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Clinical Trial Results:
An Open Label, Multicenter, Exploratory Phase 2 Study to Evaluate the Efficacy and Safety of the Bispecific T-Cell Engager (BiTE®) Blinatumomab in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Summary
EudraCT number	2011-005781-38
Trial protocol	DE
Global end of trial date	09 Sep 2015

Results information
Results version number	v1(current)
This version publication date	25 Sep 2016
First version publication date	25 Sep 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

MT103-208

ISRCTN number

US NCT number

NCT01741792

WHO universal trial number (UTN)

Sponsor organisation name

Amgen, Inc

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Sep 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Sep 2015

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to confirm whether the bispecific T-cell engager blinatumomab is effective and safe in the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, and other regulations, as applicable. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Jul 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

24 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 25

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Adults with a diagnosis of diffuse large B-cell lymphoma (DLBCL) which was refractory to first or subsequent treatment or who had a first or later relapse and were not eligible for autologous hematopoietic stem cell transplant (HSCT), or relapsed after autologous HSCT were eligible to enrol. The primary analysis cut-off date was 10 July 2014.

Screening details

The study was conducted sequentially in 2 stages and 3 cohorts: In Stage 1, Cohort 1 received an escalating dose of 9/28/112 µg/day blinatumomab and Cohort 2 received a constant dose of 112 µg/day for 8 weeks. In Stage 2, the Cohort 3 dose regimen was determined from the outcome of Cohorts 1 and 2.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: Blinatumomab 9/28/112 µg/d

Arm description

Participants received blinatumomab administered via a continuous intravenous infusion (CIV) 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during Cycle 1. Participants who achieved a complete response (CR) or partial response (PR), or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Arm type

Experimental

Investigational medicinal product name

Blinatumomab

Investigational medicinal product code

MT103

Other name

AMG103, BLINCYTO®

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered by continuous intravenous infusion over 8 weeks in the first cycle and 4 weeks in the second cycle.

Cohort 2: Blinatumomab 112 µg/d

Arm description

Participants received blinatumomab administered CIV at a constant dose of 112 µg/day for 8 weeks of treatment during Cycle 1. Participants who achieved a CR or PR, or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Arm type

Experimental

Investigational medicinal product name

Blinatumomab

Investigational medicinal product code

MT103

Other name

AMG103, BLINCYTO®

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered by continuous intravenous infusion over 8 weeks in the first cycle and 4 weeks in the second cycle.

Cohort 3: Blinatumomab 9/28/112 µg/d

Arm description

Participants received blinatumomab administered CIV 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during Cycle 1. Participants who achieved CR or PR, or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Arm type

Experimental

Investigational medicinal product name

Blinatumomab

Investigational medicinal product code

MT103

Other name

AMG103, BLINCYTO®

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered by continuous intravenous infusion over 8 weeks in the first cycle and 4 weeks in the second cycle.

Number of subjects in period 1	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Started	9	2	14
Efficacy Set	7	1	13
Completed	3	1	2
Not completed	6	1	12
Death	6	1	12

Baseline characteristics

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Reporting group title

Cohort 1: Blinatumomab 9/28/112 µg/d

Reporting group description

Reporting group title

Cohort 2: Blinatumomab 112 µg/d

Reporting group description

Reporting group title

Cohort 3: Blinatumomab 9/28/112 µg/d

Reporting group description

Reporting group values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d	Total
Number of subjects	9	2	14	25
Age categorical
Units: Subjects
18 - 64 years	2	1	9	12
65 - 84 years	6	1	5	12
85 years and over	1	0	0	1
Age Continuous
Units: years
arithmetic mean (standard deviation)	71.7 ± 7.8	64.5 ± 13.4	57.1 ± 13.6	-
Gender, Male/Female
Units: participants
Female	7	0	4	11
Male	2	2	10	14
Race/Ethnicity, Customized
Units: Subjects
White	9	2	14	25
Relapsed/refractory Status to Last Prior Treatment
Units: Subjects
Relapsed	4	1	4	9
Refractory	5	1	10	16
Number of Previous Autologous Hematopoietic Stem Cell Transplants (HSCT)
Units: Subjects
None	7	1	10	18
≥ 1	2	1	4	7

End points

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Reporting group title

Cohort 1: Blinatumomab 9/28/112 µg/d

Reporting group description

Reporting group title

Cohort 2: Blinatumomab 112 µg/d

Reporting group description

Reporting group title

Cohort 3: Blinatumomab 9/28/112 µg/d

Reporting group description

Subject analysis set title

Blinatumomab 9 μg/d

Subject analysis set type

Full analysis

Subject analysis set description

Participants received blinatumomab administered via a continuous intravenous infusion (CIV) 9 µg/day.

Subject analysis set title

Blinatumomab 28 μg/d

Subject analysis set type

Full analysis

Subject analysis set description

Participants received blinatumomab CIV 28 µg/day.

Subject analysis set title

Blinatumomab 112 μg/d

Subject analysis set type

Full analysis

Subject analysis set description

Participants received blinatumomab administered CIV 112 µg/day.

Subject analysis set title

Blinatumomab

Subject analysis set type

Full analysis

Subject analysis set description

All participants who received blinatumomab by continuous intravenous infusion during the core study.

Primary: Overall objective response rate during treatment cycle 1

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End point title

Overall objective response rate during treatment cycle 1 ^[1]

End point description

Overall response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Overall objective response rate (ORR) is the percentage of participants with a best overall response of complete response (CR) or partial response (PR). Complete response is defined as the disappearance of all evidence of disease and partial response is defined as regression of measureable disease and no new sites. Objective response was analyzed in the Efficacy Set which includes all participants who completed at least 7 days of infusion on the highest intended dose level.

End point type

Primary

End point timeframe

During the first 8 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Since all subjects received blinatumomab, no statistical comparisons between arms was performed. The null hypothesis was that the response rate for participants with DLBCL treated with blinatumomab was less than 15%; if the lower bound of the 95% CI around the ORR rate was ≥ 15% the null hypothesis was rejected.

End point values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Number of subjects analysed	7	1	13
Units: percentage of participants
number (confidence interval 95%)	57.1 (18.4 to 90.1)	100 (2.5 to 100)	30.8 (9.1 to 61.4)

No statistical analyses for this end point

Secondary: Percentage of participants with a best overall response of Complete response

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End point title

Percentage of participants with a best overall response of Complete response

End point description

Response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Complete response is defined as the disappearance of all evidence of disease.

End point type

Secondary

End point timeframe

During the first 8 weeks

End point values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Number of subjects analysed	7	1	13
Units: percentage of participants
number (confidence interval 95%)	28.6 (3.7 to 71)	0 (0 to 97.5)	15.4 (1.9 to 45.4)

No statistical analyses for this end point

Secondary: Percentage of participants with a Best overall Response of Partial response

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End point title

Percentage of participants with a Best overall Response of Partial response

End point description

Response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Partial response is defined as regression (<50% decrease in size of masses) of measureable disease and no new sites.

End point type

Secondary

End point timeframe

During the first 8 weeks

End point values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Number of subjects analysed	7	1	13
Units: percentage of participants
number (confidence interval 95%)	28.6 (3.7 to 71)	100 (2.5 to 100)	15.4 (1.9 to 45.4)

No statistical analyses for this end point

Secondary: Duration of objective response

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End point title

Duration of objective response

End point description

The time from documentation of the first assessment of either partial or complete response until the start of new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death, whichever is the earliest event. A patient who did not have new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death was censored at last tumor assessment date. Disease progression is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. "99999" indicates data that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

From first infusion of blinatumomab until the end of study; median follow-up time for duration of response was 23.7 months.

