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Clinical Trial Results:
A Phase 1/2, Open-label Randomized Study of Ulocuplumab (BMS-936564) In Combination with Low Dose Cytarabine in Subjects with Newly Diagnosed Acute Myeloid Leukemia

Summary
EudraCT number	2016-004275-40
Trial protocol	RO
Global end of trial date	04 Jun 2019

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

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

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Trial information

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Sponsor protocol code

CA212-016

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

Bristol-Myers Squibb International Corporation, EU Study Start-Up Unit, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

10 Sep 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

04 Jun 2019

Global end of trial reached?

Yes

Global end of trial date

04 Jun 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

In Phase 1 (escalation cohort): To assess the safety and tolerability of ulocuplumab in combination with low-dose cytarabine (LDAC) in participants with AML. In Phase 2 (expansion cohort): To estimate preliminary efficacy in terms of complete remission (CR/CRi=CR+CRi) in participants treated at two different dose levels of ulocuplumab, 800 mg and 1000 mg, in combination with low-dose cytarabine (LDAC).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

10 Apr 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 5

Country: Number of subjects enrolled

Israel: 5

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Japan: 22

Country: Number of subjects enrolled

Korea, Republic of: 3

Country: Number of subjects enrolled

Taiwan: 6

Country: Number of subjects enrolled

United States: 24

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

6 participants in Phase 1 and 64 participants in Phase 2 (70 in total) were assigned to treatment. 2 participants randomized to the LDAC-only arm in Phase 2 did not receive treatment. 68 participants in total (phases 1 and 2) were treated.

Period 1 title

Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

ULO 600mg + LDAC - Ph1

Arm description

Ulocuplumab (ULO) at 600mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Arm type

Experimental

Investigational medicinal product name

ulocuplumab; LDAC

Investigational medicinal product code

Other name

BMS-936564; low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

600mg for ulocuplumab; 20 mg BID for LDAC

ULO 800mg + LDAC - Ph1

Arm description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Arm type

Experimental

Investigational medicinal product name

ulocuplumab; LDAC

Investigational medicinal product code

Other name

BMS-936564; low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

800mg for ulocuplumab; 20 mg BID for LDAC

ULO 800mg + LDAC - Ph2

Arm description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Arm type

Experimental

Investigational medicinal product name

ulocuplumab; LDAC

Investigational medicinal product code

Other name

BMS-936564; low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

800mg for ulocuplumab; 20 mg BID for LDAC

ULO 1000mg + LDAC - Ph2

Arm description

Ulocuplumab (ULO) at 1000mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Arm type

Experimental

Investigational medicinal product name

ulocuplumab; LDAC

Investigational medicinal product code

Other name

BMS-936564; low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1000mg for ulocuplumab; 20 mg BID for LDAC

LDAC - Ph2

Arm description

Low dose cytarabine (LDAC) - Phase 2 (Ph2)

Arm type

Active comparator

Investigational medicinal product name

LDAC

Investigational medicinal product code

Other name

low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

20 mg BID for LDAC

Number of subjects in period 1	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Started	3	3	26	14	24
Completed	1	1	1	0	0
Not completed	2	2	25	14	24
Adverse event, serious fatal	-	-	-	2	1
Disease progression	-	-	15	6	6
Administrative reason by Sponsor	-	-	-	-	1
Participant withdrew consent	-	-	1	1	1
Maximum clinical benefit	-	-	-	-	1
Participant request to stop therapy	-	2	-	1	-
added ULO; then other reason	-	-	-	-	1
other reason	2	-	2	2	1
Adverse Event (AE) unrelated to drug	-	-	7	1	2
added ULO, then disease progression	-	-	-	-	4
added ULO, then request to stop	-	-	-	-	1
Study drug toxicity	-	-	-	1	2
Randomized but not treated	-	-	-	-	2
Poor/non-compliance	-	-	-	-	1

Period 2 title

Follow-up Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

ULO 600mg + LDAC - Ph1

Arm description

Ulocuplumab (ULO) at 600mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Arm type

Experimental

Investigational medicinal product name

ulocuplumab; LDAC

Investigational medicinal product code

Other name

BMS-936564; low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

600mg for ulocuplumab; 20 mg BID for LDAC

ULO 800mg + LDAC - Ph1

Arm description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Arm type

Experimental

Investigational medicinal product name

ulocuplumab; LDAC

Investigational medicinal product code

Other name

BMS-936564; low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

800mg for ulocuplumab; 20 mg BID for LDAC

ULO 800mg + LDAC - Ph2

Arm description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Arm type

Experimental

Investigational medicinal product name

ulocuplumab; LDAC

Investigational medicinal product code

Other name

BMS-936564; low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

800mg for ulocuplumab; 20 mg BID for LDAC

ULO 1000mg + LDAC - Ph2

Arm description

Ulocuplumab (ULO) at 1000mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Arm type

Experimental

Investigational medicinal product name

ulocuplumab; LDAC

Investigational medicinal product code

Other name

BMS-936564; low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1000mg for ulocuplumab; 20 mg BID for LDAC

LDAC - Ph2

Arm description

Low dose cytarabine (LDAC) - Phase 2 (Ph2)

Arm type

Active comparator

Investigational medicinal product name

LDAC

Investigational medicinal product code

Other name

low dose cytarabine

Pharmaceutical forms

Injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

20 mg BID for LDAC

Number of subjects in period 2	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Started	1	1	11	6	12
Completed	1	1	0	0	0
Not completed	0	0	11	6	12
Adverse event, serious fatal	-	-	5	4	7
Participant withdrew consent	-	-	2	1	-
Followup no longer required per protocol	-	-	4	1	4
other reason	-	-	-	-	1

Baseline characteristics

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Reporting group title

ULO 600mg + LDAC - Ph1

Reporting group description

Ulocuplumab (ULO) at 600mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Reporting group title

ULO 800mg + LDAC - Ph1

Reporting group description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Reporting group title

ULO 800mg + LDAC - Ph2

Reporting group description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Reporting group title

ULO 1000mg + LDAC - Ph2

Reporting group description

Ulocuplumab (ULO) at 1000mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Reporting group title

LDAC - Ph2

Reporting group description

Low dose cytarabine (LDAC) - Phase 2 (Ph2)

