Download PDF

Clinical Trial Results:
A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)

Summary
EudraCT number	2017-003778-15
Trial protocol	Outside EU/EEA
Global end of trial date	04 Jul 2019

Results information
Results version number	v1(current)
This version publication date	05 Jan 2020
First version publication date	05 Jan 2020
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

20130265

ISRCTN number

US NCT number

NCT02412306

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

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

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?

Yes

Analysis stage

Final

Date of interim/final analysis

04 Jul 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Jul 2019

Was the trial ended prematurely?

Main objective of the trial

• Phase 1b part: to determine the maximum tolerated dose (MTD) of blinatumomab in adult and pediatric subjects with R/R B precursor ALL • Phase 2 part: to further evaluate in adults the recommended dose identified in the phase 1b portion of the study and to evaluate the rate of complete remission/complete remission with partial hematological recovery (CR/CRh*) in adult subjects with R/R B precursor ALL who receive blinatumomab • Expansion part: to observe the incidence of treatment-emergent and treatment-related adverse events during treatment with blinatumomab in adult and pediatric subjects with R/R B precursor ALL

Protection of trial subjects

The study protocol and all amendments, the informed consent form, and any accompanying materials provided to the subjects were reviewed and approved by an institutional review board (IRB) at each center. This study was conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Jun 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Japan: 66

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

Top of page

Recruitment details

Study was conducted at 16 centers in Japan. Cohort enrollment periods were: adult phase 1b, from 04 Jun 2015 to 13 Jan 2016; pediatric phase 1b, from 17 Feb 2016 to 20 Jun 2016; adult phase 2, from 11 Apr 2016 to 12 Jun 2017; adult expansion cohort, from 04 Dec 2017 to 13 Nov 2018; pediatric expansion cohort, from 05 Nov 2017 to 05 Sep 2018.

Screening details

After a 2-week screening and pre-phase period, participants were treated in an open-label phase 1b part (adult or pediatric), a phase 2 part (adult), or in an expansion cohort (adult or pediatric).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1b: Blinatumomab 9/28 μg/day (Adults)

Arm description

Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.

Arm type

Experimental

Investigational medicinal product name

blinatumomab

Investigational medicinal product code

Other name

Blincyto®

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Blinatumomab was administered per protocol for a maximum of 5 treatment cycles, or until documented disease progression, intolerable adverse event, or withdrawal of consent.

Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)

Arm description

Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.

Arm type

Experimental

Investigational medicinal product name

blinatumomab

Investigational medicinal product code

Other name

Blincyto®

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Blinatumomab was administered per protocol for a maximum of 5 treatment cycles, or until documented disease progression, intolerable adverse event, or withdrawal of consent.

Phase 2: Blinatumomab 9/28 μg/day (Adults)

Arm description

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.

Arm type

Experimental

Investigational medicinal product name

blinatumomab

Investigational medicinal product code

Other name

Blincyto®

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Blinatumomab was administered per protocol for a maximum of 5 treatment cycles, or until documented disease progression, intolerable adverse event, or withdrawal of consent.

Expansion Cohort: Blinatumomab 9/28 μg/day (Adults)

Arm description

Arm type

Experimental

Investigational medicinal product name

blinatumomab

Investigational medicinal product code

Other name

Blincyto®

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Blinatumomab was administered per protocol for a maximum of 5 treatment cycles, or until documented disease progression, intolerable adverse event, or withdrawal of consent.

Expansion Cohort: Blinatumomab 5/15 µg/m²/day (Pediatric)

Arm description

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.

Arm type

Experimental

Investigational medicinal product name

blinatumomab

Investigational medicinal product code

Other name

Blincyto®

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Blinatumomab was administered per protocol for a maximum of 5 treatment cycles, or until documented disease progression, intolerable adverse event, or withdrawal of consent.

Number of subjects in period 1	Phase 1b: Blinatumomab 9/28 μg/day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/day (Adults)	Expansion Cohort: Blinatumomab 9/28 μg/day (Adults)	Expansion Cohort: Blinatumomab 5/15 µg/m²/day (Pediatric)
Started	5	9	21	14	17
Completed	0	1	5	14	15
Not completed	5	8	16	0	2
Adverse event, serious fatal	5	7	15	-	2
Consent withdrawn by subject	-	-	1	-	-
Lost to follow-up	-	1	-	-	-

Baseline characteristics

Top of page

Reporting group title

Phase 1b: Blinatumomab 9/28 μg/day (Adults)

Reporting group description

Reporting group title

Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)

Reporting group description

Reporting group title

Phase 2: Blinatumomab 9/28 μg/day (Adults)

Reporting group description

Reporting group title

Expansion Cohort: Blinatumomab 9/28 μg/day (Adults)

Reporting group description

Reporting group title

Expansion Cohort: Blinatumomab 5/15 µg/m²/day (Pediatric)

Reporting group description

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.

Reporting group values	Phase 1b: Blinatumomab 9/28 μg/day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/day (Adults)	Expansion Cohort: Blinatumomab 9/28 μg/day (Adults)	Expansion Cohort: Blinatumomab 5/15 µg/m²/day (Pediatric)	Total
Number of subjects	5	9	21	14	17	66
Age, Customized
Units: Subjects
< 2 years	0	0	0	0	1	1
2 to 6 years	0	0	0	0	5	5
7 to 17 years	0	9	0	0	11	20
18 to 34 years	1	0	6	5	0	12
35 to 54 years	1	0	14	6	0	21
55 to 64 years	2	0	1	1	0	4
≥ 65 years	1	0	0	2	0	3
Sex: Female, Male
Units: Subjects
Female	4	5	12	9	8	38
Male	1	4	9	5	9	28
Race/Ethnicity, Customized
Units: Subjects
Japanese	5	9	21	14	17	66

End points

Top of page

Reporting group title

Phase 1b: Blinatumomab 9/28 μg/day (Adults)

Reporting group description

Reporting group title

Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)

Reporting group description

Reporting group title

Phase 2: Blinatumomab 9/28 μg/day (Adults)

Reporting group description

Reporting group title

Expansion Cohort: Blinatumomab 9/28 μg/day (Adults)

Reporting group description

Reporting group title

Expansion Cohort: Blinatumomab 5/15 µg/m²/day (Pediatric)

Reporting group description

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.

Subject analysis set title

Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)

Subject analysis set type

Full analysis

Subject analysis set description

Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.

Subject analysis set title

Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Blinatumomab 9/28 μg/day (Phase 1b Only Adults)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Blinatumomab 5/15 µg/m²/day (Phase 1b Only Pediatric)

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Phase 1b: Number of Participants with Dose-limiting Toxicities

Top of page

End point title

Phase 1b: Number of Participants with Dose-limiting Toxicities ^[1] ^[2]

End point description

Dose-limiting toxicities (DLTs) were defined as any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade ≥ 3 adverse event related to blinatumomab, excluding specific CTCAE grade ≥ 3 adverse events considered consistent with the current known safety profile of blinatumomab, CTCAE grade ≥ 3 fever or infection, and laboratory parameters of CTCAE grade ≥ 3 not considered clinically relevant and/or responding to routine medical management. Analysis Population Description: Phase 1b participants in who received any infusion of blinatumomab.