End point values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Number of subjects analysed	4	1	4
Units: months
median (confidence interval 95%)	8.7 (0.9 to 99999)	99999 (99999 to 99999)	4 (1.9 to 99999)

No statistical analyses for this end point

Secondary: Duration of complete response

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End point title

Duration of complete response

End point description

The time from documentation of the first assessment of complete response until the start of new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death, whichever is the earliest event. A patient who did not have new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death was censored at last tumor assessment date. Disease progression is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. "99999" indicates values that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

From first infusion of blinatumomab until the end of study; median follow-up time for duration of response was 23.7 months.

End point values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Number of subjects analysed	2	0 ^[2]	2
Units: months
median (confidence interval 95%)	99999 (11.6 to 99999)	( to )	99999 (5.9 to 99999)

Notes
[2] - No subjects had a complete response

No statistical analyses for this end point

Secondary: Duration of partial response

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End point title

Duration of partial response

End point description

The time from documentation of the first assessment of partial response until the start of new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death, whichever is the earliest event. A patient who did not have new anti-tumor treatment (excluding any stem cell transplantation), progression of disease, or death was censored at last tumor assessment date. Disease progression is defined as any new lesion or increase by ≥ 50% of previously involved sites from nadir. "99999" indicates values that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

From first infusion of blinatumomab until the end of study; median follow-up time for duration of response was 23.7 months.

End point values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Number of subjects analysed	2	1	2
Units: months
median (confidence interval 95%)	3.3 (0.9 to 5.8)	99999 (99999 to 99999)	2 (1.9 to 2.1)

No statistical analyses for this end point

Secondary: Progression-free survival (PFS)

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End point title

Progression-free survival (PFS)

End point description

The time from the date of first blinatumomab infusion until the date of diagnosis of progression of lymphoma, the start date of new anti-tumor treatment (excluding any stem cell transplantation) or date of death, whichever is the earliest. Patients alive who did not have progression or new anti-tumor treatment (excluding any stem cell transplantation) were censored at last date of tumor assessment. "99999" indicates values that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

From first infusion of blinatumomab until the end of study; median time on follow-up for PFS was 27.0 months.

End point values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Number of subjects analysed	7	1	13
Units: months
median (confidence interval 95%)	3.7 (0.7 to 14.1)	99999 (99999 to 99999)	1.6 (0.6 to 4.6)

No statistical analyses for this end point

Secondary: Overall survival (OS)

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End point title

Overall survival (OS)

End point description

The time from the date of first blinatumomab infusion until death as a result of any cause. Patients still 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. For patients who withdrew their informed consent, only information until the date of withdrawal was analyzed. "99999" indicates values that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

From the first infusion of blinatumomab until the end of study; median time on follow-up for overall survival was 26.6 months.

End point values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Number of subjects analysed	7	1	13
Units: months
median (confidence interval 95%)	20.1 (2.3 to 99999)	99999 (99999 to 99999)	3.6 (1.5 to 14.8)

No statistical analyses for this end point

Secondary: Number of participants with adverse events

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End point title

Number of participants with adverse events

End point description

Adverse events were evaluated for severity according to the grading scale provided in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. An adverse event or suspected adverse drug reaction was considered "serious" if it resulted in one of the following outcomes: - Resulted in death; - Was life-threatening; - Required inpatient hospitalization or prolongation of existing hospitalization; - Resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions; - Was a congenital anomaly or birth defect; - Was a medically important condition. The Investigator used medical judgment to determine whether there was a causal relationship (ie, related [reasonably possible] or unrelated [not reasonably possible]) between an adverse event and blinatumomab.

End point type

Secondary

End point timeframe

From the first dose of blinatumomab until up to 30 days after the last dose or until the data cut-off date of 10 July 2014, whichever occurred first; the overall median duration of treatment exposure was 46.8 days.

End point values	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d
Number of subjects analysed	9	2	14
Units: participants
number (not applicable)
Any adverse event (AE)	9	2	14
AE of Grade ≥ 3	9	2	13
AE of Grade ≥ 4	0	2	6
Serious adverse event (SAE)	9	2	12
Fatal adverse events	0	0	2
Led to discontinuation of study drug	3	1	2
Led to interruption of study drug	4	1	6
Related adverse events	9	2	11
Related AE Grade ≥ 3	5	2	5
Related AE Grade ≥ 4	0	1	2
Serious related adverse events	5	2	3
Related AE led to discontinuation of study drug	2	1	2
Related AE led to interruption of study drug	3	1	3

No statistical analyses for this end point

Secondary: Blinatumomab steady state serum concentration

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End point title

Blinatumomab steady state serum concentration

End point description

Blinatumomab serum levels were analyzed using a validated cluster of differentiation (CD)69 activation bioassay with a lower limit of quantification (LLOQ) of 50 pg/mL. Steady-state concentration (Css) was based on actual dose received, rather than based on cohort or time or day. Analyses were performed n the Pharmacokinetic (PK) data set which includes all participants who received any infusion of blinatumomab and had at least one PK sample collected.

End point type

Secondary

End point timeframe

Cycle 1: predose; Day 3 and Day 8 (Css for 9 ug/day); Day 15 (Css for 28 ug/day); and Day 29, Day 43 and Day 57 (Css for 112 ug/day)

End point values	Blinatumomab 9 μg/d	Blinatumomab 28 μg/d	Blinatumomab 112 μg/d
Number of subjects analysed	20	16	12
Units: pg/mL
arithmetic mean (standard deviation)	277 ± 210	565 ± 208	2800 ± 1150

No statistical analyses for this end point

Secondary: Leukocyte Counts

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End point title

Leukocyte Counts

End point description

Leukocyte (white blood cells) counts were analyzed by differential blood count analysis. The analysis Population for all pharmacodynamic endpoints includes enrolled participants with available data at each time point. All participants are included in pre-infusion and follow-up data points, only those participants in Cohorts 1 and 3 who had the same treatment schedule of 9/28/112 µg/day step dosing are included in the infusion time points (day 8 through end of infusion).

End point type

Secondary

End point timeframe

Screening (Day -20 to Day 0), Day 1 pre-infusion, Days 8, 15, 29, 43, end of infusion (day 53), end of core study (day 87), and follow-up at 3, 6, 9, 12, 15, 18, 21 and 24 months after the first response assessment

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	6.376 ± 3.284
Day 1 Prior (N = 24)	5.729 ± 2.891
Day 8 (N = 21)	6.819 ± 3.201
Day 15 (N = 16)	6.4 ± 2.486
Day 29 (N = 11)	3.764 ± 2.16
Day 43 (N = 8)	4.95 ± 3.819
End of Infusion (N = 9)	4.611 ± 2.114
End of Core Study (N = 6)	6.85 ± 2.818
3-Month Follow-up (N = 5)	4.82 ± 1.616
6-Month Follow-up (N = 6)	5.183 ± 1.38
9-Month Follow-up (N = 4)	4.425 ± 0.854
12-Month Follow-up (N = 4)	5.7 ± 1.424
15-Month Follow-up (N = 3)	4.767 ± 0.874
18-Month Follow-up (N = 3)	6.467 ± 1.779
21-Month Follow-up (N = 21)	5.45 ± 0.495
24-Month Follow-up (N = 3)	4.533 ± 1.069