Reporting group values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2	Total
Number of subjects	3	3	26	14	24	70
Age Categorical
Age categorical
Units: Participants
<70	1	0	4	3	3	11
>=70	2	3	22	11	21	59
Age Continuous
Units: Years
arithmetic mean (standard deviation)	73.7 ± 8.02	77.3 ± 1.53	74.9 ± 5.4	73.1 ± 3.7	75.9 ± 5.7	-
Sex: Female, Male
Units: Participants
Female	3	0	9	7	14	33
Male	0	3	17	7	10	37
Race/Ethnicity, Customized
Race
Units: Subjects
White	0	0	15	4	12	31
Black/African American	0	0	0	0	0	0
Japanese	3	3	6	6	4	22
Chinese	0	0	2	2	3	7
Asian Indian	0	0	0	0	0	0
Asian Other	0	0	3	0	2	5
American Indian/Alaskan Native	0	0	0	1	0	1
Native Hawaiian/Other Pacific Islander	0	0	0	0	0	0
Other	0	0	0	1	3	4
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	0	0	0
Not Hispanic or Latino	0	0	0	0	0	0
Unknown or Not Reported	3	3	26	14	24	70

End points

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Reporting group title

ULO 600mg + LDAC - Ph1

Reporting group description

Ulocuplumab (ULO) at 600mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Reporting group title

ULO 800mg + LDAC - Ph1

Reporting group description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Reporting group title

ULO 800mg + LDAC - Ph2

Reporting group description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Reporting group title

ULO 1000mg + LDAC - Ph2

Reporting group description

Ulocuplumab (ULO) at 1000mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Reporting group title

LDAC - Ph2

Reporting group description

Low dose cytarabine (LDAC) - Phase 2 (Ph2)

Reporting group title

ULO 600mg + LDAC - Ph1

Reporting group description

Ulocuplumab (ULO) at 600mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Reporting group title

ULO 800mg + LDAC - Ph1

Reporting group description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 1 (Ph1)

Reporting group title

ULO 800mg + LDAC - Ph2

Reporting group description

Ulocuplumab (ULO) at 800mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Reporting group title

ULO 1000mg + LDAC - Ph2

Reporting group description

Ulocuplumab (ULO) at 1000mg + low dose cytarabine (LDAC) - Phase 2 (Ph2)

Reporting group title

LDAC - Ph2

Reporting group description

Low dose cytarabine (LDAC) - Phase 2 (Ph2)

Primary: Number of participants with Dose-Limiting Toxicities (DLTs) in treatment cycle 1 - Phase 1

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End point title

Number of participants with Dose-Limiting Toxicities (DLTs) in treatment cycle 1 - Phase 1 ^[1] ^[2]

End point description

Safety data evaluated for DLTs. DLTs and all other toxicities were defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03). DLTs were defined based upon events that were considered to be related to ulocuplumab in combination with LDAC and that occurred during the first cycle of drug administration (28 days). Note: an entry of "9999" is equivalent to "NA" (not available).

End point type

Primary

End point timeframe

From first dose to end of cycle 1 (28 days)

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: Only summary statistics were planned for this endpoint
[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: Only phase 1 summary statistics were planned for this endpoint

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1
Number of subjects analysed	3	3
Units: Participants	9999	9999

No statistical analyses for this end point

Primary: Number of participants with Adverse Events (AEs) - Phase 1

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End point title

Number of participants with Adverse Events (AEs) - Phase 1 ^[3] ^[4]

End point description

The number of participants with an on-study adverse event (AE). Safety data are evaluated for AEs, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03).

End point type

Primary

End point timeframe

From first dose to 30 days post last dose

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: Only summary statistics were planned for this endpoint
[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: Only phase 1 summary statistics were planned for this endpoint

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1
Number of subjects analysed	3	3
Units: Participants	3	3

No statistical analyses for this end point

Primary: Number of participants with >= Grade 3 AEs - Phase 1

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End point title

Number of participants with >= Grade 3 AEs - Phase 1 ^[5] ^[6]

End point description

The number of participants with an on-study adverse event >= Grade level 3. Safety data are evaluated for >= Grade 3 AEs, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03).

End point type

Primary

End point timeframe

From first dose to 30 days post last dose

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: Only summary statistics were planned for this endpoint
[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: Only phase 1 summary statistics were planned for this endpoint

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1
Number of subjects analysed	3	3
Units: Participants	3	3

No statistical analyses for this end point

Primary: Number of participants with AEs leading to discontinuation - Phase 1

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End point title

Number of participants with AEs leading to discontinuation - Phase 1 ^[7] ^[8]

End point description

The number of participants with an on-study adverse event (AE) leading to discontinuation. Safety data are evaluated for AEs leading to discontinuation, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03).

End point type

Primary

End point timeframe

From first dose to 30 days post last dose

Notes
[7] - 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: Only summary statistics were planned for this endpoint
[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: Only phase 1 summary statistics were planned for this endpoint

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1
Number of subjects analysed	3	3
Units: Participants	0	0

No statistical analyses for this end point

Primary: Number of participants with Serious Adverse Events (SAEs) - Phase 1

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End point title

Number of participants with Serious Adverse Events (SAEs) - Phase 1 ^[9] ^[10]

End point description

The number of participants with an on-study serious adverse event (SAE). Safety data are evaluated for SAEs, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03).

End point type

Primary

End point timeframe

From first dose to 30 days post last dose

Notes
[9] - 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: Only summary statistics were planned for this endpoint
[10] - 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: Only phase 1 summary statistics were planned for this endpoint

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1
Number of subjects analysed	3	3
Units: Participants	2	1

No statistical analyses for this end point

Primary: Number of deaths - Phase 1

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End point title

Number of deaths - Phase 1 ^[11] ^[12]

End point description

The number of participants who died.

End point type

Primary

End point timeframe

From first dose to 30 days post last dose

Notes
[11] - 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: Only summary statistics were planned for this endpoint
[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: Only phase 1 summary statistics were planned for this endpoint

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1
Number of subjects analysed	3	3
Units: Participants	0	0

No statistical analyses for this end point

Primary: Number of participants with laboratory abnormalities - Phase 1

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End point title

Number of participants with laboratory abnormalities - Phase 1 ^[13] ^[14]

End point description

The number of participants with an on-study laboratory abnormality. Safety data are evaluated for laboratory abnormalities, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03).