End point type

Primary

End point timeframe

Days 1 to 14

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: Percentages are presented in the data table per protocol.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 1b: Blinatumomab 9/28 μg/day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)
Number of subjects analysed	5	9
Units: participants	0	0

No statistical analyses for this end point

Primary: Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Top of page

End point title

Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment ^[3] ^[4]

End point description

Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: - Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. - Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl. Analysis Population Description: Phase 2 participants who received any infusion of blinatumomab.

End point type

Primary

End point timeframe

Within the first 2 cycles of treatment, 12 weeks

Notes
[3] - 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: Percentages are presented in the data table per protocol.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 2: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	21
Units: percentage of participants
number (confidence interval 95%)	38.1 (18.1 to 61.6)

No statistical analyses for this end point

Primary: Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

Top of page

End point title

Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs ^[5]

End point description

TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 – Mild AE; Grade 2 – Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. Analysis Population Description: Expansion Cohort participants in the who received any infusion of blinatumomab.

End point type

Primary

End point timeframe

From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 55.6 (25, 140) and 28.0 (8, 56) days in the adult and pediatric expansion cohorts, respectively.

Notes
[5] - 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: Descriptive statistics are presented in the data table per protocol.

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)
Number of subjects analysed	14	17
Units: participants
All TEAEs	14	17
TEAEs ≥ Grade 3	11	15
TEAEs ≥ Grade 4	7	7
Serious TEAEs (STEAEs)	2	3
TEAEs Leading to Interruption of Blinatumomab	2	2
STEAEs Leading to Interruption of Blinatumomab	0	0
TEAEs Leading to Blinatumomab Discontinuation	0	1
STEAEs Leading to Blinatumomab Discontinuation	0	0
Fatal TEAEs	0	2
All Treatment-Related (TR) TEAEs	14	14
TR TEAEs ≥ Grade 3	9	9
TR TEAEs ≥ Grade 4	5	5
TR STEAEs	0	0
TR TEAEs Leading to Blinatumomab Interruption	2	1
TR STEAEs Leading to Blinatumomab Interruption	0	0
TR TEAEs Leading to Blinatumomab Discontinuation	0	1
TR STEAEs Leading to Blinatumomab Discontinuation	0	0
TR Fatal TEAEs	0	0

No statistical analyses for this end point

Secondary: Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Top of page

End point title

Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment ^[6]

End point description

Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: - Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. - Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl. Analysis Population Description: Phase 1b adult participants who received any infusion of blinatumomab.

End point type

Secondary

End point timeframe

Within the first 2 cycles of treatment, 12 weeks

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 1b: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	5
Units: percentage of participants
number (confidence interval 95%)	80.0 (28.4 to 99.5)

No statistical analyses for this end point

Secondary: Phase 1b Pediatric: Percentage of Participants with M1 Remission Within 2 Cycles of Treatment

Top of page

End point title

Phase 1b Pediatric: Percentage of Participants with M1 Remission Within 2 Cycles of Treatment ^[7]

End point description

M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease. Analysis Population Description: Phase 1b pediatric participants who received any infusion of blinatumomab.

End point type

Secondary

End point timeframe

The first 2 cycles of treatment, 12 weeks

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)
Number of subjects analysed	9
Units: percentage of participants
number (confidence interval 95%)	55.6 (21.2 to 86.3)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Duration of Response

Top of page

End point title

Phase 1b and Phase 2: Duration of Response ^[8]

End point description

Duration of response was calculated from the date of bone marrow aspiration when response (CR/CRh*) was detected for the first time during the first 2 cycles of treatment until the earlier of the following events: • the date of bone marrow aspiration at which hematological relapse or progressive disease (PD) was first detected, • the date of diagnosis on which the hematological or extra medullary relapse was documented, • the date of death if patient died due to PD • the date of end of induction phase if primary reason for treatment termination was hematological or extramedullary relapse. For a responder who did not report an event and was alive during the study, the end date of duration (censoring) was based on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis. Participants with response who did not report an event and who died due to reasons other than PD, were censored on the date of death, with death treated as a competing risk.

End point type

Secondary

End point timeframe

Median (minimum [min], maximum [max]) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 1b: Blinatumomab 9/28 μg/day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	4 ^[9]	5 ^[10]	8 ^[11]
Units: months
median (confidence interval 95%)	13.0 (4.2 to 19.7)	2.3 (1.1 to 6.8)	13.1 (3.5 to 20.7)

Notes
[9] - participants who received any infusion of blinatumomab and achieved CR/CRh* during the 1st 2 cycles
[10] - participants who received any infusion of blinatumomab and achieved CR/CRh* during the 1st 2 cycles
[11] - participants who received any infusion of blinatumomab and achieved CR/CRh* during the 1st 2 cycles

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Relapse-free Survival

Top of page

End point title

Phase 1b and Phase 2: Relapse-free Survival ^[12]

End point description

Relapse-free survival (RFS) was defined for participants who achieved a response (CR/CRh*) during the first 2 cycles of treatment. RFS was calculated from the date of bone marrow aspiration when response was detected for the first time to the date of bone marrow aspiration at which hematological relapse was first detected or the date of diagnosis on which the hematological or extra medullary relapse was documented or the date of death due to any cause, whichever was earlier. Participants who did not experience hematological relapse and did not die were censored on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis. Analysis Population Description: Phase 1b and Phase 2 participants who received any infusion of blinatumomab and achieved CR/CRh* during the first 2 cycles of treatment.

End point type

Secondary

End point timeframe

Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 1b: Blinatumomab 9/28 μg/day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	4	5	8
Units: months
median (confidence interval 95%)	11.4 (4.2 to 19.7)	2.3 (1.1 to 6.8)	13.1 (3.5 to 20.7)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Overall Survival

Top of page

End point title

Phase 1b and Phase 2: Overall Survival ^[13]

End point description

Overall survival (OS) was calculated from the start date of blinatumomab infusion in the first treatment cycle. All deaths were counted as events on the date of death. Participants still alive were censored on the last documented visit date or the date of the last phone contact when the participant was last known to have been alive. For participants who withdrew their informed consent, only information until the date of withdrawal was used in the analysis. Analysis Population Description: Phase 1b and Phase 2 participants who received any infusion of blinatumomab.