No statistical analyses for this end point

Secondary: Lymphocyte Counts

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End point title

Lymphocyte Counts

End point description

Lymphocyte counts were analyzed by differential blood count analysis.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.779 ± 0.425
Day 1 Prior (N = 24)	0.491 ± 0.259
Day 8 (N = 21)	0.382 ± 0.215
Day 15 (N = 16)	0.277 ± 0.165
Day 29 (N = 11)	0.472 ± 0.273
Day 43 (N = 8)	0.847 ± 0.511
End of Infusion (N = 9)	0.767 ± 0.505
End of Core Study (N = 6)	1.06 ± 0.489
3-Month Follow-up (N = 5)	1.053 ± 0.421
6-Month Follow-up (N = 6)	1.12 ± 0.621
9-Month Follow-up (N = 4)	1.048 ± 0.381
12-Month Follow-up (N = 4)	1.12 ± 0.449
15-Month Follow-up (N = 3)	0.998 ± 0.527
18-Month Follow-up (N = 3)	0.565 ± 0.18
21-Month Follow-up (N = 21)	1.205 ± 0.839
24-Month Follow-up (N = 3)	0.737 ± 0.478

No statistical analyses for this end point

Secondary: Monocyte Counts

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End point title

Monocyte Counts

End point description

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.638 ± 0.415
Day 1 Prior (N = 24)	0.3 ± 0.565
Day 8 (N = 21)	0.202 ± 0.386
Day 15 (N = 16)	0.188 ± 0.317
Day 29 (N = 11)	0.318 ± 0.185
Day 43 (N = 8)	0.646 ± 0.375
End of Infusion (N = 9)	0.473 ± 0.241
End of Core Study (N = 6)	0.711 ± 0.569
3-Month Follow-up (N = 5)	0.585 ± 0.28
6-Month Follow-up (N = 6)	0.487 ± 0.239
9-Month Follow-up (N = 4)	0.452 ± 0.112
12-Month Follow-up (N = 4)	0.469 ± 0.061
15-Month Follow-up (N = 3)	0.511 ± 0.053
18-Month Follow-up (N = 3)	0.29 ± 0.123
21-Month Follow-up (N = 21)	0.516 ± 0.008
24-Month Follow-up (N = 3)	0.234 ± 0.176

No statistical analyses for this end point

Secondary: Granulocyte Count

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End point title

Granulocyte Count

End point description

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	4.968 ± 3.187
Day 1 Prior (N = 24)	4.91 ± 2.425
Day 8 (N = 21)	6.235 ± 2.881
Day 15 (N = 16)	5.935 ± 2.387
Day 29 (N = 11)	2.974 ± 2.019
Day 43 (N = 8)	3.457 ± 3.395
End of Infusion (N = 9)	3.353 ± 2.134
End of Core Study (N = 6)	5.08 ± 3.012
3-Month Follow-up (N = 5)	3.182 ± 1.117
6-Month Follow-up (N = 6)	3.594 ± 0.95
9-Month Follow-up (N = 4)	2.925 ± 0.675
12-Month Follow-up (N = 4)	4.111 ± 1.382
15-Month Follow-up (N = 3)	3.258 ± 0.745
18-Month Follow-up (N = 3)	5.612 ± 1.713
21-Month Follow-up (N = 21)	3.729 ± 0.352
24-Month Follow-up (N = 3)	3.563 ± 0.711

No statistical analyses for this end point

Secondary: CD19+ B-Cell Count

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End point title

CD19+ B-Cell Count

End point description

CD19+ B-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.026 ± 0.072
Day 1 Prior (N = 24)	0.029 ± 0.085
Day 8 (N = 21)	0.001 ± 0.002
Day 15 (N = 16)	0 ± 0.001
Day 29 (N = 11)	0 ± 0
Day 43 (N = 8)	0 ± 0.001
End of Infusion (N = 9)	0.001 ± 0.001
End of Core Study (N = 6)	0.001 ± 0.002
3-Month Follow-up (N = 5)	0.025 ± 0.026
6-Month Follow-up (N = 6)	0.029 ± 0.043
9-Month Follow-up (N = 4)	0.054 ± 0.066
12-Month Follow-up (N = 4)	0.082 ± 0.113
15-Month Follow-up (N = 3)	0.094 ± 0.118
18-Month Follow-up (N = 3)	0.071 ± 0.075
21-Month Follow-up (N = 21)	0.131 ± 0.17
24-Month Follow-up (N = 3)	0.108 ± 0.12

No statistical analyses for this end point

Secondary: CD19+ B-Cells as a Percentage of All Lymphocytes

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End point title

CD19+ B-Cells as a Percentage of All Lymphocytes

End point description

CD19+ B-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of lymphocytes
arithmetic mean (standard deviation)
Screening (N = 25)	2 ± 7
Day 1 Prior (N = 24)	4 ± 9
Day 8 (N = 21)	0 ± 0
Day 15 (N = 16)	0 ± 0
Day 29 (N = 11)	0 ± 0
Day 43 (N = 8)	0 ± 0
End of Infusion (N = 9)	0 ± 0
End of Core Study (N = 6)	0 ± 0
3-Month Follow-up (N = 5)	2 ± 2
6-Month Follow-up (N = 6)	2 ± 3
9-Month Follow-up (N = 4)	5 ± 5
12-Month Follow-up (N = 4)	7 ± 9
15-Month Follow-up (N = 3)	7 ± 7
18-Month Follow-up (N = 3)	11 ± 9
21-Month Follow-up (N = 21)	8 ± 8
24-Month Follow-up (N = 3)	12 ± 7

No statistical analyses for this end point

Secondary: CD3+ T-Cell Count

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End point title

CD3+ T-Cell Count

End point description

CD3+ T-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.578 ± 0.355
Day 1 Prior (N = 24)	0.349 ± 0.233
Day 8 (N = 21)	0.282 ± 0.194
Day 15 (N = 16)	0.199 ± 0.159
Day 29 (N = 11)	0.348 ± 0.231
Day 43 (N = 8)	0.613 ± 0.426
End of Infusion (N = 9)	0.543 ± 0.421
End of Core Study (N = 6)	0.825 ± 0.431
3-Month Follow-up (N = 5)	0.773 ± 0.443
6-Month Follow-up (N = 6)	0.782 ± 0.345
9-Month Follow-up (N = 4)	0.671 ± 0.184
12-Month Follow-up (N = 4)	0.703 ± 0.203
15-Month Follow-up (N = 3)	0.594 ± 0.227
18-Month Follow-up (N = 3)	0.298 ± 0.049
21-Month Follow-up (N = 21)	0.623 ± 0.266
24-Month Follow-up (N = 3)	0.456 ± 0.257

No statistical analyses for this end point

Secondary: CD3+ T-Cells as a Percentage of All Lymphocytes

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End point title

CD3+ T-Cells as a Percentage of All Lymphocytes

End point description

CD3+ T-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of lymphocytes
arithmetic mean (standard deviation)
Screening (N = 25)	72 ± 14
Day 1 Prior (N = 24)	68 ± 18
Day 8 (N = 21)	70 ± 19
Day 15 (N = 16)	67 ± 19
Day 29 (N = 11)	73 ± 15
Day 43 (N = 8)	71 ± 13
End of Infusion (N = 9)	66 ± 14
End of Core Study (N = 6)	76 ± 16
3-Month Follow-up (N = 5)	73 ± 11
6-Month Follow-up (N = 6)	66 ± 21
9-Month Follow-up (N = 4)	66 ± 6
12-Month Follow-up (N = 4)	65 ± 9
15-Month Follow-up (N = 3)	61 ± 7
18-Month Follow-up (N = 3)	57 ± 20
21-Month Follow-up (N = 21)	58 ± 16
24-Month Follow-up (N = 3)	63 ± 8