End point type

Primary

End point timeframe

From first dose to 30 days post last dose

Notes
[13] - 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: Only summary statistics were planned for this endpoint
[14] - 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: Only phase 1 summary statistics were planned for this endpoint

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1
Number of subjects analysed	3	3
Units: Participants
ABSOLUTE NEUTROPHIL COUNT - grade 3	0	1
ABSOLUTE NEUTROPHIL COUNT - grade 4	3	2
ALANINE AMINOTRANSFERASE - grade 0	2	2
ALANINE AMINOTRANSFERASE - grade 1	1	1
ALBUMIN - grade 0	1	0
ALBUMIN - grade 1	0	2
ALBUMIN - grade 2	2	1
ALKALINE PHOSPHATASE - grade 0	2	2
ALKALINE PHOSPHATASE grade 1	1	1
ASPARTATE AMINOTRANSFERASE - grade 0	3	2
ASPARTATE AMINOTRANSFERASE - grade 1	0	1
BILIRUBIN, TOTAL - grade 0	3	2
BILIRUBIN, TOTAL - grade 2	0	1
CALCIUM, TOTAL - grade 0	1	1
CALCIUM, TOTAL - grade 1	0	1
CALCIUM, TOTAL - grade 2	2	1
CREATINE KINASE - grade 0	3	3
CREATININE - grade 0	2	3
CREATININE - grade 1	1	0
FIBRINOGEN - grade 0	1	0
GLUCOSE, FASTING SERUM - grade 0	1	1
GLUCOSE, FASTING SERUM - grade 1	2	0
GLUCOSE, FASTING SERUM - grade 2	0	2
HEMOGLOBIN - grade 2	1	1
HEMOGLOBIN - grade 3	2	2
LEUKOCYTES - grade 0	0	1
LEUKOCYTES - grade 3	1	1
LEUKOCYTES - grade 4	2	1
LIPASE, TOTAL (COLORIMETRIC ASSAY) - grade 0	2	1
LIPASE, TOTAL (COLORIMETRIC ASSAY) - grade 1	1	0
LIPASE, TOTAL (COLORIMETRIC ASSAY) - grade 3	0	2
LYMPHOCYTES (ABSOLUTE) - grade 0	0	1
LYMPHOCYTES (ABSOLUTE) - grade 1	0	1
LYMPHOCYTES (ABSOLUTE) - grade 2	2	1
LYMPHOCYTES (ABSOLUTE) - grade 3	1	0
NEUTROPHILS (ABSOLUTE) - grade 3	0	1
NEUTROPHILS (ABSOLUTE) - grade 4	3	2
PHOSPHORUS, INORGANIC - grade 0	3	2
PHOSPHORUS, INORGANIC - grade 3	0	1
PLATELET COUNT - grade 3	0	1
PLATELET COUNT - grade 4	3	2
POTASSIUM, SERUM - grade 0	1	2
POTASSIUM, SERUM - grade 1	0	1
POTASSIUM, SERUM - grade 3	2	0
SODIUM, SERUM - grade 0	2	1
SODIUM, SERUM - grade 1	0	2
SODIUM, SERUM - grade 3	1	0
URIC ACID - grade 0	3	2
URIC ACID - grade 1	0	1

No statistical analyses for this end point

Primary: Best Overall Response (BOR) - Phase 2

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End point title

Best Overall Response (BOR) - Phase 2 ^[15] ^[16]

End point description

The phase 2 primary endpoint was based on the rate of Complete Remission (CR/CRi) prior to the initiation of any alternative therapy (including any subsequent ulocuplumab 800 mg for participants in the LDAC alone arm). The phase 2 primary analysis was conducted after all participants had an opportunity for 6 months of follow-up. Complete remission rate: CR + CRi, confidence interval based on the Clopper and Pearson method. CR = complete response CRi = complete response, incomplete blood count

End point type

Primary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

Notes
[15] - 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: Only summary statistics were planned for this endpoint
[16] - 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: Only phase 2 summary statistics were planned for this endpoint

End point values	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	26	14	24
Units: Percentage of participants
number (confidence interval 95%)	15.4 (4.4 to 34.9)	7.1 (0.2 to 33.9)	25.0 (9.8 to 46.7)

No statistical analyses for this end point

Secondary: Best Overall Response (BOR) - Phase 1

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End point title

Best Overall Response (BOR) - Phase 1 ^[17]

End point description

Investigator assessed best overall response prior to the initiation of any alternative therapy for Phase 1 participants.

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 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: Only phase 1 summary statistics were planned for this endpoint

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1
Number of subjects analysed	3	3
Units: Participants	1	3

No statistical analyses for this end point

Secondary: Number of participants with AEs - Phase 2

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End point title

Number of participants with AEs - Phase 2 ^[18]

End point description

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

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: Only phase 2 summary statistics were planned for this endpoint

End point values	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	26	14	22
Units: Participants	25	14	22

No statistical analyses for this end point

Secondary: Number of participants with AEs leading to discontinuation - Phase 2

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End point title

Number of participants with AEs leading to discontinuation - Phase 2 ^[19]

End point description

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

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: Only phase 2 summary statistics were planned for this endpoint

End point values	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	26	14	22
Units: Participants	7	3	4

No statistical analyses for this end point

Secondary: Number of participants with SAEs - Phase 2

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End point title

Number of participants with SAEs - Phase 2 ^[20]

End point description

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

Notes
[20] - 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: Only phase 2 summary statistics were planned for this endpoint

End point values	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	26	14	22
Units: Participants	21	8	15

No statistical analyses for this end point

Secondary: Number of deaths- Phase 2

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End point title

Number of deaths- Phase 2 ^[21]

End point description

The number of participants who died. Safety data are evaluated for deaths, defined and evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03).