End point type

Secondary

End point timeframe

Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 1b: Blinatumomab 9/28 μg/day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	5	9 ^[14]	21
Units: months
median (confidence interval 95%)	11.0 (9.3 to 20.7)	10.6 (0.9 to 99999)	14.8 (2.7 to 21.6)

Notes
[14] - 99999=not applicable (could not be estimated due to the low number of events)

No statistical analyses for this end point

Secondary: Phase 2: Best Overall Response Within 2 Cycles of Treatment

Top of page

End point title

Phase 2: Best Overall Response Within 2 Cycles of Treatment ^[15]

End point description

Best response was defined as one of the following: CR: ≤ 5% blasts in the bone marrow (BM); No evidence of disease; Full recovery of peripheral blood counts: Platelets > 100,000/µl, and absolute neutrophil count (ANC) > 1,000/µl CRh*: ≤ 5% blasts in BM; No evidence of disease; Partial recovery of peripheral blood counts: Platelets > 50,000/µl, and ANC > 500/µl CRi: CR with incomplete count recovery without CRh* Blast free hypoplastic or aplastic BM: ≤ 5 % blasts in BM; No evidence of disease; Insufficient recovery of peripheral blood counts: platelets ≤ 50,000/µl and/or ANC ≤ 500/µl Partial Remission: BM blasts > 5 to < 25% with at least a 50% reduction from baseline Hematological Relapse: > 5% blasts in BM or blasts in peripheral blood after documented CR/CRh* during the study PD: An increase from baseline of ≥ 25% of BM blasts or an absolute increase of ≥ 5,000 cells/µL in the number of circulating leukemia cells.

End point type

Secondary

End point timeframe

Within the first 2 cycles of treatment, 12 weeks

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 2: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	21 ^[16]
Units: participants
CR	5
CRh*	3
CRi	0
Blast-free hypoplastic or aplastic bone marrow	6
Partial remission	0
Hematological relapse	0
Progressive disease	2
No response (none of the above)	5

Notes
[16] - participants who received any infusion of blinatumomab.

No statistical analyses for this end point

Secondary: Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission

Top of page

End point title

Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission ^[17]

End point description

Participants who were eligible for allogeneic HSCT were those who achieved remission (complete response or complete response with partial recovery of peripheral blood counts) after 2 cycles of blinatumomab treatment, and no further anti-leukemic medication was given before HSCT. Analysis Population Description: Phase 2 participants who received any infusion of blinatumomab.

End point type

Secondary

End point timeframe

Median (min, max) follow-up time was 26.7 (3.0, 28.5) months.

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 2: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	21
Units: percentage of participants
number (not applicable)	81.0

No statistical analyses for this end point

Secondary: Phase 2: 100-Day Mortality After Allogeneic HSCT

Top of page

End point title

Phase 2: 100-Day Mortality After Allogeneic HSCT ^[18]

End point description

The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in any CR following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. Participants still alive 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. The 100-day mortality rate after allogeneic HSCT was defined as the percentage of patients having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Analysis Population Description: Phase 2 participants who received an allogeneic HSCT.

End point type

Secondary

End point timeframe

100 days, from the date of allogeneic HSCT; median (min, max) follow-up time was 26.7 (3.0, 28.5)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 2: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	17
Units: percentage of participants
number (not applicable)	11.8

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Number of Participants with TEAEs

Top of page

End point title

Phase 1b and Phase 2: Number of Participants with TEAEs ^[19]

End point description

TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 – Mild AE; Grade 2 – Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. Analysis Population Description: Phase 1b and Phase 2 participants who received any infusion of blinatumomab.

End point type

Secondary

End point timeframe

From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 108 (56, 140), 56.0 (5, 84), and 56.0 (11, 115) days in adult phase 1b, adult phase 2 and pediatric phase 1b cohort respectively.

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 1b: Blinatumomab 9/28 μg/day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	5	9	21
Units: participants
All TEAEs	5	9	21
TEAEs ≥ Grade 3	4	9	21
TEAEs ≥ Grade 4	2	7	14
Serious TEAEs (STEAEs)	0	1	7
TEAEs Leading to Blinatumomab Interruption	1	6	3
STEAEs Leading to Blinatumomab Interruption	0	0	0
TEAEs Leading to Blinatumomab Discontinuation	0	1	1
STEAEs Leading to Blinatumomab Discontinuation	0	0	1
Fatal TEAEs	0	1	1
All Treatment-Related (TR) TEAEs	5	8	21
TR TEAEs ≥ Grade 3	2	8	18
TR TEAEs ≥ Grade 4	1	5	11
TR STEAEs	0	0	4
TR TEAEs Leading to Blinatumomab Interruption	1	6	1
TR STEAEs Leading to Blinatumomab Interruption	0	0	0
TR TEAEs Leading to Blinatumomab Discontinuation	0	1	1
TR STEAEs Leading to Blinatumomab Discontinuation	0	0	1
TR Fatal TEAEs	0	0	0

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State

Top of page

End point title

Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State

End point description

The steady-state concentration (Css) of serum blinatumomab was summarized as the average of the observed concentrations collected after 5 half-lives or after 24 hours from the start of continuous IV (CIV) infusion. Cycle 1, day 2 values represent steady-state concentration after CIV with the initial dose of blinatumomab (9 µg/day for adults and 5 µg/m²/day for pediatric patients). All other time points were measured after the dose step to 28 µg/day (adults) / 15 µg/m²/day (pediatric participants). Analysis Population Description: phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected with available data.

End point type

Secondary

End point timeframe

After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult).

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)	Blinatumomab 9/28 μg/day (Phase 1b Only Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b Only Pediatric)
Number of subjects analysed	25 ^[20]	7 ^[21]	5 ^[22]	7 ^[23]
Units: pg/mL
arithmetic mean (standard deviation)
Cycle 1 before dose step; n=23, 7, 4, 7	191 ( 90.8 )	113 ( 65.0 )	135 ( 41.7 )	107 ( 42.7 )
Cycle 1 after dose step; n=25, 7, 5, 7	948 ( 488 )	361 ( 137 )	907 ( 403 )	361 ( 137 )
Cycle 2; n=21, 6, 5, 6	1150 ( 575 )	427 ( 66.0 )	1040 ( 493 )	427 ( 66.0 )
Cycle 3+; n=8, 1, 4, 0	1420 ( 685 )	780 ( 99999 )	1280 ( 396 )	999999 ( 999999 )

Notes
[20] - n=participants with available data at each time point.
[21] - n=participants with available data at each time point; 99999=not applicable (n=1)
[22] - n=participants with available data at each time point.
[23] - n=participants with available data at each time point; 999999=not applicable (n=0)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Systemic Clearance of Blinatumomab

Top of page

End point title

Phase 1b and Phase 2: Systemic Clearance of Blinatumomab

End point description

Systemic clearance (CL) was calculated as CL = R0/Css, where R0 is the infusion rate (µg/hour or µg/m²/hour). Analysis Population Description: phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected with available data.

End point type

Secondary

End point timeframe

After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult).