No statistical analyses for this end point

Secondary: CD4+ T-Cell Count

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End point title

CD4+ T-Cell Count

End point description

CD4+ T-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.254 ± 0.16
Day 1 Prior (N = 24)	0.152 ± 0.128
Day 8 (N = 21)	0.131 ± 0.128
Day 15 (N = 16)	0.085 ± 0.084
Day 29 (N = 11)	0.17 ± 0.172
Day 43 (N = 8)	0.261 ± 0.219
End of Infusion (N = 9)	0.241 ± 0.254
End of Core Study (N = 6)	0.375 ± 0.251
3-Month Follow-up (N = 5)	0.371 ± 0.216
6-Month Follow-up (N = 6)	0.371 ± 0.237
9-Month Follow-up (N = 4)	0.309 ± 0.184
12-Month Follow-up (N = 4)	0.399 ± 0.193
15-Month Follow-up (N = 3)	0.326 ± 0.22
18-Month Follow-up (N = 3)	0.178 ± 0.042
21-Month Follow-up (N = 21)	0.373 ± 0.279
24-Month Follow-up (N = 3)	0.258 ± 0.248

No statistical analyses for this end point

Secondary: CD4+ T-Cells as a Percentage of All Lymphocytes

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End point title

CD4+ T-Cells as a Percentage of All Lymphocytes

End point description

CD4+ T-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of lymphocytes
arithmetic mean (standard deviation)
Screening (N = 25)	33 ± 11
Day 1 Prior (N = 24)	28 ± 14
Day 8 (N = 21)	32 ± 17
Day 15 (N = 16)	29 ± 13
Day 29 (N = 11)	34 ± 18
Day 43 (N = 8)	30 ± 12
End of Infusion (N = 9)	28 ± 13
End of Core Study (N = 6)	32 ± 15
3-Month Follow-up (N = 5)	33 ± 9
6-Month Follow-up (N = 6)	30 ± 10
9-Month Follow-up (N = 4)	31 ± 13
12-Month Follow-up (N = 4)	35 ± 7
15-Month Follow-up (N = 3)	31 ± 7
18-Month Follow-up (N = 3)	32 ± 6
21-Month Follow-up (N = 21)	29 ± 4
24-Month Follow-up (N = 3)	34 ± 8

No statistical analyses for this end point

Secondary: CD8+ T-Cell Count

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End point title

CD8+ T-Cell Count

End point description

CD8+ T-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.298 ± 0.256
Day 1 Prior (N = 24)	0.186 ± 0.136
Day 8 (N = 21)	0.134 ± 0.099
Day 15 (N = 16)	0.102 ± 0.095
Day 29 (N = 11)	0.14 ± 0.076
Day 43 (N = 8)	0.299 ± 0.237
End of Infusion (N = 9)	0.284 ± 0.195
End of Core Study (N = 6)	0.438 ± 0.284
3-Month Follow-up (N = 5)	0.381 ± 0.254
6-Month Follow-up (N = 6)	0.403 ± 0.304
9-Month Follow-up (N = 4)	0.225 ± 0.039
12-Month Follow-up (N = 4)	0.31 ± 0.2
15-Month Follow-up (N = 3)	0.214 ± 0.023
18-Month Follow-up (N = 3)	0.105 ± 0.057
21-Month Follow-up (N = 21)	0.185 ± 0.026
24-Month Follow-up (N = 3)	0.187 ± 0.068

No statistical analyses for this end point

Secondary: CD8+ T-Cells as a Percentage of All Lymphocytes

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End point title

CD8+ T-Cells as a Percentage of All Lymphocytes

End point description

CD8+ T-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of lymphocytes
arithmetic mean (standard deviation)
Screening (N = 25)	37 ± 18
Day 1 Prior (N = 24)	37 ± 19
Day 8 (N = 21)	35 ± 19
Day 15 (N = 16)	35 ± 17
Day 29 (N = 11)	33 ± 17
Day 43 (N = 8)	37 ± 15
End of Infusion (N = 9)	36 ± 16
End of Core Study (N = 6)	43 ± 23
3-Month Follow-up (N = 5)	36 ± 19
6-Month Follow-up (N = 6)	34 ± 16
9-Month Follow-up (N = 4)	25 ± 11
12-Month Follow-up (N = 4)	28 ± 13
15-Month Follow-up (N = 3)	24 ± 9
18-Month Follow-up (N = 3)	21 ± 13
21-Month Follow-up (N = 21)	20 ± 12
24-Month Follow-up (N = 3)	27 ± 16

No statistical analyses for this end point

Secondary: CD19+ B-Cell to CD3+ T-Cell Ratio

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End point title

CD19+ B-Cell to CD3+ T-Cell Ratio

End point description

CD19+ B-cells and CD3+ T-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: ratio
arithmetic mean (standard deviation)
Screening (N = 25)	0.04 ± 0.15
Day 1 Prior (N = 24)	0.07 ± 0.24
Day 8 (N = 21)	0 ± 0.01
Day 15 (N = 16)	0 ± 0
Day 29 (N = 11)	0 ± 0
Day 43 (N = 8)	0 ± 0
End of Infusion (N = 9)	0 ± 0.01
End of Core Study (N = 6)	0 ± 0
3-Month Follow-up (N = 5)	0.03 ± 0.03
6-Month Follow-up (N = 6)	0.04 ± 0.05
9-Month Follow-up (N = 4)	0.08 ± 0.08
12-Month Follow-up (N = 4)	0.12 ± 0.15
15-Month Follow-up (N = 3)	0.13 ± 0.13
18-Month Follow-up (N = 3)	0.25 ± 0.3
21-Month Follow-up (N = 21)	0.17 ± 0.2
24-Month Follow-up (N = 3)	0.19 ± 0.13

No statistical analyses for this end point

Secondary: CD4+ T-Cell to CD8+ T-Cell Ratio

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End point title

CD4+ T-Cell to CD8+ T-Cell Ratio

End point description

CD4+ T-cells and CD8+ T-cell counts were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: ratio
arithmetic mean (standard deviation)
Screening (N = 25)	1.32 ± 1.19
Day 1 Prior (N = 24)	1.16 ± 1.45
Day 8 (N = 21)	1.2 ± 0.96
Day 15 (N = 16)	1.03 ± 0.71
Day 29 (N = 11)	1.43 ± 1.08
Day 43 (N = 8)	0.96 ± 0.53
End of Infusion (N = 9)	1.09 ± 1
End of Core Study (N = 6)	1.03 ± 0.8
3-Month Follow-up (N = 5)	1.18 ± 0.79
6-Month Follow-up (N = 6)	1.1 ± 0.7
9-Month Follow-up (N = 4)	1.53 ± 1.25
12-Month Follow-up (N = 4)	1.7 ± 1.47
15-Month Follow-up (N = 3)	1.47 ± 0.81
18-Month Follow-up (N = 3)	2.23 ± 1.7
21-Month Follow-up (N = 21)	1.85 ± 1.34
24-Month Follow-up (N = 3)	1.73 ± 1.21

No statistical analyses for this end point

Secondary: CD4+ Naive T Cell Count

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End point title

CD4+ Naive T Cell Count

End point description

CD4+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.028 ± 0.056
Day 1 Prior (N = 24)	0.013 ± 0.022
Day 8 (N = 21)	0.014 ± 0.033
Day 15 (N = 16)	0.012 ± 0.024
Day 29 (N = 11)	0.032 ± 0.071
Day 43 (N = 8)	0.036 ± 0.06
End of Infusion (N = 9)	0.037 ± 0.088
End of Core Study (N = 6)	0.05 ± 0.083
3-Month Follow-up (N = 5)	0.015 ± 0.019
6-Month Follow-up (N = 6)	0.023 ± 0.044
9-Month Follow-up (N = 4)	0.053 ± 0.09
12-Month Follow-up (N = 4)	0.053 ± 0.084
15-Month Follow-up (N = 3)	0.044 ± 0.059
18-Month Follow-up (N = 3)	0.035 ± 0.041
21-Month Follow-up (N = 21)	0.098 ± 0.103
24-Month Follow-up (N = 3)	0.016 ± 0.013