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

Notes
[21] - 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: Only phase 2 summary statistics were planned for this endpoint

End point values	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	26	14	22
Units: Participants	19	10	16

No statistical analyses for this end point

Secondary: Number of participants with laboratory abnormalities - Phase 2

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End point title

Number of participants with laboratory abnormalities - Phase 2 ^[22]

End point description

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

Notes
[22] - 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: Only phase 2 summary statistics were planned for this endpoint

End point values	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	26	14	22
Units: Participants	9999	9999	9999

No statistical analyses for this end point

Secondary: Number of participants with anti-drug antibodies (ADA) positive for ulocuplumab - Phases 1 and 2

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End point title

Number of participants with anti-drug antibodies (ADA) positive for ulocuplumab - Phases 1 and 2 ^[23]

End point description

Serum samples from ulocuplumab treated participants were evaluated for the presence of anti-ulocuplumab antibodies

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

Notes
[23] - 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: Only drug summary statistics were planned for this endpoint

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2
Number of subjects analysed	3	3	21	14
Units: Participants	9999	9999	6	0

No statistical analyses for this end point

Secondary: Maximum observed serum concentration (Cmax) - Phases 1 and 2

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End point title

Maximum observed serum concentration (Cmax) - Phases 1 and 2

End point description

The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration EOT = end of treatment

End point type

Secondary

End point timeframe

Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up)

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: ng/mL
geometric mean (geometric coefficient of variation)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999

No statistical analyses for this end point

Secondary: Trough observed serum concentration (Ctrough) - Phases 1 and 2

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End point title

Trough observed serum concentration (Ctrough) - Phases 1 and 2

End point description

The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment

End point type

Secondary

End point timeframe

Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up)

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: ng/mL
geometric mean (geometric coefficient of variation)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999

No statistical analyses for this end point

Secondary: Time of maximum observed ulocuplumab serum concentration (Tmax) - Phases 1 and 2

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End point title

Time of maximum observed ulocuplumab serum concentration (Tmax) - Phases 1 and 2

End point description

The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment

End point type

Secondary

End point timeframe

Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up)

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: hour (H)
median (full range (min-max))	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (-9999 to 9999)

No statistical analyses for this end point

Secondary: Area under the ulocuplumab concentration-time curve from time zero to the last quantifiable concentration [AUC(0-T)] - Phases 1 and 2

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End point title

Area under the ulocuplumab concentration-time curve from time zero to the last quantifiable concentration [AUC(0-T)] - Phases 1 and 2

End point description

The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment AUC(0-T) calculated by log- and linear-trapezoidal summation

End point type

Secondary

End point timeframe

Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up)

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: ng.h/mL
geometric mean (geometric coefficient of variation)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999

No statistical analyses for this end point

Secondary: Area under the ulocuplumab concentration-time curve in one dosing interval [AUC(TAU)] - Phases 1 and 2

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End point title

Area under the ulocuplumab concentration-time curve in one dosing interval [AUC(TAU)] - Phases 1 and 2

End point description

The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment

End point type

Secondary

End point timeframe

Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up)

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: ng.h/mL
geometric mean (geometric coefficient of variation)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999

No statistical analyses for this end point

Secondary: Area under the ulocuplumab concentration-time curve from time zero to infinity [AUC(INF)] - Phases 1 and 2

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End point title

Area under the ulocuplumab concentration-time curve from time zero to infinity [AUC(INF)] - Phases 1 and 2

End point description

The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment AUC(INF) calculated by summing AUC(0-T) and the extrapolated area, computed by the quotient Clast/λz

End point type

Secondary

End point timeframe

Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up)

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: ng.h/mL
geometric mean (geometric coefficient of variation)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999

No statistical analyses for this end point

Secondary: Elimination half-life (T-HALF) - Phases 1 and 2

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End point title

Elimination half-life (T-HALF) - Phases 1 and 2

End point description

The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment T-HALF determined as 0.693/λz

End point type

Secondary

End point timeframe

Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up)

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: hour (H)
arithmetic mean (standard deviation)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999

No statistical analyses for this end point

Secondary: Total body clearance of ulocuplumab (CLT) - Phases 1 and 2

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End point title

Total body clearance of ulocuplumab (CLT) - Phases 1 and 2

End point description

The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment CLT calculated by dividing the total dose of ulocuplumab by its corresponding AUC(INF) value

End point type

Secondary

End point timeframe

Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up)

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: mL/h
geometric mean (geometric coefficient of variation)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999

No statistical analyses for this end point

Secondary: Volume of distribution at steady state (Vss) - Phases 1 and 2

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End point title

Volume of distribution at steady state (Vss) - Phases 1 and 2

End point description

The Pharmacokinetic (PK) parameters are assessed for ulocuplumab following study drug administration. EOT = end of treatment

End point type

Secondary

End point timeframe

Days 1, 8, 15 for cycles 1 and 2; Days 1, 8 for cycles 3-5; Day 1 every 4th cycle thereafter; EOT; 30 days post last dose (follow-up)

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: liter (L)
geometric mean (geometric coefficient of variation)	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999	9999 ± 9999

No statistical analyses for this end point

Secondary: Overall rate of remission in participants treated with ulocuplumab at two different dose levels 800 mg and 1000 mg in combination with LDAC - Phase 2

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End point title

Overall rate of remission in participants treated with ulocuplumab at two different dose levels 800 mg and 1000 mg in combination with LDAC - Phase 2 ^[24]

End point description

This phase 2 secondary endpoint was based on the rate of Overall Remission (OR=PR+CR +CRi) prior to the initiation of any alternative therapy (including any subsequent ulocuplumab 800 mg for participants in the LDAC alone arm). The phase 2 analysis was conducted after all participants had an opportunity for 6 months of follow-up. Overall remission rate: CR + CRi, + PR confidence interval based on the Clopper and Pearson method. CR = complete response CRi = complete response, incomplete blood count PR = partial remission

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

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: Only phase 2 summary statistics were planned for this endpoint

End point values	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2
Number of subjects analysed	26	14
Units: Percentage of participants
number (confidence interval 95%)	19.2 (6.6 to 39.4)	7.1 (0.2 to 33.9)

No statistical analyses for this end point

Secondary: Duration of response in participants with CR/CRi treated with ulocuplumab at two different dose levels 800 mg and 1000 mg in combination with LDAC - Phase 2

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End point title

Duration of response in participants with CR/CRi treated with ulocuplumab at two different dose levels 800 mg and 1000 mg in combination with LDAC - Phase 2 ^[25]

End point description

This phase 2 secondary endpoint was based on the duration of complete remission prior to the initiation of any alternative therapy (including any subsequent ulocuplumab 800 mg for participants in the LDAC alone arm). The phase 2 analysis was conducted after all participants had an opportunity for 6 months of follow-up.