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)	Blinatumomab 9/28 μg/day (Phase 1b Only Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b Only Pediatric)
Number of subjects analysed	26	9	5	9
Units: liters/hour
arithmetic mean (standard deviation)	1.59 ( 0.812 )	1.88 ( 0.789 )	1.59 ( 0.998 )	1.83 ( 0.801 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Terminal Half-life of Blinatumomab

Top of page

End point title

Phase 1b and Phase 2: Terminal Half-life of Blinatumomab

End point description

Analysis Population Description: phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected with available data.

End point type

Secondary

End point timeframe

Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)	Blinatumomab 9/28 μg/day (Phase 1b Only Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b Only Pediatric)
Number of subjects analysed	24	5	5	5
Units: hours
arithmetic mean (standard deviation)	2.38 ( 1.36 )	1.92 ( 1.12 )	2.60 ( 2.03 )	2.62 ( 1.67 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Volume of Distribution of Blinatumomab

Top of page

End point title

Phase 1b and Phase 2: Volume of Distribution of Blinatumomab

End point description

Analysis Population Description: phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected with available data.

End point type

Secondary

End point timeframe

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)	Blinatumomab 9/28 μg/day (Phase 1b Only Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b Only Pediatric)
Number of subjects analysed	24	5	5	5
Units: liters
arithmetic mean (standard deviation)	6.02 ( 6.09 )	5.05 ( 3.35 )	8.22 ( 11.7 )	6.38 ( 3.95 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Number of Participants who Developed Anti-blinatumomab Antibodies

Top of page

End point title

Phase 1b and Phase 2: Number of Participants who Developed Anti-blinatumomab Antibodies ^[24]

End point description

Antibodies to blinatumomab were detected using an electrochemiluminescence (ECL)-based assay. Analysis Population Description: Phase 1b and Phase 2 participants who received any infusion of blinatumomab.

End point type

Secondary

End point timeframe

Day 1 before first dose; cycles 1 and 2 day 29, 6 hours after end of infusion; 30 days after last dose.

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Phase 1b: Blinatumomab 9/28 μg/day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	5	9	21
Units: participants	0	0	0

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Interleukin-2 Concentration

Top of page

End point title

Phase 1b and Phase 2: Interleukin-2 Concentration

End point description

The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL). Analysis Population Description: Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacodynamic sample collected, with available data at each time point.

End point type

Secondary

End point timeframe

Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)
Number of subjects analysed	26 ^[25]	9 ^[26]
Units: pg/mL
arithmetic mean (standard deviation)
Cycle 1 day 1, 2 hrs after infusion start; n=26,0	16.1 ( 17.1 )	999999 ( 999999 )
Cycle 1 day 1, 6 hrs after infusion start; n=26,9	30.2 ( 72.8 )	10.0 ( 0.0 )
Cycle 1 day 1, 10 hrs after infusion start; n=26,9	32.6 ( 85.0 )	10.0 ( 0.0 )
Cycle 1 day 1, 24 hrs after infusion start; n=26,9	17.2 ( 36.7 )	29.8 ( 55.9 )
Cycle 1 day 8, 2 hrs after infusion start; n=25,0	10.0 ( 0.0 )	999999 ( 999999 )
Cycle 1 day 8, 6 hrs after infusion start; n=25,0	10.0 ( 0.0 )	999999 ( 999999 )
Cycle 1 day 8, 10 hrs after infusion start; n=25,0	10.0 ( 0.0 )	999999 ( 999999 )
Cycle 2 day 1, 6 hrs after infusion start; n=20,7	12.6 ( 11.7 )	10.0 ( 0.0 )
Cycle 3 day 1, 6 hrs after infusion start; n=8,2	10.0 ( 0.0 )	10.0 ( 0.0 )
Cycle 4 day 1, 6 hrs after infusion start; n=3,1	10.0 ( 0.0 )	10.0 ( 99999 )
Cycle 5 day 1, 6 hrs after infusion start; n=2,1	10.0 ( 0.0 )	10.0 ( 99999 )

Notes
[25] - n=participants with an assessment at given time point
[26] - 99999=not applicable (n=1); 999999=not applicable (n=0)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Interleukin-6 Concentration

Top of page

End point title

Phase 1b and Phase 2: Interleukin-6 Concentration

End point description

End point type

Secondary

End point timeframe

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)
Number of subjects analysed	26 ^[27]	9 ^[28]
Units: pg/mL
arithmetic mean (standard deviation)
Cycle 1 day 1, 2 hrs after infusion start; n=26,0	29.1 ( 40.1 )	999999 ( 999999 )
Cycle 1 day 1, 6 hrs after infusion start; n=26,9	173 ( 198.1 )	275 ( 371 )
Cycle 1 day 1, 10 hrs after infusion start; n=26,9	186 ( 301.5 )	317 ( 358 )
Cycle 1 day 1, 24 hrs after infusion start; n=26,9	246 ( 907.6 )	3714 ( 10740 )
Cycle 1 day 8, 2 hrs after infusion start; n=25,0	14.2 ( 14.5 )	999999 ( 999999 )
Cycle 1 day 8, 6 hrs after infusion start; n=25,0	10.0 ( 0.0 )	999999 ( 999999 )
Cycle 1 day 8, 10 hrs after infusion start; n=25,0	10.0 ( 0.0 )	999999 ( 999999 )
Cycle 2 day 1, 6 hrs after infusion start; n=20,7	20.3 ( 35.6 )	17.5 ( 19.8 )
Cycle 3 day 1, 6 hrs after infusion start; n=8,2	16.6 ( 18.6 )	36.3 ( 37.1 )
Cycle 4 day 1, 6 hrs after infusion start; n=3,1	10.0 ( 0.0 )	62.5 ( 99999 )
Cycle 5 day 1, 6 hrs after infusion start; n=2,1	10.0 ( 0.0 )	62.5 ( 99999 )

Notes
[27] - n=participants with an assessment at given time point
[28] - 99999=not applicable (n=1); 999999=not applicable (n=0)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Interleukin-10 Concentration