No statistical analyses for this end point

Secondary: CD4+ Naive T Cells as a Percentage of All CD4+ T-Cells

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End point title

CD4+ Naive T Cells as a Percentage of All CD4+ T-Cells

End point description

CD4+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of CD4+ T-cells
arithmetic mean (standard deviation)
Screening (N = 25)	8 ± 9
Day 1 Prior (N = 24)	7 ± 7
Day 8 (N = 21)	7 ± 7
Day 15 (N = 16)	10 ± 9
Day 29 (N = 11)	9 ± 11
Day 43 (N = 8)	10 ± 10
End of Infusion (N = 9)	8 ± 9
End of Core Study (N = 6)	9 ± 13
3-Month Follow-up (N = 5)	4 ± 3
6-Month Follow-up (N = 6)	4 ± 7
9-Month Follow-up (N = 4)	11 ± 15
12-Month Follow-up (N = 4)	12 ± 14
15-Month Follow-up (N = 3)	10 ± 9
18-Month Follow-up (N = 3)	19 ± 19
21-Month Follow-up (N = 21)	23 ± 9
24-Month Follow-up (N = 3)	8 ± 10

No statistical analyses for this end point

Secondary: CD4+ Central Memory T-Cell (TCM) Count

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End point title

CD4+ Central Memory T-Cell (TCM) Count

End point description

Central memory T cells are characterized by the cell-surface expression of CD197 but not CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.048 ± 0.053
Day 1 Prior (N = 24)	0.029 ± 0.034
Day 8 (N = 21)	0.027 ± 0.042
Day 15 (N = 16)	0.014 ± 0.025
Day 29 (N = 11)	0.032 ± 0.065
Day 43 (N = 8)	0.032 ± 0.035
End of Infusion (N = 9)	0.049 ± 0.103
End of Core Study (N = 6)	0.062 ± 0.075
3-Month Follow-up (N = 5)	0.019 ± 0.009
6-Month Follow-up (N = 6)	0.027 ± 0.02
9-Month Follow-up (N = 4)	0.043 ± 0.056
12-Month Follow-up (N = 4)	0.065 ± 0.073
15-Month Follow-up (N = 3)	0.039 ± 0.02
18-Month Follow-up (N = 3)	0.033 ± 0.031
21-Month Follow-up (N = 21)	0.056 ± 0.054
24-Month Follow-up (N = 3)	0.021 ± 0.01

No statistical analyses for this end point

Secondary: CD4+ TCM Cells as a Percentage of All CD4+ T-Cells

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End point title

CD4+ TCM Cells as a Percentage of All CD4+ T-Cells

End point description

Central memory T cells are characterized by the cell-surface expression of CD197 but not CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of CD4+ T-cells
arithmetic mean (standard deviation)
Screening (N = 25)	18 ± 12
Day 1 Prior (N = 24)	20 ± 15
Day 8 (N = 21)	19 ± 15
Day 15 (N = 16)	14 ± 12
Day 29 (N = 11)	13 ± 10
Day 43 (N = 8)	13 ± 9
End of Infusion (N = 9)	15 ± 11
End of Core Study (N = 6)	14 ± 11
3-Month Follow-up (N = 5)	6 ± 3
6-Month Follow-up (N = 6)	9 ± 4
9-Month Follow-up (N = 4)	11 ± 9
12-Month Follow-up (N = 4)	18 ± 16
15-Month Follow-up (N = 3)	13 ± 6
18-Month Follow-up (N = 3)	18 ± 14
21-Month Follow-up (N = 21)	14 ± 4
24-Month Follow-up (N = 3)	12 ± 11

No statistical analyses for this end point

Secondary: CD4+ Effector Memory T-Cell (TEM) Count

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End point title

CD4+ Effector Memory T-Cell (TEM) Count

End point description

Effector memory T cells are characterized by the lack of expression of CD197 and CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.161 ± 0.089
Day 1 Prior (N = 24)	0.099 ± 0.096
Day 8 (N = 21)	0.083 ± 0.076
Day 15 (N = 16)	0.051 ± 0.044
Day 29 (N = 11)	0.097 ± 0.059
Day 43 (N = 8)	0.169 ± 0.117
End of Infusion (N = 9)	0.14 ± 0.091
End of Core Study (N = 6)	0.22 ± 0.142
3-Month Follow-up (N = 5)	0.279 ± 0.153
6-Month Follow-up (N = 6)	0.267 ± 0.158
9-Month Follow-up (N = 4)	0.191 ± 0.037
12-Month Follow-up (N = 4)	0.226 ± 0.1
15-Month Follow-up (N = 3)	0.199 ± 0.087
18-Month Follow-up (N = 3)	0.106 ± 0.066
21-Month Follow-up (N = 21)	0.181 ± 0.107
24-Month Follow-up (N = 3)	0.175 ± 0.133

No statistical analyses for this end point

Secondary: CD4+ TEM Cells as a Percentage of All CD4+ T-Cells

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End point title

CD4+ TEM Cells as a Percentage of All CD4+ T-Cells

End point description

Effector memory T cells are characterized by the lack of expression of CD197 and CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of CD4+ T-cells
arithmetic mean (standard deviation)
Screening (N = 25)	41 ± 19
Day 1 Prior (N = 24)	39 ± 19
Day 8 (N = 21)	36 ± 19
Day 15 (N = 16)	46 ± 17
Day 29 (N = 11)	34 ± 20
Day 43 (N = 8)	39 ± 26
End of Infusion (N = 9)	41 ± 24
End of Core Study (N = 6)	41 ± 24
3-Month Follow-up (N = 5)	46 ± 26
6-Month Follow-up (N = 6)	41 ± 21
9-Month Follow-up (N = 4)	42 ± 18
12-Month Follow-up (N = 4)	40 ± 15
15-Month Follow-up (N = 3)	46 ± 17
18-Month Follow-up (N = 3)	43 ± 12
21-Month Follow-up (N = 21)	45 ± 3
24-Month Follow-up (N = 3)	51 ± 22

No statistical analyses for this end point

Secondary: CD8+ Naive T-Cell Count

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End point title

CD8+ Naive T-Cell Count

End point description

CD8+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.029 ± 0.043
Day 1 Prior (N = 24)	0.024 ± 0.05
Day 8 (N = 21)	0.01 ± 0.012
Day 15 (N = 16)	0.006 ± 0.005
Day 29 (N = 11)	0.012 ± 0.014
Day 43 (N = 8)	0.019 ± 0.036
End of Infusion (N = 9)	0.011 ± 0.015
End of Core Study (N = 6)	0.023 ± 0.018
3-Month Follow-up (N = 5)	0.011 ± 0.007
6-Month Follow-up (N = 6)	0.02 ± 0.022
9-Month Follow-up (N = 4)	0.011 ± 0.012
12-Month Follow-up (N = 4)	0.011 ± 0.009
15-Month Follow-up (N = 3)	0.014 ± 0.011
18-Month Follow-up (N = 3)	0.007 ± 0.008
21-Month Follow-up (N = 21)	0.015 ± 0.006
24-Month Follow-up (N = 3)	0.01 ± 0.009