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

Notes
[25] - 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: Only phase 2 summary statistics were planned for this endpoint

End point values	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2
Number of subjects analysed	4	1
Units: Months
median (full range (min-max))	2.4 (0.5 to 5.6)	4.3 (-9999 to 9999)

No statistical analyses for this end point

Secondary: Rate of Complete Remission (CR/CRi) and Overall rate of remission in participants treated with LDAC only - Phase 2

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End point title

Rate of Complete Remission (CR/CRi) and Overall rate of remission in participants treated with LDAC only - Phase 2 ^[26]

End point description

This phase 2 secondary endpoint was based on the rate of Complete Remission (CR/CRi) and rate of Overall Remission (OR=PR+CR +CRi) prior to the initiation of any alternative therapy (including any subsequent ulocuplumab 800 mg for participants in the LDAC alone arm). The phase 2 analysis was conducted after all participants had an opportunity for 6 months of follow-up. Overall remission rate: CR + CRi, + PR confidence interval based on the Clopper and Pearson method. CR = complete response CRi = complete response, incomplete blood count PR = partial remission

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

Notes
[26] - 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: Only phase 2 summary statistics were planned for this endpoint

End point values	LDAC - Ph2
Number of subjects analysed	24
Units: Percentage of participants
number (confidence interval 95%)
CR/CRi	25.0 (9.8 to 46.7)
Overall remission rate	25.0 (9.8 to 46.7)

No statistical analyses for this end point

Secondary: Duration of response in participants with CR/CRi treated with LDAC only - Phase 2

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End point title

Duration of response in participants with CR/CRi treated with LDAC only - Phase 2 ^[27]

End point description

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

Notes
[27] - 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: Only phase 2 summary statistics were planned for this endpoint

End point values	LDAC - Ph2
Number of subjects analysed	6
Units: Months
median (full range (min-max))	5.7 (0.9 to 9999)

No statistical analyses for this end point

Secondary: Change in baseline of electrocardiogram (ECG) endpoints - Phases 1 and 2

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End point title

Change in baseline of electrocardiogram (ECG) endpoints - Phases 1 and 2

End point description

Change in baseline of ECG endpoints:

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	24
Units: Percent change from baseline	9999	9999	9999	9999	9999

No statistical analyses for this end point

Secondary: Overall survival (OS) - Phases 1 and 2

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End point title

Overall survival (OS) - Phases 1 and 2

End point description

OS is defined as the time between the first date of treatment and the date of death due to any cause. A participant who has not died was be censored at the last known alive date.

End point type

Secondary

End point timeframe

From first dose until a minimum follow-up of up to 2 months

End point values	ULO 600mg + LDAC - Ph1	ULO 800mg + LDAC - Ph1	ULO 800mg + LDAC - Ph2	ULO 1000mg + LDAC - Ph2	LDAC - Ph2
Number of subjects analysed	3	3	26	14	22
Units: Months
median (full range (min-max))	9999 (-9999 to 9999)	9999 (-9999 to 9999)	3.3 (1.8 to 8.7)	3.0 (1.8 to 4.7)	6.9 (1.6 to 12.7)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events are reported from start of treatment up to 30 days after last dose of study treatment.

Adverse event reporting additional description

Analysis was performed in All treated subjects defined as all subjects who received at least one dose of any study medication.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Dose escalation: Ulocuplumab 600 mg + LDAC

Reporting group description

During escalation phase subjects were administered intravenously (IV) with 600 mg ulocuplumab on Days 1, 8, and 15 in combination with low dose cytarabine (LDAC) (20 milligram (mg) twice daily (BID) [40 mg/day], administered subcutaneously [SC]) on Days 1 through 10 of each 28-day cycle (Cycles 1 and 2). For Cycle 3 and subsequent cycles subjects received ulocuplumab 600 mg on Days 1 and 8 in combination with LDAC (20 mg BID, SC) on Days 1 through 10.

Reporting group title

Dose escalation: Ulocuplumab 800 mg + LDAC

Reporting group description

During escalation phase subjects were administered IV with 800 mg ulocuplumab on Days 1, 8, and 15 in combination with LDAC (20 mg BID [40 mg/day], administered SC) on Days 1 through 10 of each 28-day cycle (Cycles 1 and 2). For Cycle 3 and subsequent cycles subjects received ulocuplumab 800 mg on Days 1 and 8 in combination with LDAC (20 mg BID, SC) on Days 1 through 10.

Reporting group title

Dose expansion: Ulocuplumab 800mg + LDAC

Reporting group description

During expansion phase subjects were administered IV with 800 mg ulocuplumab on Days 1, 8, and 15 in combination with LDAC (20 mg BID [40 mg/day], administered SC) on Days 1 through 10 of each 28-day cycle (Cycles 1 and 2). For Cycle 3 and subsequent cycles subjects received ulocuplumab 800 mg on Days 1 and 8 in combination with LDAC (20 mg BID, SC) on Days 1 through 10.

Reporting group title

Dose expansion: Ulocuplumab 1000mg + LDAC

Reporting group description

During expansion phase subjects were administered IV with 1000 mg ulocuplumab on Days 1, 8, and 15 in combination with LDAC (20 mg BID [40 mg/day], administered SC) on Days 1 through 10 of each 28-day cycle (Cycles 1 and 2). For Cycle 3 and subsequent cycles subjects received ulocuplumab 1000 mg on Days 1 and 8 in combination with LDAC (20 mg BID, SC) on Days 1 through 10.

Reporting group title

Dose expansion: LDAC alone

Reporting group description

During expansion phase subjects were administered SC with LDAC (20 mg BID [40 mg/day]) on Days 1 through 10 for cycle 1 and subsequent cycles (28-day cycle).

Serious adverse events	Dose escalation: Ulocuplumab 600 mg + LDAC	Dose escalation: Ulocuplumab 800 mg + LDAC	Dose expansion: Ulocuplumab 800mg + LDAC	Dose expansion: Ulocuplumab 1000mg + LDAC	Dose expansion: LDAC alone
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	21 / 26 (80.77%)	8 / 14 (57.14%)	15 / 22 (68.18%)
number of deaths (all causes)	0	0	19	10	16
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (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 / 1	0 / 0
Epstein-Barr virus associated lymphoproliferative disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 26 (19.23%)	2 / 14 (14.29%)	6 / 22 (27.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 5	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 5	0 / 2	0 / 6
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
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
Neurogenic shock
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
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
General disorders and administration site conditions
Catheter site haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Complication associated with device
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Death
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (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 / 1	0 / 0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
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
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Pulmonary haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Pulmonary oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Investigations
Amylase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	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
Wound dehiscence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Cardiac disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (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 / 1	0 / 0
Cardiac failure
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
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
Seizure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
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
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	8 / 26 (30.77%)	5 / 14 (35.71%)	6 / 22 (27.27%)
occurrences causally related to treatment / all	2 / 2	0 / 0	7 / 12	1 / 7	5 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Eye disorders
Cataract
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
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
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Oesophagitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
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
Infections and infestations
Bacterial infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
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
Clostridium difficile colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 26 (11.54%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Pneumonia fungal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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 / 3 (0.00%)	0 / 3 (0.00%)	3 / 26 (11.54%)	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 3	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 1
Septic shock
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (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
Skin infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Lactic acidosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (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
Tumour lysis syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0

