 cycles of blinatumomab treatment and did not receive any additional antileukemic treatment. 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	From the date of allogeneic HSCT until the data cut-off date of 20 May 2015; median observation time was 3.2 months.

Outcome Measure Data

Analysis Population Description

Participants who received allogeneic HSCT and were in remission with a CR/CRh* after 2 cycles of treatment and received the transplant without receiving any additional antileukemic medication.

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	4
Number (95% Confidence Interval) [percentage of participants]	25.0 55.6%

10. Secondary Outcome

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 the first dose of blinatumomab until 30 days after the last dose, up to the cut-off date of 20 May 2015; the median duration of treatment was 53.8 days.

Outcome Measure Data

Analysis Population Description

All participants who received an infusion of blinatumomab

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	45
Any adverse event	45 100%
AE grade ≥ 3	37 82.2%
AE grade ≥ 4	18 40%
Serious adverse events	28 62.2%
Leading to discontinuation of blinatumomab	3 6.7%
Leading to interruption of blinatumomab	16 35.6%
Fatal adverse events	5 11.1%
Treatment-related adverse events	41 91.1%
Treatment-related AE grade ≥ 3	20 44.4%
Treatment-related AE grade ≥ 4	7 15.6%
Treatment-related serious adverse events	12 26.7%
TRAE leading to discontinuation of blinatumomab	2 4.4%
TRAE leading to interruption of blinatumomab	12 26.7%
Treatment-related fatal adverse events	1 2.2%

11. Secondary Outcome

Title	Number of Participants Who Developed Anti-blinatumomab Antibodies
Description	Anti-blinatumomab binding antibodies were evaluated with a validated blinatumomab anti-drug antibody assay with the electrochemiluminescence detection technology.
Time Frame	Day 29 of each treatment period and 30 days after the last dose

Outcome Measure Data

Analysis Population Description

Participants with available post-baseline antibody results

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	29
Number [participants]	0 0%

12. Secondary Outcome

Title	Steady State Concentration of Blinatumomab
Time Frame	Cycle 1, day 8, 6 to 8 hours after the dose step to 28 μg/day, and Cycle 2, day 1, 6 to 8 hours after blinatumomab infusion

Outcome Measure Data

Analysis Population Description

Participants with available serum concentration data

Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
Measure Participants	28
Cycle 1	449 (125.6)
Cycle 2 (n = 21)	532 (128.7)