No statistical analyses for this end point

Secondary: CD8+ Naive T-Cells as a Percentage of All CD8+ T-Cells

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End point title

CD8+ Naive T-Cells as a Percentage of All CD8+ T-Cells

End point description

CD8+ naive T-cell counts are native T-cells characterized by the cell-surface expression of CD197 and CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of CD8+ T-cells
arithmetic mean (standard deviation)
Screening (N = 25)	10 ± 10
Day 1 Prior (N = 24)	12 ± 13
Day 8 (N = 21)	9 ± 8
Day 15 (N = 16)	8 ± 7
Day 29 (N = 11)	8 ± 7
Day 43 (N = 8)	6 ± 7
End of Infusion (N = 9)	3 ± 3
End of Core Study (N = 6)	6 ± 6
3-Month Follow-up (N = 5)	4 ± 4
6-Month Follow-up (N = 6)	5 ± 5
9-Month Follow-up (N = 4)	6 ± 7
12-Month Follow-up (N = 4)	6 ± 6
15-Month Follow-up (N = 3)	6 ± 5
18-Month Follow-up (N = 3)	10 ± 8
21-Month Follow-up (N = 21)	8 ± 4
24-Month Follow-up (N = 3)	10 ± 12

No statistical analyses for this end point

Secondary: CD8+ TCM Cell Counts

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End point title

CD8+ TCM Cell Counts

End point description

Central memory T cells are characterized by the cell-surface expression of CD197 but not CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 100 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.02 ± 0.027
Day 1 Prior (N = 24)	0.014 ± 0.021
Day 8 (N = 21)	0.01 ± 0.013
Day 15 (N = 16)	0.004 ± 0.005
Day 29 (N = 11)	0.007 ± 0.007
Day 43 (N = 8)	0.012 ± 0.015
End of Infusion (N = 9)	0.009 ± 0.009
End of Core Study (N = 6)	0.016 ± 0.023
3-Month Follow-up (N = 5)	0.008 ± 0.003
6-Month Follow-up (N = 6)	0.016 ± 0.014
9-Month Follow-up (N = 4)	0.006 ± 0.004
12-Month Follow-up (N = 4)	0.01 ± 0.01
15-Month Follow-up (N = 3)	0.004 ± 0.002
18-Month Follow-up (N = 3)	0.002 ± 0.001
21-Month Follow-up (N = 21)	0.002 ± 0.001
24-Month Follow-up (N = 3)	0.006 ± 0.004

No statistical analyses for this end point

Secondary: CD8+ TCM Cells as a Percentage of All CD8+ T-Cells

Top of page

End point title

CD8+ TCM Cells as a Percentage of All CD8+ T-Cells

End point description

Central memory T cells are characterized by the cell-surface expression of CD197 but not CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of CD8+ T-cells
arithmetic mean (standard deviation)
Screening (N = 25)	7 ± 7
Day 1 Prior (N = 24)	8 ± 11
Day 8 (N = 21)	10 ± 13
Day 15 (N = 16)	4 ± 5
Day 29 (N = 11)	7 ± 10
Day 43 (N = 8)	9 ± 18
End of Infusion (N = 9)	5 ± 6
End of Core Study (N = 6)	5 ± 8
3-Month Follow-up (N = 5)	3 ± 2
6-Month Follow-up (N = 6)	4 ± 3
9-Month Follow-up (N = 4)	3 ± 2
12-Month Follow-up (N = 4)	3 ± 3
15-Month Follow-up (N = 3)	2 ± 1
18-Month Follow-up (N = 3)	2 ± 1
21-Month Follow-up (N = 21)	1 ± 0
24-Month Follow-up (N = 3)	6 ± 8

No statistical analyses for this end point

Secondary: CD8+ Effector Memory T-Cell (TEM) Count

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End point title

CD8+ Effector Memory T-Cell (TEM) Count

End point description

Effector memory T cells are characterized by the lack of expression of CD197 and CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.127 ± 0.162
Day 1 Prior (N = 24)	0.075 ± 0.066
Day 8 (N = 21)	0.065 ± 0.058
Day 15 (N = 16)	0.045 ± 0.053
Day 29 (N = 11)	0.067 ± 0.039
Day 43 (N = 8)	0.135 ± 0.108
End of Infusion (N = 9)	0.128 ± 0.077
End of Core Study (N = 6)	0.18 ± 0.089
3-Month Follow-up (N = 5)	0.146 ± 0.071
6-Month Follow-up (N = 6)	0.179 ± 0.158
9-Month Follow-up (N = 4)	0.116 ± 0.061
12-Month Follow-up (N = 4)	0.174 ± 0.162
15-Month Follow-up (N = 3)	0.095 ± 0.025
18-Month Follow-up (N = 3)	0.049 ± 0.027
21-Month Follow-up (N = 21)	0.085 ± 0.013
24-Month Follow-up (N = 3)	0.054 ± 0.027

No statistical analyses for this end point

Secondary: CD8+ TEM Cells as a Percentage of All CD8+ T-Cells

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End point title

CD8+ TEM Cells as a Percentage of All CD8+ T-Cells

End point description

Effector memory T cells are characterized by the lack of expression of CD197 and CD45RA and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of CD8+ T-cells
arithmetic mean (standard deviation)
Screening (N = 25)	42 ± 19
Day 1 Prior (N = 24)	42 ± 17
Day 8 (N = 21)	46 ± 18
Day 15 (N = 16)	43 ± 13
Day 29 (N = 11)	51 ± 19
Day 43 (N = 8)	46 ± 23
End of Infusion (N = 9)	51 ± 21
End of Core Study (N = 6)	49 ± 22
3-Month Follow-up (N = 5)	47 ± 23
6-Month Follow-up (N = 6)	50 ± 24
9-Month Follow-up (N = 4)	50 ± 21
12-Month Follow-up (N = 4)	51 ± 13
15-Month Follow-up (N = 3)	46 ± 15
18-Month Follow-up (N = 3)	46 ± 7
21-Month Follow-up (N = 21)	46 ± 1
24-Month Follow-up (N = 3)	33 ± 9

No statistical analyses for this end point

Secondary: CD8+ Terminally Differentiated Effector Memory T-cells (TEMRA) Count

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End point title

CD8+ Terminally Differentiated Effector Memory T-cells (TEMRA) Count

End point description

Terminally differentiated effector memory T cells are characterized by the cell-surface expression of CD45RA but not CD197 and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: 1000 cells/µL
arithmetic mean (standard deviation)
Screening (N = 25)	0.123 ± 0.099
Day 1 Prior (N = 24)	0.072 ± 0.069
Day 8 (N = 21)	0.051 ± 0.042
Day 15 (N = 16)	0.047 ± 0.048
Day 29 (N = 11)	0.058 ± 0.05
Day 43 (N = 8)	0.132 ± 0.126
End of Infusion (N = 9)	0.135 ± 0.131
End of Core Study (N = 6)	0.226 ± 0.249
3-Month Follow-up (N = 5)	0.214 ± 0.22
6-Month Follow-up (N = 6)	0.187 ± 0.182
9-Month Follow-up (N = 4)	0.094 ± 0.046
12-Month Follow-up (N = 4)	0.117 ± 0.065
15-Month Follow-up (N = 3)	0.099 ± 0.041
18-Month Follow-up (N = 3)	0.047 ± 0.035
21-Month Follow-up (N = 21)	0.086 ± 0.016
24-Month Follow-up (N = 3)	0.1 ± 0.084

No statistical analyses for this end point

Secondary: CD8+ TEMRA Cells as a Percentage of All CD8+ T-Cells

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End point title

CD8+ TEMRA Cells as a Percentage of All CD8+ T-Cells

End point description

Terminally differentiated effector memory T cells are characterized by the cell-surface expression of CD45RA but not CD197 and were analyzed by flow cytometry.