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

Non-serious adverse events	Dose escalation: Ulocuplumab 600 mg + LDAC	Dose escalation: Ulocuplumab 800 mg + LDAC	Dose expansion: Ulocuplumab 800mg + LDAC	Dose expansion: Ulocuplumab 1000mg + LDAC	Dose expansion: LDAC alone
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	23 / 26 (88.46%)	14 / 14 (100.00%)	21 / 22 (95.45%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	3 / 22 (13.64%)
occurrences all number	0	0	1	0	3
Vascular disorders
Haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	2	0	2
Haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Hypertension
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 26 (11.54%)	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	1	0	3	2	1
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Vasculitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 26 (11.54%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	4	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 26 (11.54%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	3	0	2
Catheter site erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0	0
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	3 / 14 (21.43%)	2 / 22 (9.09%)
occurrences all number	0	0	1	5	3
Early satiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 26 (19.23%)	4 / 14 (28.57%)	5 / 22 (22.73%)
occurrences all number	0	0	5	4	5
Generalised oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	1	1	0
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 26 (11.54%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	3	0	1
Mass
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	0	1	1
Oedema peripheral
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	6 / 26 (23.08%)	1 / 14 (7.14%)	4 / 22 (18.18%)
occurrences all number	4	2	6	1	8
Pyrexia
subjects affected / exposed	2 / 3 (66.67%)	2 / 3 (66.67%)	8 / 26 (30.77%)	5 / 14 (35.71%)	5 / 22 (22.73%)
occurrences all number	4	4	9	7	9
Non-Cardiac chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	0	0	2	2	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 26 (3.85%)	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	1	1	1	5	0
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Genital ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Prostatitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	6 / 26 (23.08%)	3 / 14 (21.43%)	2 / 22 (9.09%)
occurrences all number	0	2	6	3	2
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 26 (19.23%)	4 / 14 (28.57%)	1 / 22 (4.55%)
occurrences all number	0	0	6	5	1
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	3	1	0
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	1	1	0
Interstitial lung disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 26 (11.54%)	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	0	1	3	2	1
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	1	1	1
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 26 (11.54%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	3	0	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	0	0	0	2	0
Stridor
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Upper respiratory tract inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Wheezing
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	0	0	0	2	1
Psychiatric disorders
Adjustment disorder with depressed mood
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	0	0	0	2	0
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0	0
Delirium
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 26 (26.92%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	9	1	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 26 (7.69%)	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	1	0	2	1	2
Amylase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	1	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 26 (3.85%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	1	1	1	1
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 26 (11.54%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	1	3	1	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	1	1	0
Lipase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	5	0	2	0	2
Neutrophil count decreased
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	3 / 26 (11.54%)	1 / 14 (7.14%)	6 / 22 (27.27%)
occurrences all number	5	0	4	1	15
Platelet count decreased
subjects affected / exposed	2 / 3 (66.67%)	3 / 3 (100.00%)	6 / 26 (23.08%)	4 / 14 (28.57%)	8 / 22 (36.36%)
occurrences all number	17	5	7	5	18
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	2
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 26 (19.23%)	1 / 14 (7.14%)	3 / 22 (13.64%)
occurrences all number	0	0	5	1	15
C-Reactive protein increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	2
Electrocardiogram qt prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	1	1	0
Troponin t increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Injury, poisoning and procedural complications
Allergic transfusion reaction
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	2	0	0	0
Compression fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	1	0	2
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	2 / 14 (14.29%)	2 / 22 (9.09%)
occurrences all number	0	0	0	3	2
Procedural pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	1	1	0
Transfusion reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	2	0	0
Cardiac failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	3 / 22 (13.64%)
occurrences all number	0	0	0	0	3
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	2	0	2
Headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 26 (11.54%)	3 / 14 (21.43%)	2 / 22 (9.09%)
occurrences all number	0	0	3	6	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 3 (66.67%)	3 / 3 (100.00%)	11 / 26 (42.31%)	3 / 14 (21.43%)	8 / 22 (36.36%)
occurrences all number	3	4	22	4	15
Febrile neutropenia
subjects affected / exposed	1 / 3 (33.33%)	3 / 3 (100.00%)	5 / 26 (19.23%)	4 / 14 (28.57%)	7 / 22 (31.82%)
occurrences all number	1	3	7	4	9
Increased tendency to bruise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Leukocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	1	1	1
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 26 (15.38%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	4	0	0
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 26 (23.08%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	16	0	2
Ear and labyrinth disorders
Ear congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Ear discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Eye disorders
Dry eye
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	0	0	1	1	2
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	2	1	1
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	1	1	0
Constipation
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	10 / 26 (38.46%)	2 / 14 (14.29%)	5 / 22 (22.73%)
occurrences all number	1	1	11	2	6
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 26 (23.08%)	3 / 14 (21.43%)	5 / 22 (22.73%)
occurrences all number	0	0	6	3	6
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	2	0	1
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0	0
Enteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Flatulence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Gastritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	0	1	1
Glossodynia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Haemorrhoids
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	1	0	1	1	2
Ileus
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	0	0	0	2	1
Nausea
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	6 / 26 (23.08%)	8 / 14 (57.14%)	6 / 22 (27.27%)
occurrences all number	3	2	9	11	9
Pancreatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	1	1	1
Periodontal disease
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	1	1	0	0
Stomatitis
subjects affected / exposed	1 / 3 (33.33%)	3 / 3 (100.00%)	5 / 26 (19.23%)	3 / 14 (21.43%)	4 / 22 (18.18%)
occurrences all number	1	3	5	5	6
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 26 (15.38%)	1 / 14 (7.14%)	3 / 22 (13.64%)
occurrences all number	1	1	6	1	3
Hepatobiliary disorders
Hepatic congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Hepatic function abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	3	0	1
Hepatosplenomegaly
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Hyperbilirubinaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	0	1	1
Drug-Induced liver injury
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	0
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	2
Dermatitis allergic
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	0	0	0
Drug eruption
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	0
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	0	1	1
Ecchymosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	0	0	0	1	2
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	0	0	0	2	1
Petechiae
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	0	0	2	2	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 26 (0.00%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	1	0	1	1
Rash
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	3 / 14 (21.43%)	2 / 22 (9.09%)
occurrences all number	1	0	0	3	2
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	0	0	3	1	3
Skin exfoliation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	1	0	1	1	0
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Renal tubular disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	0	0	0	1	2
Back pain
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 26 (0.00%)	4 / 14 (28.57%)	0 / 22 (0.00%)
occurrences all number	2	0	0	4	0
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	2	0
Costochondritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	1	1	1
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	0	0	1	2	1
Pain in extremity
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 26 (3.85%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	1	0	0
Polymyalgia rheumatica
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	0
Tendonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Infections and infestations
Device related infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	2
Gingivitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	2 / 14 (14.29%)	0 / 22 (0.00%)
occurrences all number	0	0	0	2	0
Herpes simplex
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	0
Herpes zoster
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	0
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	3 / 22 (13.64%)
occurrences all number	0	0	3	1	3
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	0	0	1	1	2
Otitis media
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	1	1	1
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	1	1	0
Skin infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences all number	1	0	0	0	2
Subcutaneous abscess
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences all number	1	0	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 26 (3.85%)	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	0	0	2	1	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 26 (11.54%)	2 / 14 (14.29%)	4 / 22 (18.18%)
occurrences all number	3	0	4	2	5
Dehydration
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences all number	1	0	2	0	1
Diabetes mellitus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Fluid overload
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Glucose tolerance impaired
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 26 (0.00%)	0 / 14 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	1	0	0	1
Hyperglycaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 26 (0.00%)	0 / 14 (0.00%)	2 / 22 (9.09%)
occurrences all number	1	0	0	0	2
Hyperkalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	2 / 22 (9.09%)
occurrences all number	0	0	0	1	2
Hypermagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	0
Hypernatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	2	1	1
Hypoglycaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 26 (0.00%)	1 / 14 (7.14%)	0 / 22 (0.00%)
occurrences all number	0	1	0	1	0
Hypokalaemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 26 (3.85%)	3 / 14 (21.43%)	3 / 22 (13.64%)
occurrences all number	3	1	1	3	7
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 26 (11.54%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	3	0	0
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	2 / 14 (14.29%)	1 / 22 (4.55%)
occurrences all number	0	0	2	2	1
Metabolic acidosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 26 (0.00%)	1 / 14 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	0	0	1	1
Tumour lysis syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 26 (7.69%)	0 / 14 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0	0