Top of page

End point title

Phase 1b and Phase 2: Interleukin-10 Concentration

End point description

End point type

Secondary

End point timeframe

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)
Number of subjects analysed	26 ^[29]	9 ^[30]
Units: pg/mL
arithmetic mean (standard deviation)
Cycle 1 day 1, 2 hrs after infusion start; n=26,0	101 ( 81.1 )	999999 ( 999999 )
Cycle 1 day 1, 6 hrs after infusion start; n=26, 9	597 ( 637 )	153 ( 94.7 )
Cycle 1 day 1, 10 hrs after infusion start; n=26,9	423 ( 373 )	230 ( 178 )
Cycle 1 day 1, 24 hrs after infusion start; n=26,9	400 ( 699 )	641 ( 1168 )
Cycle 1 day 8, 2 hrs after infusion start; n=25,0	28.9 ( 25.7 )	999999 ( 999999 )
Cycle 1 day 8, 6 hrs after infusion start; n=25,0	33.1 ( 26.6 )	999999 ( 999999 )
Cycle 1 day 8, 10 hrs after infusion start; n=25,0	33.1 ( 26.6 )	999999 ( 999999 )
Cycle 2 day 1, 6 hrs after infusion start; n=20,7	220 ( 357 )	142 ( 173 )
Cycle 3 day 1, 6 hrs after infusion start; n=8,2	121 ( 146 )	62.5 ( 0.0 )
Cycle 4 day 1, 6 hrs after infusion start; n=3,1	88.2 ( 93.7 )	62.5 ( 99999 )
Cycle 5 day 1, 6 hrs after infusion start; n=2,1	36.3 ( 37.1 )	62.5 ( 99999 )

Notes
[29] - n=participants with an assessment at given time point
[30] - 99999=not applicable (n=1); 999999=not applicable (n=0)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration

Top of page

End point title

Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration

End point description

End point type

Secondary

End point timeframe

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)
Number of subjects analysed	26 ^[31]	9 ^[32]
Units: pg/mL
arithmetic mean (standard deviation)
Cycle 1 day 1, 2 hrs after infusion start; n=26,0	37.3 ( 61.8 )	999999 ( 999999 )
Cycle 1 day 1, 6 hrs after infusion start; n=26,9	24.1 ( 23.7 )	15.8 ( 17.5 )
Cycle 1 day 1, 10 hrs after infusion start; n=26,9	20.1 ( 21.1 )	15.8 ( 17.5 )
Cycle 1 day 1, 24 hrs after infusion start; n=26,9	10.0 ( 0.0 )	15.8 ( 17.5 )
Cycle 1 day 8, 2 hrs after infusion start; n=25,0	16.6 ( 32.8 )	999999 ( 999999 )
Cycle 1 day 8, 6 hrs after infusion start; n=25,0	10.0 ( 0.0 )	999999 ( 999999 )
Cycle 1 day 8, 10 hrs after infusion start; n=25,0	10.0 ( 0.0 )	999999 ( 999999 )
Cycle 2 day 1, 6 hrs after infusion start; n=20,7	12.6 ( 11.7 )	17.5 ( 19.8 )
Cycle 3 day 1, 6 hrs after infusion start; n=8,2	16.6 ( 18.6 )	10.0 ( 0.0 )
Cycle 4 day 1, 6 hrs after infusion start; n=3,1	10.0 ( 0.0 )	10.0 ( 99999 )
Cycle 5 day 1, 6 hrs after infusion start; n=2,1	10.0 ( 0.0 )	10.0 ( 99999 )

Notes
[31] - n= participants with an assessment at given time point
[32] - 99999=not applicable (n=1); 999999=not applicable (n=0)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration

Top of page

End point title

Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration

End point description

End point type

Secondary

End point timeframe

End point values	Blinatumomab 9/28 μg/day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/day (Phase 1b and Phase 2 Pediatric)
Number of subjects analysed	26 ^[33]	9 ^[34]
Units: pg/mL
arithmetic mean (standard deviation)
Cycle 1 day 1, 2 hrs after infusion start; n=26,0	26.2 ( 24.7 )	999999 ( 999999 )
Cycle 1 day 1, 6 hrs after infusion start; n=26,9	52.3 ( 56.2 )	41.2 ( 42.8 )
Cycle 1 day 1, 10 hrs after infusion start; n=26,9	65.8 ( 71.6 )	64.5 ( 107 )
Cycle 1 day 1, 24 hrs after infusion start; n=26,9	42.1 ( 51.8 )	129 ( 176 )
Cycle 1 day 8, 2 hrs after infusion start; n=25,0	16.3 ( 17.4 )	999999 ( 999999 )
Cycle 1 day 8, 6 hrs after infusion start; n=25,0	14.2 ( 14.5 )	999999 ( 999999 )
Cycle 1 day 8, 10 hrs after infusion start; n=25,0	14.2 ( 14.5 )	999999 ( 999999 )
Cycle 2 day 1, 6 hrs after infusion start; n=20,7	17.9 ( 19.2 )	40.0 ( 28.1 )
Cycle 3 day 1, 6 hrs after infusion start; n=8,2	35.8 ( 55.0 )	10.0 ( 0.0 )
Cycle 4 day 1, 6 hrs after infusion start; n=3,1	10.0 ( 0.0 )	10.0 ( 99999 )
Cycle 5 day 1, 6 hrs after infusion start; n=2,1	10.0 ( 0.0 )	10.0 ( 99999 )

Notes
[33] - n=participants with an assessment at given time point
[34] - 99999=not applicable (n=1); 999999=not applicable (n=0)

No statistical analyses for this end point

Secondary: Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Top of page

End point title

Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment ^[35]

End point description

Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: - Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. - Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl. Analysis Population Description: Expansion Cohort adult participants who received any infusion of blinatumomab.

End point type

Secondary

End point timeframe

Within the first 2 cycles of treatment, 12 weeks

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Expansion Cohort: Blinatumomab 9/28 μg/day (Adults)
Number of subjects analysed	14
Units: percentage of participants
number (confidence interval 95%)	78.6 (49.2 to 95.3)

No statistical analyses for this end point

Secondary: Expansion Cohort Pediatric: Percentage of Participants with M1 Remission Within 2 Cycles of Treatment

Top of page

End point title

Expansion Cohort Pediatric: Percentage of Participants with M1 Remission Within 2 Cycles of Treatment ^[36]

End point description

M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease. Analysis Population Description: Expansion Cohort pediatric participants who received any infusion of blinatumomab.

End point type

Secondary

End point timeframe

Within the first 2 cycles of treatment, 12 weeks

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Unique endpoints were were planned for each Phase, per protocol.