End point type

Secondary

End point timeframe

End point values	Blinatumomab
Number of subjects analysed	25
Units: percentage of CD8+ T-cells
arithmetic mean (standard deviation)
Screening (N = 25)	41 ± 19
Day 1 Prior (N = 24)	39 ± 19
Day 8 (N = 21)	36 ± 19
Day 15 (N = 16)	46 ± 17
Day 29 (N = 11)	34 ± 20
Day 43 (N = 8)	39 ± 26
End of Infusion (N = 9)	41 ± 24
End of Core Study (N = 6)	41 ± 24
3-Month Follow-up (N = 5)	46 ± 26
6-Month Follow-up (N = 6)	41 ± 21
9-Month Follow-up (N = 4)	42 ± 18
12-Month Follow-up (N = 4)	40 ± 15
15-Month Follow-up (N = 3)	46 ± 17
18-Month Follow-up (N = 3)	43 ± 12
21-Month Follow-up (N = 21)	45 ± 3
24-Month Follow-up (N = 3)	51 ± 22

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose of blinatumomab until up to 30 days after the last dose, until the data cut-off date of 10 July 2014; the overall median duration of treatment exposure was 46.8 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Cohort 1: Blinatumomab 9/28/112 µg/d

Reporting group description

Participants received blinatumomab administered CIV 9 µg/day for the first week, followed by 28 µg/day for the second week, then 112 µg/day for the remaining 6 weeks of treatment during Cycle 1. Participants who achieved a CR or PR, or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Reporting group title

Cohort 2: Blinatumomab 112 µg/d

Reporting group description

Participants received blinatumomab administered CIV at a constant dose of 112 µg/day for 8 weeks of treatment during Cycle 1. Participants who achieved CR or PR, or had stable disease after the first treatment cycle were eligible to receive a second (consolidation) cycle of treatment over 4 weeks, following a 4-week treatment-free interval.

Reporting group title

Cohort 3: Blinatumomab 9/28/112 µg/d

Reporting group description

Reporting group title

Cohort 1 + 3: Blinatumomab 9/28/112 µg/d

Reporting group description

Serious adverse events	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d	Cohort 1 + 3: Blinatumomab 9/28/112 µg/d
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 9 (100.00%)	2 / 2 (100.00%)	12 / 14 (85.71%)	21 / 23 (91.30%)
number of deaths (all causes)	5	1	9	14
number of deaths resulting from adverse events
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 9 (11.11%)	1 / 2 (50.00%)	2 / 14 (14.29%)	3 / 23 (13.04%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleurisy
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Pancreatic enzymes increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug administration error
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Supraventricular tachycardia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	1 / 14 (7.14%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neurological symptom
subjects affected / exposed	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Speech disorder
subjects affected / exposed	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Agranulocytosis
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone marrow toxicity
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Oesophagitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Catheter site infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	5 / 14 (35.71%)	5 / 23 (21.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes virus infection
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 9 (33.33%)	1 / 2 (50.00%)	2 / 14 (14.29%)	5 / 23 (21.74%)
occurrences causally related to treatment / all	0 / 3	0 / 1	2 / 3	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Viral infection
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort 1: Blinatumomab 9/28/112 µg/d	Cohort 2: Blinatumomab 112 µg/d	Cohort 3: Blinatumomab 9/28/112 µg/d	Cohort 1 + 3: Blinatumomab 9/28/112 µg/d
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 9 (100.00%)	2 / 2 (100.00%)	14 / 14 (100.00%)	23 / 23 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm progression
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Oncologic complication
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Tumour pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Vascular disorders
Embolism
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Haematoma
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Hypotension
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Thrombosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Catheter site erythema
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Catheter site rash
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Chills
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	2 / 14 (14.29%)	3 / 23 (13.04%)
occurrences all number	1	0	2	3
Disease progression
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	3 / 14 (21.43%)	3 / 23 (13.04%)
occurrences all number	0	0	4	4
Facial pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Fatigue
subjects affected / exposed	3 / 9 (33.33%)	1 / 2 (50.00%)	3 / 14 (21.43%)	6 / 23 (26.09%)
occurrences all number	4	1	7	11
General physical health deterioration
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Mucosal inflammation
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Oedema
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	5 / 14 (35.71%)	6 / 23 (26.09%)
occurrences all number	1	0	5	6
Oedema peripheral
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Pyrexia
subjects affected / exposed	4 / 9 (44.44%)	1 / 2 (50.00%)	5 / 14 (35.71%)	9 / 23 (39.13%)
occurrences all number	9	2	5	14
Ulcer
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	1	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 9 (33.33%)	1 / 2 (50.00%)	1 / 14 (7.14%)	4 / 23 (17.39%)
occurrences all number	3	1	1	4
Dysphonia
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Dyspnoea
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Nasal disorder
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Pleural effusion
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Pulmonary congestion
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Pulmonary embolism
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Rhinorrhoea
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	2	0	0	2
Tachypnoea
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	1 / 14 (7.14%)	2 / 23 (8.70%)
occurrences all number	1	0	1	2
Disorientation
subjects affected / exposed	2 / 9 (22.22%)	1 / 2 (50.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	1	0	2
Encopresis
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Fear
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Insomnia
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	2 / 14 (14.29%)	2 / 23 (8.70%)
occurrences all number	0	0	2	2
Nervousness
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Sleep disorder
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	2 / 14 (14.29%)	2 / 23 (8.70%)
occurrences all number	0	0	2	2
Investigations
Antithrombin III decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Blood fibrinogen increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Blood glucose increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	4 / 14 (28.57%)	4 / 23 (17.39%)
occurrences all number	0	0	5	5
Blood immunoglobulin G decreased
subjects affected / exposed	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	0	0	2
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Blood magnesium decreased
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Blood potassium decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	2	2
Blood sodium decreased
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Blood uric acid increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
C-reactive protein increased
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	3 / 14 (21.43%)	4 / 23 (17.39%)
occurrences all number	1	0	4	5
Corneal reflex decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Fibrin D dimer increased
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	1 / 14 (7.14%)	2 / 23 (8.70%)
occurrences all number	1	0	1	2
Fibrinolysis increased
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Hepatic enzyme increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Neutrophil count decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
PO2 decreased
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Platelet count decreased
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	1	1	1
Weight increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	3 / 14 (21.43%)	3 / 23 (13.04%)
occurrences all number	0	0	3	3
White blood cell count decreased
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	1	1	1
Injury, poisoning and procedural complications
Spinal compression fracture
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	2	0	0	2
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	1	0	0
Cardiac failure
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Cardiovascular insufficiency
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Tachycardia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Burning sensation
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Coordination abnormal
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	1	0	0
Dizziness
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	1 / 14 (7.14%)	2 / 23 (8.70%)
occurrences all number	1	0	1	2
Dyscalculia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Dysgeusia
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Encephalopathy
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Epilepsy
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Facial paresis
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Headache
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	2	0	0	2
Hyporeflexia
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	1	0	0
Memory impairment
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Paraesthesia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	1 / 14 (7.14%)	2 / 23 (8.70%)
occurrences all number	1	0	1	2
Radiculopathy
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Sensory disturbance
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Somnolence
subjects affected / exposed	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	0	0	2
Speech disorder
subjects affected / exposed	3 / 9 (33.33%)	1 / 2 (50.00%)	0 / 14 (0.00%)	3 / 23 (13.04%)
occurrences all number	3	1	0	3
Tremor
subjects affected / exposed	6 / 9 (66.67%)	2 / 2 (100.00%)	4 / 14 (28.57%)	10 / 23 (43.48%)
occurrences all number	7	2	6	13
Vocal cord paralysis
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	1	1	1
Leukopenia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	3 / 14 (21.43%)	4 / 23 (17.39%)
occurrences all number	1	0	8	9
Neutropenia
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	2	2
Thrombocytopenia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	4 / 14 (28.57%)	5 / 23 (21.74%)
occurrences all number	1	0	5	6
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Vertigo
subjects affected / exposed	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	0	0	2
Eye disorders
Blepharospasm
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Keratitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Visual acuity reduced
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	2	2
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Abdominal pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Aphthous stomatitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Constipation
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Diarrhoea
subjects affected / exposed	4 / 9 (44.44%)	1 / 2 (50.00%)	1 / 14 (7.14%)	5 / 23 (21.74%)
occurrences all number	7	1	1	8
Dyspepsia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	2	0	0	2
Flatulence
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	2 / 14 (14.29%)	2 / 23 (8.70%)
occurrences all number	0	0	2	2
Gastrointestinal motility disorder
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Mouth ulceration
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Nausea
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Odynophagia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Vomiting
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Hepatobiliary disorders
Jaundice
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	1	0	0
Drug eruption
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Eczema asteatotic
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Hyperhidrosis
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	2 / 14 (14.29%)	3 / 23 (13.04%)
occurrences all number	1	0	3	4
Night sweats
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	2 / 14 (14.29%)	3 / 23 (13.04%)
occurrences all number	2	0	2	4
Rash
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Skin ulcer
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Renal and urinary disorders
Enuresis
subjects affected / exposed	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	0	0	2
Haematuria
subjects affected / exposed	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	0	0	2
Renal failure
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	1	0	0
Ureteric obstruction
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Urinary retention
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	2 / 14 (14.29%)	3 / 23 (13.04%)
occurrences all number	1	0	2	3
Bone pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Intervertebral disc protrusion
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Muscular weakness
subjects affected / exposed	2 / 9 (22.22%)	1 / 2 (50.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	1	0	2
Musculoskeletal pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Myopathy
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Neck pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Pain in extremity
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	2	0	0	2
Candida infection
subjects affected / exposed	2 / 9 (22.22%)	0 / 2 (0.00%)	0 / 14 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	0	0	2
Candiduria
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Conjunctivitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Diverticulitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Fungal infection
subjects affected / exposed	1 / 9 (11.11%)	1 / 2 (50.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	3	1	0	3
Herpes simplex
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Nasopharyngitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	3 / 14 (21.43%)	3 / 23 (13.04%)
occurrences all number	0	0	3	3
Otitis media
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Pneumonia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	1 / 14 (7.14%)	2 / 23 (8.70%)
occurrences all number	1	0	1	2
Respiratory tract infection
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Rhinitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	2	0	0	2
Urinary tract infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 2 (0.00%)	1 / 14 (7.14%)	1 / 23 (4.35%)
occurrences all number	0	0	1	1
Vulvovaginal candidiasis
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1
Hyperglycaemia
subjects affected / exposed	2 / 9 (22.22%)	1 / 2 (50.00%)	2 / 14 (14.29%)	4 / 23 (17.39%)
occurrences all number	3	1	2	5
Hypocalcaemia
subjects affected / exposed	0 / 9 (0.00%)	1 / 2 (50.00%)	0 / 14 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	1	0	0
Hypokalaemia
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	3 / 14 (21.43%)	4 / 23 (17.39%)
occurrences all number	2	0	3	5
Vitamin K deficiency
subjects affected / exposed	1 / 9 (11.11%)	0 / 2 (0.00%)	0 / 14 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	0	0	1