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Were there any global substantial amendments to the protocol? Yes

24 Oct 2014

This amendment of the protocol is in response to the 30-day review by Pharmaceuticals and Medical Devices Association (PMDA) for Clinical Trial Notification. Additional changes for a clarification purpose are also incorporated in this amendment.

07 May 2015

This amendment of the protocol is to implement following changes: modify the target population to remove the restriction on AML (newly diagnosed, elderly), extend the period of contraception use, modify prior therapy related criteria, and modify hepatitis B and C infection criteria to only exclude active infection. This amendment is also to change Medical Monitor.

02 Nov 2016

This amendment expands the study globally to provide insights of safety and efficacy of two different dose levels of ulocuplumab (800 mg and 1000 mg) in combination with low dose cytarabine (LDAC) and LDAC alone for the treatment of Acute Myeloid Leukemia (AML). The expansion will enroll subjects ( 18 years old) with newly diagnosed AML that are unfit for high induction chemotherapy or stem cell transplant because of age or comorbidities. The changes include addition of a Phase 2 (expansion cohort) with 1:1:1 randomization of approximately 120 subjects, 40 subjects per treatment group, to assess preliminary efficacy by complete remission with blast count reduction  5% (CR) or complete remission with incomplete blood count recovery (CRi) and overall survival (OS). The changes include collection of samples for exploratory biomarker assessment such as CXR4, receptor occupancy and evaluation of ulocuplumab pharmacokinetics and interaction with LDAC. For safety, DLTs will be evaluated and ECG evaluation was added for a subset of subjects to measure QT intervals by Fridericia method.

10 Feb 2017

This amendment implements the following changes: revises the telephone/fax numbers and location of the BMS Medical Monitor; corrects study title in synopsis; clarifies that exclusion criterion 2b is applicable; clarifies dose modifications and addition of ulocuplumab to LDAC alone arm; clarifies local lab bone marrow results sent to BMS; clarifies standard of care testing for extramedullary disease; adds central lab cytogenetic testing; deletes local cytogenetic testing; clarifies time point for end of cycle leukemia assessment; clarifies bone marrow aspirate is sufficient for leukemia evaluation; reduces pregnancy test requirement (WOBCP) to once per cycle and monthly during dose delays; adds pregnancy test to EOT; clarifies and/or corrects Time and Events Schedule footnotes; clarifies hematology blast percentage is included in hematology lab tests; clarifies PK, ADA, and receptor occupancy samples are not collected for subjects randomized to the LDAC alone arm; clarifies footnotes in PK and biomarker tables; clarifies safety and serial ECG requirements; provides details of biomarker testing; Appendices 1 and 3 updated.

29 Mar 2017

This amendment implements the following changes: revises synopsis to align with revisions in sections 3.1, 8.3.1 and 8.3.2; revises study design description; revises study treatment and dose timing sections to clarify when LDAC only arm may add ulocuplumab; revises discontinuation, dose modifications, infusion delays, and missed doses sections; adds whole exome sequencing to bone marrow and peripheral blood biomarker testing; revises Tables 5.1-2, 5.1-3, 5.7.2-1; moves cytogenetic testing to other assessments section; adds ECG analyses section; adds whole exome sequencing to biomarker analyses section; revises primary endpoint analysis details; revises secondary endpoint details; moves ECG analyses details from biomarker analyses section to a new section; adds cytogenetic analyses section.