End point values	Expansion Cohort: Blinatumomab 5/15 µg/m²/day (Pediatric)
Number of subjects analysed	17
Units: percentage of participants
number (confidence interval 95%)	29.4 (10.3 to 56.0)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

The median treatment duration for Blinatumomab is 108 days for Adult Phase 1b Cohort, 56 days for Pediatric Phase 1b Cohort, 56 days for Adult Phase 2 Cohort, 55.6 days for Adult Expansion Cohort and 28 days for Pediatric Expansion Cohort

Adverse event reporting additional description

A Phase 1b/2 Study of Blinatumomab in Japanese Adult Subjects with Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Blinatumomab 9-28 ug/day Phase 1b Adult Population

Reporting group description

Reporting group title

Blinatumomab 5-15 ug/m^2/day Phase 1b Pediatric Population

Reporting group description

Reporting group title

Blinatumomab 9-28 ug/day Phase 2 Adult Population

Reporting group description

Reporting group title

Blinatumomab 9-28 ug/day Adult Expansion Population

Reporting group description

Reporting group title

Blinatumomab 5-15 ug/m^2/day Pediatric Expansion Population

Reporting group description

Serious adverse events	Blinatumomab 9-28 ug/day Phase 1b Adult Population	Blinatumomab 5-15 ug/m^2/day Phase 1b Pediatric Population	Blinatumomab 9-28 ug/day Phase 2 Adult Population	Blinatumomab 9-28 ug/day Adult Expansion Population	Blinatumomab 5-15 ug/m^2/day Pediatric Expansion Population
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	7 / 21 (33.33%)	2 / 14 (14.29%)	3 / 17 (17.65%)
number of deaths (all causes)	5	7	15	0	2
number of deaths resulting from adverse events
Investigations
Neutrophil count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Shock haemorrhagic
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Immune system disorders
Cytokine release syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	2 / 17 (11.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0