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: An Open Label, Multicenter, Exploratory Phase 2 Study to Evaluate the Efficacy and Safety of the Bispecific T-Cell Engager (BiTE®) Blinatumomab in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall objective response rate during treatment cycle 1

Primary: Overall objective response rate during treatment cycle 1

Secondary: Percentage of participants with a best overall response of Complete response

Secondary: Percentage of participants with a best overall response of Complete response

Secondary: Percentage of participants with a Best overall Response of Partial response

Secondary: Percentage of participants with a Best overall Response of Partial response

Secondary: Duration of objective response

Secondary: Duration of objective response

Secondary: Duration of complete response

Secondary: Duration of complete response

Secondary: Duration of partial response

Secondary: Duration of partial response

Secondary: Progression-free survival (PFS)

Secondary: Progression-free survival (PFS)

Secondary: Overall survival (OS)

Secondary: Overall survival (OS)

Secondary: Number of participants with adverse events

Secondary: Number of participants with adverse events

Secondary: Blinatumomab steady state serum concentration

Secondary: Blinatumomab steady state serum concentration

Secondary: Leukocyte Counts

Secondary: Leukocyte Counts

Secondary: Lymphocyte Counts

Secondary: Lymphocyte Counts

Secondary: Monocyte Counts

Secondary: Monocyte Counts

Secondary: Granulocyte Count

Secondary: Granulocyte Count

Secondary: CD19+ B-Cell Count

Secondary: CD19+ B-Cell Count

Secondary: CD19+ B-Cells as a Percentage of All Lymphocytes

Secondary: CD19+ B-Cells as a Percentage of All Lymphocytes

Secondary: CD3+ T-Cell Count

Secondary: CD3+ T-Cell Count

Secondary: CD3+ T-Cells as a Percentage of All Lymphocytes

Secondary: CD3+ T-Cells as a Percentage of All Lymphocytes

Secondary: CD4+ T-Cell Count

Secondary: CD4+ T-Cell Count

Secondary: CD4+ T-Cells as a Percentage of All Lymphocytes

Secondary: CD4+ T-Cells as a Percentage of All Lymphocytes

Secondary: CD8+ T-Cell Count

Secondary: CD8+ T-Cell Count

Secondary: CD8+ T-Cells as a Percentage of All Lymphocytes

Secondary: CD8+ T-Cells as a Percentage of All Lymphocytes

Secondary: CD19+ B-Cell to CD3+ T-Cell Ratio

Secondary: CD19+ B-Cell to CD3+ T-Cell Ratio

Secondary: CD4+ T-Cell to CD8+ T-Cell Ratio

Secondary: CD4+ T-Cell to CD8+ T-Cell Ratio

Secondary: CD4+ Naive T Cell Count

Secondary: CD4+ Naive T Cell Count

Secondary: CD4+ Naive T Cells as a Percentage of All CD4+ T-Cells

Secondary: CD4+ Naive T Cells as a Percentage of All CD4+ T-Cells

Secondary: CD4+ Central Memory T-Cell (TCM) Count

Secondary: CD4+ Central Memory T-Cell (TCM) Count

Secondary: CD4+ TCM Cells as a Percentage of All CD4+ T-Cells

Secondary: CD4+ TCM Cells as a Percentage of All CD4+ T-Cells

Secondary: CD4+ Effector Memory T-Cell (TEM) Count

Secondary: CD4+ Effector Memory T-Cell (TEM) Count

Secondary: CD4+ TEM Cells as a Percentage of All CD4+ T-Cells

Secondary: CD4+ TEM Cells as a Percentage of All CD4+ T-Cells

Secondary: CD8+ Naive T-Cell Count

Secondary: CD8+ Naive T-Cell Count

Secondary: CD8+ Naive T-Cells as a Percentage of All CD8+ T-Cells

Secondary: CD8+ Naive T-Cells as a Percentage of All CD8+ T-Cells

Secondary: CD8+ TCM Cell Counts

Secondary: CD8+ TCM Cell Counts

Secondary: CD8+ TCM Cells as a Percentage of All CD8+ T-Cells

Secondary: CD8+ TCM Cells as a Percentage of All CD8+ T-Cells

Secondary: CD8+ Effector Memory T-Cell (TEM) Count

Secondary: CD8+ Effector Memory T-Cell (TEM) Count

Clinical Trial Results:
An Open Label, Multicenter, Exploratory Phase 2 Study to Evaluate the Efficacy and Safety of the Bispecific T-Cell Engager (BiTE®) Blinatumomab in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)