Adverse Events

Time Frame	From the first dose of blinatumomab until 30 days after the last dose, up to the cut-off date of 20 May 2015; the median duration of treatment was 53.8 days.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Blinatumomab
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for 2 cycles. Participants who achieved a complete remission or complete remission with partial or incomplete hematologic recovery within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. The initial dose was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 and for all subsequent cycles of treatment.
All Cause Mortality
	Blinatumomab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Blinatumomab
	Affected / at Risk (%)	# Events
Total	28/45 (62.2%)
Blood and lymphatic system disorders
Anaemia	1/45 (2.2%)
Febrile neutropenia	4/45 (8.9%)
Leukocytosis	2/45 (4.4%)
Lymph node pain	1/45 (2.2%)
Lymphoblastosis	1/45 (2.2%)
Pancytopenia	1/45 (2.2%)
Congenital, familial and genetic disorders
Aplasia	1/45 (2.2%)
Gastrointestinal disorders
Colitis	1/45 (2.2%)
Nausea	1/45 (2.2%)
Vomiting	1/45 (2.2%)
General disorders
Device infusion issue	1/45 (2.2%)
Device malfunction	1/45 (2.2%)
General physical health deterioration	1/45 (2.2%)
Multi-organ failure	1/45 (2.2%)
Non-cardiac chest pain	2/45 (4.4%)
Pyrexia	2/45 (4.4%)
Hepatobiliary disorders
Hepatic failure	1/45 (2.2%)
Immune system disorders
Acute graft versus host disease	1/45 (2.2%)
Cytokine release syndrome	1/45 (2.2%)
Infections and infestations
Catheter site infection	1/45 (2.2%)
Device related infection	3/45 (6.7%)
Lung infection	1/45 (2.2%)
Neutropenic sepsis	1/45 (2.2%)
Pneumonia	1/45 (2.2%)
Sepsis	3/45 (6.7%)
Septic shock	1/45 (2.2%)
Urinary tract infection	1/45 (2.2%)
Injury, poisoning and procedural complications
Femur fracture	1/45 (2.2%)
Overdose	1/45 (2.2%)
Investigations
Alanine aminotransferase increased	1/45 (2.2%)
Aspartate aminotransferase increased	1/45 (2.2%)
Chest X-ray abnormal	1/45 (2.2%)
Metabolism and nutrition disorders
Hyperglycaemia	1/45 (2.2%)
Musculoskeletal and connective tissue disorders
Arthritis	1/45 (2.2%)
Bone pain	1/45 (2.2%)
Myalgia	1/45 (2.2%)
Nervous system disorders
Aphasia	1/45 (2.2%)
Cerebral haemorrhage	1/45 (2.2%)
Depressed level of consciousness	1/45 (2.2%)
Encephalopathy	1/45 (2.2%)
Hemiplegia	1/45 (2.2%)
Spinal cord compression	1/45 (2.2%)
Tremor	3/45 (6.7%)
Respiratory, thoracic and mediastinal disorders
Alveolitis	1/45 (2.2%)
Pulmonary haemorrhage	1/45 (2.2%)
Respiratory failure	2/45 (4.4%)
Other (Not Including Serious) Adverse Events
	Blinatumomab
	Affected / at Risk (%)	# Events
Total	45/45 (100%)
Blood and lymphatic system disorders
Anaemia	12/45 (26.7%)
Febrile neutropenia	15/45 (33.3%)
Neutropenia	3/45 (6.7%)
Thrombocytopenia	10/45 (22.2%)
Cardiac disorders
Atrial fibrillation	3/45 (6.7%)
Tachycardia	4/45 (8.9%)
Gastrointestinal disorders
Abdominal pain	3/45 (6.7%)
Constipation	7/45 (15.6%)
Diarrhoea	9/45 (20%)
Haemorrhoids	3/45 (6.7%)
Nausea	6/45 (13.3%)
Vomiting	5/45 (11.1%)
General disorders
Asthenia	6/45 (13.3%)
Chest pain	5/45 (11.1%)
Chills	4/45 (8.9%)
Fatigue	6/45 (13.3%)
Oedema peripheral	8/45 (17.8%)
Pain	7/45 (15.6%)
Pyrexia	26/45 (57.8%)
Immune system disorders
Cytokine release syndrome	3/45 (6.7%)
Hypogammaglobulinaemia	3/45 (6.7%)
Infections and infestations
Nasopharyngitis	3/45 (6.7%)
Staphylococcal infection	3/45 (6.7%)
Urinary tract infection	4/45 (8.9%)
Investigations
Alanine aminotransferase increased	4/45 (8.9%)
Aspartate aminotransferase increased	5/45 (11.1%)
Blood bilirubin increased	3/45 (6.7%)
Blood calcium decreased	3/45 (6.7%)
Metabolism and nutrition disorders
Decreased appetite	3/45 (6.7%)
Hypoalbuminaemia	3/45 (6.7%)
Hypocalcaemia	3/45 (6.7%)
Hypokalaemia	8/45 (17.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/45 (8.9%)
Back pain	4/45 (8.9%)
Bone pain	8/45 (17.8%)
Musculoskeletal pain	5/45 (11.1%)
Pain in extremity	3/45 (6.7%)
Nervous system disorders
Dizziness	4/45 (8.9%)
Headache	14/45 (31.1%)
Paraesthesia	6/45 (13.3%)
Psychiatric disorders
Confusional state	5/45 (11.1%)
Insomnia	3/45 (6.7%)
Respiratory, thoracic and mediastinal disorders
Cough	5/45 (11.1%)
Dyspnoea	6/45 (13.3%)
Epistaxis	5/45 (11.1%)
Skin and subcutaneous tissue disorders
Erythema	5/45 (11.1%)
Hyperhidrosis	3/45 (6.7%)
Petechiae	4/45 (8.9%)
Pruritus	3/45 (6.7%)
Vascular disorders
Hypertension	4/45 (8.9%)
Hypotension	6/45 (13.3%)

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.