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

Non-serious adverse events	Blinatumomab 9-28 ug/day Phase 1b Adult Population	Blinatumomab 5-15 ug/m^2/day Phase 1b Pediatric Population	Blinatumomab 9-28 ug/day Phase 2 Adult Population	Blinatumomab 9-28 ug/day Adult Expansion Population	Blinatumomab 5-15 ug/m^2/day Pediatric Expansion Population
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	9 / 9 (100.00%)	21 / 21 (100.00%)	14 / 14 (100.00%)	16 / 17 (94.12%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Central nervous system leukaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Leukaemic infiltration extramedullary
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 5 (0.00%)	4 / 9 (44.44%)	0 / 21 (0.00%)	1 / 14 (7.14%)	2 / 17 (11.76%)
occurrences all number	0	10	0	1	3
Hypotension
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	1	1	0	0
Hot flush
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	1	1	0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	2	0	0
Fatigue
subjects affected / exposed	2 / 5 (40.00%)	2 / 9 (22.22%)	0 / 21 (0.00%)	0 / 14 (0.00%)	3 / 17 (17.65%)
occurrences all number	5	3	0	0	9
Localised oedema
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0	0	0
Malaise
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	6 / 21 (28.57%)	3 / 14 (21.43%)	0 / 17 (0.00%)
occurrences all number	1	2	8	4	0
Oedema
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	3 / 14 (21.43%)	0 / 17 (0.00%)
occurrences all number	2	1	0	3	0
Pain
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	0 / 21 (0.00%)	1 / 14 (7.14%)	3 / 17 (17.65%)
occurrences all number	0	8	0	1	4
Pyrexia
subjects affected / exposed	1 / 5 (20.00%)	7 / 9 (77.78%)	15 / 21 (71.43%)	4 / 14 (28.57%)	15 / 17 (88.24%)
occurrences all number	1	21	21	10	34
Catheter site pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	1 / 17 (5.88%)
occurrences all number	0	0	1	1	1
Chills
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1
Disease progression
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Face oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1
Infusion site extravasation
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Oedema peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2	0	1
Immune system disorders
Acute graft versus host disease
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Cytokine release syndrome
subjects affected / exposed	4 / 5 (80.00%)	5 / 9 (55.56%)	8 / 21 (38.10%)	5 / 14 (35.71%)	6 / 17 (35.29%)
occurrences all number	9	9	12	7	6
Hypogammaglobulinaemia
subjects affected / exposed	2 / 5 (40.00%)	2 / 9 (22.22%)	2 / 21 (9.52%)	6 / 14 (42.86%)	0 / 17 (0.00%)
occurrences all number	2	2	2	6	0
Engraftment syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Graft versus host disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Hypersensitivity
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Reproductive system and breast disorders
Balanoposthitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Metrorrhagia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	2	0	0	0
Pelvic pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	2 / 17 (11.76%)
occurrences all number	1	0	1	1	2
Epistaxis
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	1 / 21 (4.76%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	4	1	0	1
Hiccups
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	1	0	0
Rhinorrhoea
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1
Hypoxia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1
Laryngeal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	5	0	0	1
Delirium
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	2	0	0	0
Insomnia
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	3 / 21 (14.29%)	3 / 14 (21.43%)	1 / 17 (5.88%)
occurrences all number	0	2	3	3	1
Sleep disorder
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Disorientation
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	1	1	0
Hallucination
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 5 (0.00%)	3 / 9 (33.33%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	4	0	0	1
Alanine aminotransferase increased
subjects affected / exposed	1 / 5 (20.00%)	5 / 9 (55.56%)	4 / 21 (19.05%)	2 / 14 (14.29%)	6 / 17 (35.29%)
occurrences all number	1	17	6	2	10
Amylase increased
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	5	1	1	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 5 (20.00%)	4 / 9 (44.44%)	3 / 21 (14.29%)	0 / 14 (0.00%)	6 / 17 (35.29%)
occurrences all number	1	9	3	0	15
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 5 (0.00%)	3 / 9 (33.33%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	4	2	0	0
Blood glucose decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Blood uric acid increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	2	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 5 (0.00%)	4 / 9 (44.44%)	1 / 21 (4.76%)	1 / 14 (7.14%)	3 / 17 (17.65%)
occurrences all number	0	7	1	1	4
Glucose urine present
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Hepatic enzyme increased
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	2	0	0	0
Immunoglobulins decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	3 / 21 (14.29%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	3	1	0
International normalised ratio increased
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	1 / 21 (4.76%)	1 / 14 (7.14%)	2 / 17 (11.76%)
occurrences all number	0	4	1	1	3
Lipase increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	6	0	0	0
Lymphocyte count decreased
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	3 / 21 (14.29%)	1 / 14 (7.14%)	2 / 17 (11.76%)
occurrences all number	13	0	3	6	5
Neutrophil count decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	5 / 21 (23.81%)	1 / 14 (7.14%)	3 / 17 (17.65%)
occurrences all number	0	1	6	4	7
Oxygen saturation decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Platelet count decreased
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	5 / 21 (23.81%)	1 / 14 (7.14%)	5 / 17 (29.41%)
occurrences all number	4	1	8	3	10
Prothrombin time prolonged
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Serum ferritin increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Weight decreased
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Weight increased
subjects affected / exposed	1 / 5 (20.00%)	2 / 9 (22.22%)	1 / 21 (4.76%)	2 / 14 (14.29%)	2 / 17 (11.76%)
occurrences all number	1	7	1	2	4
White blood cell count decreased
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	4 / 21 (19.05%)	2 / 14 (14.29%)	4 / 17 (23.53%)
occurrences all number	11	1	5	7	11
Antithrombin III decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	3 / 17 (17.65%)
occurrences all number	0	0	0	0	4
Bilirubin conjugated increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Blast cell count increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Blood cholesterol increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Blood fibrinogen decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	0 / 14 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	1	0	2
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	1	1	0	2	0
Infusion related reaction
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	2	2	0	1	0
Wrist fracture
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Arthropod bite
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	1	0	0
Sinus bradycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	3	0	0
Arrhythmia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Ventricular tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Nervous system disorders
Altered state of consciousness
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Aphasia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	2	1	0	0
Facial paralysis
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Headache
subjects affected / exposed	3 / 5 (60.00%)	4 / 9 (44.44%)	6 / 21 (28.57%)	3 / 14 (21.43%)	4 / 17 (23.53%)
occurrences all number	3	6	7	5	9
Hypoaesthesia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Intention tremor
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	1	0	0
Lethargy
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	2	0	1	1	0
Seizure
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Somnolence
subjects affected / exposed	2 / 5 (40.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	1	0	0	0
Tremor
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	2 / 21 (9.52%)	1 / 14 (7.14%)	3 / 17 (17.65%)
occurrences all number	0	1	2	1	3
Haemorrhage intracranial
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Movement disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Posterior reversible encephalopathy syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Wernicke's encephalopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 5 (20.00%)	4 / 9 (44.44%)	7 / 21 (33.33%)	4 / 14 (28.57%)	6 / 17 (35.29%)
occurrences all number	1	18	10	7	11
Bone marrow failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	2	0	0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	7 / 21 (33.33%)	2 / 14 (14.29%)	3 / 17 (17.65%)
occurrences all number	0	0	7	2	3
Febrile neutropenia
subjects affected / exposed	2 / 5 (40.00%)	5 / 9 (55.56%)	10 / 21 (47.62%)	7 / 14 (50.00%)	4 / 17 (23.53%)
occurrences all number	3	6	15	8	5
Leukopenia
subjects affected / exposed	0 / 5 (0.00%)	4 / 9 (44.44%)	3 / 21 (14.29%)	2 / 14 (14.29%)	0 / 17 (0.00%)
occurrences all number	0	17	6	4	0
Lymphopenia
subjects affected / exposed	0 / 5 (0.00%)	4 / 9 (44.44%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	19	2	0	0
Neutropenia
subjects affected / exposed	2 / 5 (40.00%)	5 / 9 (55.56%)	5 / 21 (23.81%)	6 / 14 (42.86%)	0 / 17 (0.00%)
occurrences all number	13	12	8	10	0
Thrombocytopenia
subjects affected / exposed	0 / 5 (0.00%)	3 / 9 (33.33%)	5 / 21 (23.81%)	3 / 14 (21.43%)	0 / 17 (0.00%)
occurrences all number	0	7	8	5	0
Hypoglobulinaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	1	1	0
Pancytopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Thrombotic microangiopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Dry eye
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	1	1	1	0
Photophobia
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Vitreous floaters
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Glaucoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	3	0	0	0
Abdominal pain
subjects affected / exposed	0 / 5 (0.00%)	3 / 9 (33.33%)	0 / 21 (0.00%)	0 / 14 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	5	0	0	3
Abdominal pain upper
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	1	0	1	0
Aphthous ulcer
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Constipation
subjects affected / exposed	1 / 5 (20.00%)	3 / 9 (33.33%)	0 / 21 (0.00%)	0 / 14 (0.00%)	2 / 17 (11.76%)
occurrences all number	1	3	0	0	2
Diarrhoea
subjects affected / exposed	0 / 5 (0.00%)	3 / 9 (33.33%)	8 / 21 (38.10%)	4 / 14 (28.57%)	2 / 17 (11.76%)
occurrences all number	0	6	9	4	2
Dyspepsia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Gastritis
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Gingival swelling
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Nausea
subjects affected / exposed	2 / 5 (40.00%)	2 / 9 (22.22%)	9 / 21 (42.86%)	8 / 14 (57.14%)	2 / 17 (11.76%)
occurrences all number	4	3	12	14	2
Oral pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Pancreatitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Proctitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Stomatitis
subjects affected / exposed	1 / 5 (20.00%)	2 / 9 (22.22%)	7 / 21 (33.33%)	5 / 14 (35.71%)	2 / 17 (11.76%)
occurrences all number	1	2	7	5	2
Vomiting
subjects affected / exposed	2 / 5 (40.00%)	5 / 9 (55.56%)	3 / 21 (14.29%)	4 / 14 (28.57%)	6 / 17 (35.29%)
occurrences all number	2	8	7	6	7
Dental caries
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Gastrointestinal disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	1	1	0
Haemorrhoids
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	1	1	0
Lip pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	2
Oral disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Proctalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Salivary gland pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Liver disorder
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	4 / 21 (19.05%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	1	6	0	0
Liver injury
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Cholecystitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Drug-induced liver injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Hepatic function abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Hepatic pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Alopecia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Asteatosis
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Dermatitis contact
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	2	0	0
Dry skin
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	3 / 21 (14.29%)	2 / 14 (14.29%)	1 / 17 (5.88%)
occurrences all number	0	0	3	2	1
Erythema
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	3 / 21 (14.29%)	3 / 14 (21.43%)	0 / 17 (0.00%)
occurrences all number	0	0	3	5	0
Ingrowing nail
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	1	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Rash
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	3 / 21 (14.29%)	2 / 14 (14.29%)	1 / 17 (5.88%)
occurrences all number	0	2	3	2	1
Rash maculo-papular
subjects affected / exposed	2 / 5 (40.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	0	0	0	1
Urticaria
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	2	0	0	1
Dermatitis acneiform
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	1	1	0
Dermatitis diaper
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Dermatitis exfoliative generalised
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Eczema
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	0	0	2
Pruritus
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	1	1	0
Renal and urinary disorders
Cystitis haemorrhagic
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	2 / 21 (9.52%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	1	2	1	0
Renal disorder
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Cystitis noninfective
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Pollakiuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Urinary retention
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Endocrine disorders
Steroid withdrawal syndrome
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	1 / 21 (4.76%)	1 / 14 (7.14%)	2 / 17 (11.76%)
occurrences all number	0	1	1	1	3
Arthritis
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Myalgia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	2	0	0
Myopathy
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Neck pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Pain in extremity
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	1 / 14 (7.14%)	3 / 17 (17.65%)
occurrences all number	0	1	0	1	4
Pain in jaw
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Spinal osteoarthritis
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Spinal pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Back pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	2 / 14 (14.29%)	0 / 17 (0.00%)
occurrences all number	0	0	1	2	0
Infections and infestations
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Conjunctivitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	2	0	0
Cystitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Cytomegalovirus infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	3	0	0
Device related infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	0	0	1
Gingivitis
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	0	0	0	1
Hepatitis B
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	1	0	1	0
Infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 21 (9.52%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	3	1	0
Nasopharyngitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	2	0	0
Otitis media
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	1	0	1	0
Sepsis
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	1	0	0
Staphylococcal sepsis
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	2 / 21 (9.52%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	2	0	0
Bacteraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1
Folliculitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Fungal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Gastroenteritis norovirus
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	0	0	2
Paronychia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	1	1	0
Pharyngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	1	2	0
Sialoadenitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0
Skin candida
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 5 (20.00%)	3 / 9 (33.33%)	3 / 21 (14.29%)	3 / 14 (21.43%)	5 / 17 (29.41%)
occurrences all number	3	4	3	5	9
Fluid retention
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	3 / 21 (14.29%)	1 / 14 (7.14%)	0 / 17 (0.00%)
occurrences all number	0	0	3	1	0
Hypercalcaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Hyperglycaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	1 / 21 (4.76%)	2 / 14 (14.29%)	1 / 17 (5.88%)
occurrences all number	0	1	1	2	5
Hyperkalaemia
subjects affected / exposed	1 / 5 (20.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	1 / 14 (7.14%)	2 / 17 (11.76%)
occurrences all number	2	1	0	1	2
Hyperlipidaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0
Hyperuricaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	1	0	0	1
Hypoalbuminaemia
subjects affected / exposed	1 / 5 (20.00%)	5 / 9 (55.56%)	2 / 21 (9.52%)	0 / 14 (0.00%)	4 / 17 (23.53%)
occurrences all number	2	15	3	0	10
Hypocalcaemia
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	0 / 21 (0.00%)	1 / 14 (7.14%)	3 / 17 (17.65%)
occurrences all number	0	4	0	1	4
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	6 / 21 (28.57%)	4 / 14 (28.57%)	1 / 17 (5.88%)
occurrences all number	0	2	7	5	4
Hypomagnesaemia
subjects affected / exposed	0 / 5 (0.00%)	2 / 9 (22.22%)	3 / 21 (14.29%)	2 / 14 (14.29%)	0 / 17 (0.00%)
occurrences all number	0	2	3	2	0
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 9 (11.11%)	0 / 21 (0.00%)	1 / 14 (7.14%)	4 / 17 (23.53%)
occurrences all number	0	1	0	2	9
Hypophosphataemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	2 / 14 (14.29%)	1 / 17 (5.88%)
occurrences all number	3	0	0	3	1
Hypernatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1
Hypertriglyceridaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	1 / 14 (7.14%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1
Hypoglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 9 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