27 Jul 2017

 The exclusion criteria was revised to specify allogeneic transplants in participants who received prior hematopoietic stem cell transplantation  The schedule for the collection of hematology samples during treatment cycles 1 and 2 was revised to eliminate the requirement for 10 days consecutive days of hematology collections, and to allow hematology sample collection flexibility up to 72 hours before infusion of ulocuplumab  Peripheral blood and serum/plasma collection criteria during End of study treatment and follow-up assessment were revised from mandatory status to include exceptions listed in Section 5.7.2 and Table 5.7.2 1  Buccal swab procedure was added to treatment procedural outline and biomarkers sampling schedule for the expansion cohort  Time and assessment ranges were revised to reflect current standards in Sections 4.6.1.1 and 4.6.1.2 and Table 4.6.1.2-1  Removed bone marrow collection for TCR sequencing.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
04 Jun 2019	The preliminary efficacy results for the Phase 2 cohort, analyzed at a pre-planned interim analysis, did not replicate the activity observed in Phase 1, with results below the expected clinical benefit from current treatment options. Based on these findings during the pre-specified interim analysis, the enrollment was terminated and the trial was discontinued.	-

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

None reported

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Clinical trials

Clinical Trial Results: A Phase 1/2, Open-label Randomized Study of Ulocuplumab (BMS-936564) In Combination with Low Dose Cytarabine in Subjects with Newly Diagnosed Acute Myeloid Leukemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants with Dose-Limiting Toxicities (DLTs) in treatment cycle 1 - Phase 1

Primary: Number of participants with Dose-Limiting Toxicities (DLTs) in treatment cycle 1 - Phase 1

Primary: Number of participants with Adverse Events (AEs) - Phase 1

Primary: Number of participants with Adverse Events (AEs) - Phase 1

Primary: Number of participants with >= Grade 3 AEs - Phase 1

Primary: Number of participants with >= Grade 3 AEs - Phase 1

Primary: Number of participants with AEs leading to discontinuation - Phase 1

Primary: Number of participants with AEs leading to discontinuation - Phase 1

Primary: Number of participants with Serious Adverse Events (SAEs) - Phase 1

Primary: Number of participants with Serious Adverse Events (SAEs) - Phase 1

Primary: Number of deaths - Phase 1

Primary: Number of deaths - Phase 1

Primary: Number of participants with laboratory abnormalities - Phase 1

Primary: Number of participants with laboratory abnormalities - Phase 1

Primary: Best Overall Response (BOR) - Phase 2

Primary: Best Overall Response (BOR) - Phase 2

Secondary: Best Overall Response (BOR) - Phase 1

Secondary: Best Overall Response (BOR) - Phase 1

Secondary: Number of participants with AEs - Phase 2

Secondary: Number of participants with AEs - Phase 2

Secondary: Number of participants with AEs leading to discontinuation - Phase 2

Secondary: Number of participants with AEs leading to discontinuation - Phase 2

Secondary: Number of participants with SAEs - Phase 2

Secondary: Number of participants with SAEs - Phase 2

Secondary: Number of deaths- Phase 2

Secondary: Number of deaths- Phase 2

Secondary: Number of participants with laboratory abnormalities - Phase 2

Secondary: Number of participants with laboratory abnormalities - Phase 2

Secondary: Number of participants with anti-drug antibodies (ADA) positive for ulocuplumab - Phases 1 and 2

Secondary: Number of participants with anti-drug antibodies (ADA) positive for ulocuplumab - Phases 1 and 2

Secondary: Maximum observed serum concentration (Cmax) - Phases 1 and 2

Secondary: Maximum observed serum concentration (Cmax) - Phases 1 and 2

Secondary: Trough observed serum concentration (Ctrough) - Phases 1 and 2

Secondary: Trough observed serum concentration (Ctrough) - Phases 1 and 2

Secondary: Time of maximum observed ulocuplumab serum concentration (Tmax) - Phases 1 and 2

Secondary: Time of maximum observed ulocuplumab serum concentration (Tmax) - Phases 1 and 2

Secondary: Area under the ulocuplumab concentration-time curve from time zero to the last quantifiable concentration [AUC(0-T)] - Phases 1 and 2

Secondary: Area under the ulocuplumab concentration-time curve from time zero to the last quantifiable concentration [AUC(0-T)] - Phases 1 and 2

Secondary: Area under the ulocuplumab concentration-time curve in one dosing interval [AUC(TAU)] - Phases 1 and 2

Secondary: Area under the ulocuplumab concentration-time curve in one dosing interval [AUC(TAU)] - Phases 1 and 2

Secondary: Area under the ulocuplumab concentration-time curve from time zero to infinity [AUC(INF)] - Phases 1 and 2

Secondary: Area under the ulocuplumab concentration-time curve from time zero to infinity [AUC(INF)] - Phases 1 and 2

Secondary: Elimination half-life (T-HALF) - Phases 1 and 2

Secondary: Elimination half-life (T-HALF) - Phases 1 and 2

Secondary: Total body clearance of ulocuplumab (CLT) - Phases 1 and 2

Secondary: Total body clearance of ulocuplumab (CLT) - Phases 1 and 2

Secondary: Volume of distribution at steady state (Vss) - Phases 1 and 2

Secondary: Volume of distribution at steady state (Vss) - Phases 1 and 2

Secondary: Overall rate of remission in participants treated with ulocuplumab at two different dose levels 800 mg and 1000 mg in combination with LDAC - Phase 2

Secondary: Overall rate of remission in participants treated with ulocuplumab at two different dose levels 800 mg and 1000 mg in combination with LDAC - Phase 2

Secondary: Duration of response in participants with CR/CRi treated with ulocuplumab at two different dose levels 800 mg and 1000 mg in combination with LDAC - Phase 2

Secondary: Duration of response in participants with CR/CRi treated with ulocuplumab at two different dose levels 800 mg and 1000 mg in combination with LDAC - Phase 2

Secondary: Rate of Complete Remission (CR/CRi) and Overall rate of remission in participants treated with LDAC only - Phase 2

Secondary: Rate of Complete Remission (CR/CRi) and Overall rate of remission in participants treated with LDAC only - Phase 2

Secondary: Duration of response in participants with CR/CRi treated with LDAC only - Phase 2

Secondary: Duration of response in participants with CR/CRi treated with LDAC only - Phase 2

Secondary: Change in baseline of electrocardiogram (ECG) endpoints - Phases 1 and 2

Secondary: Change in baseline of electrocardiogram (ECG) endpoints - Phases 1 and 2

Secondary: Overall survival (OS) - Phases 1 and 2

Secondary: Overall survival (OS) - Phases 1 and 2

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1/2, Open-label Randomized Study of Ulocuplumab (BMS-936564) In Combination with Low Dose Cytarabine in Subjects with Newly Diagnosed Acute Myeloid Leukemia