02 Nov 2015

• Added pediatric cohorts (dose de-escalation design) in phase 1b to be able to file in Japan in a pediatric setting

07 Mar 2016

• Updated and clarified the dexamethasone premedication dosing • Updated Appendix H to reflect the latest investigator’s brochure • Updated inclusion and exclusion criteria • Updated contraception and pregnancy language • Updated secondary endpoints to align with the current blinatumomab program • Added an additional subgroup covariate • Clarified time-sensitive pharmacokinetic samples • Updated Appendix B, Appendix C, Appendix D, and Appendix K • Clarified dose modifications in Table 5 • Updated Section 10.3.1 to clarify stage 1 and stage 2 of the protocol

23 May 2016

• Updated and clarified the dexamethasone premedication dosing • Updated pediatric inclusion criteria • Updated contraception and pregnancy language • Removed the capture of disease-related events: no case report forms or statistical analysis plan were updated when they were added, so these documents were not required to be updated • Removed definition of complete remission with incomplete hematological recovery • Corrected covariates for subgroup and age • Updated protocol to align with current protocol template • Corrected Appendix C and Appendix D

23 Jun 2017

12 Jul 2018

• Identified and fixed a typo in Section 6.5.2 clarifying that appropriate prophylactic anticonvulsant treatment would be administered during the next treatment round if the event was a ≥ grade 2 seizure

20 Mar 2019

• Updated the primary completion and end of study language to reflect end of evaluation in the expansion cohort instead of phase 1b/2 part of study • Revised the analysis to include expansion cohort • Aligned that the final analysis occurred when the last subject in the expansion cohort completed safety follow up

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Number of Participants with Dose-limiting Toxicities

Primary: Phase 1b: Number of Participants with Dose-limiting Toxicities

Primary: Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Primary: Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Primary: Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

Primary: Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs

Secondary: Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Secondary: Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Secondary: Phase 1b Pediatric: Percentage of Participants with M1 Remission Within 2 Cycles of Treatment

Secondary: Phase 1b Pediatric: Percentage of Participants with M1 Remission Within 2 Cycles of Treatment

Secondary: Phase 1b and Phase 2: Duration of Response

Secondary: Phase 1b and Phase 2: Duration of Response

Secondary: Phase 1b and Phase 2: Relapse-free Survival

Secondary: Phase 1b and Phase 2: Relapse-free Survival

Secondary: Phase 1b and Phase 2: Overall Survival

Secondary: Phase 1b and Phase 2: Overall Survival

Secondary: Phase 2: Best Overall Response Within 2 Cycles of Treatment

Secondary: Phase 2: Best Overall Response Within 2 Cycles of Treatment

Secondary: Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission

Secondary: Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission

Secondary: Phase 2: 100-Day Mortality After Allogeneic HSCT

Secondary: Phase 2: 100-Day Mortality After Allogeneic HSCT

Secondary: Phase 1b and Phase 2: Number of Participants with TEAEs

Secondary: Phase 1b and Phase 2: Number of Participants with TEAEs

Secondary: Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State

Secondary: Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State

Secondary: Phase 1b and Phase 2: Systemic Clearance of Blinatumomab

Secondary: Phase 1b and Phase 2: Systemic Clearance of Blinatumomab

Secondary: Phase 1b and Phase 2: Terminal Half-life of Blinatumomab

Secondary: Phase 1b and Phase 2: Terminal Half-life of Blinatumomab

Secondary: Phase 1b and Phase 2: Volume of Distribution of Blinatumomab

Secondary: Phase 1b and Phase 2: Volume of Distribution of Blinatumomab

Secondary: Phase 1b and Phase 2: Number of Participants who Developed Anti-blinatumomab Antibodies

Secondary: Phase 1b and Phase 2: Number of Participants who Developed Anti-blinatumomab Antibodies

Secondary: Phase 1b and Phase 2: Interleukin-2 Concentration

Secondary: Phase 1b and Phase 2: Interleukin-2 Concentration

Secondary: Phase 1b and Phase 2: Interleukin-6 Concentration

Secondary: Phase 1b and Phase 2: Interleukin-6 Concentration

Secondary: Phase 1b and Phase 2: Interleukin-10 Concentration

Secondary: Phase 1b and Phase 2: Interleukin-10 Concentration

Secondary: Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration

Secondary: Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration

Secondary: Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration

Secondary: Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration

Secondary: Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Secondary: Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Secondary: Expansion Cohort Pediatric: Percentage of Participants with M1 Remission Within 2 Cycles of Treatment

Secondary: Expansion Cohort Pediatric: Percentage of Participants with M1 Remission Within 2 Cycles of Treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)