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Clinical Trial Results:
An Open-Label Phase I/IIa Study of the Safety and Efficacy of Melphalan-flufenamide (Melflufen) and Dexamethasone Combination for Patients with Relapsed and/or Relapsed-Refractory Multiple Myeloma

Summary
EudraCT number	2012-004315-31
Trial protocol	SE NL IT DK
Global end of trial date	29 Oct 2019

Results information
Results version number	v2(current)
This version publication date	17 Oct 2020
First version publication date	15 Jul 2020
Other versions	v1
Version creation reason	New data added to full data set Overall Survival Data to be added to the results posting.

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

O-12-M1

ISRCTN number

US NCT number

NCT01897714

WHO universal trial number (UTN)

Sponsor organisation name

Oncopeptides AB

Sponsor organisation address

Västra Trädgårdsgatan 15, Stockholm, Sweden, 111 53

Public contact

Eva Nordström, Oncopeptides AB, +46 86152040, trials@oncopeptides.com

Scientific contact

Eva Nordström, Oncopeptides AB, +46 86152040, trials@oncopeptides.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

29 Oct 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

09 Nov 2017

Global end of trial reached?

Yes

Global end of trial date

29 Oct 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

Phase I: To determine the maximum tolerated dose (MTD) after 1 treatment cycle, of the combination of melflufen and dexamethasone in patients with relapsed and/or relapsed-refractory multiple myeloma (MM). Phase IIa: To evaluate the overall response rate (ORR) (≥ partial response [PR] or better) and the clinical benefit rate (CBR) (≥ minimal response [MR] or better) of the combination of melflufen and dexamethasone, and of melflufen as a single-agent at the MTD determined in Phase I.

Protection of trial subjects

The study was designed, implemented, and reported in accordance with International Council for Harmonisation Tripartite Guidelines for Good Clinical Practice, and with applicable local regulations (including European Directive 2001/20/EC and US Code of Federal Regulations Title 21) and the ethical principles laid down in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Jul 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 9

Country: Number of subjects enrolled

Sweden: 4

Country: Number of subjects enrolled

Denmark: 8

Country: Number of subjects enrolled

Italy: 26

Country: Number of subjects enrolled

United States: 28

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

This was an open-label, Phase I/IIa study conducted at 7 study centers in 5 countries in patients with relapsed and/or relapsed-refractory MM. Overall, 75 patients (23 during Phase I and 52 additional patients during Phase II) were enrolled in this study. Completed in subject disposition indicates patients who completed >=8 cycles of study drug.

Screening details

The study was conducted in 2 parts: Phase I (dose escalation) and Phase II (MTD). During Phase I, the standard 3 + 3 design was followed with 3 to 6 patients tested at each dose level, depending on the dose limiting toxicity (DLT) observed. During Phase II, patients were treated at the MTD determined in Phase I.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Phase I: Melflufen 15 mg + Dexamethasone

Arm description

Patients were treated with 15 milligram (mg) melflufen as intravenous (IV) infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.

Arm type

Experimental

Investigational medicinal product name

Melflufen

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A dose of 15 mg melflufen administered as a 30-minute IV infusion on Day 1 of each 21-day treatment cycle.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

A dose of 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle.

Phase I: Melflufen 25 mg + Dexamethasone

Arm description

Patients were treated with 25 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.

Arm type

Experimental

Investigational medicinal product name

Melflufen

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A dose of 25 mg melflufen administered as a 30-minute IV infusion on Day 1 of each 21-day treatment cycle.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

A dose of 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle.

Phase I: Melflufen 40 mg + Dexamethasone

Arm description

Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.

Arm type

Experimental

Investigational medicinal product name

Melflufen

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A dose of 40 mg melflufen administered as a 30-minute IV infusion on Day 1 of each 21-day treatment cycle.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

A dose of 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle.

Phase I: Melflufen 55 mg + Dexamethasone

Arm description

Patients were treated with 55 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.

Arm type

Experimental

Investigational medicinal product name

Melflufen

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A dose of 55 mg melflufen administered as a 30-minute IV infusion on Day 1 of each 21-day treatment cycle.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

A dose of 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle.

Phase I + II: Melflufen 40 mg + Dexamethasone

Arm description

Patients were treated with 40 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day or 28-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator. In Protocol amendment 4, the cycle of melflufen was increased from 21 to 28 days. For any patients on the 28-day treatment schedule, an additional dose of 40 mg dexamethasone was administered on Day 22 of each cycle.

Arm type

Experimental

Investigational medicinal product name

Melflufen

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A dose of 40 mg melflufen administered as a 30-minute IV infusion on Day 1 of each 21-day or 28-day treatment cycle.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion, Tablet

Routes of administration

Intravenous use, Oral use

Dosage and administration details

A dose of 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle and an additional dose of 40 mg dexamethasone was administered on Day 22 of each 28-day treatment cycle.

Phase II: Melflufen 40 mg (Single Agent)

Arm description

Patients were treated with 40 mg melflufen as IV infusion on Day 1 of each 28-day treatment cycle. Dexamethasone was not administered as an antitumor compound. However, all patients were treated with 8 mg dexamethasone as an antiemetic on Days 1 and 2, and an optional 4 mg dexamethasone as an antiemetic on Days 3 and 4 of the same 28-day cycle, unless the Investigator decided to switch a patient to a combination regimen. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.

Arm type

Experimental

Investigational medicinal product name

Melflufen

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

A dose of 40 mg melflufen administered as a 30-minute IV infusion on Day 1 of each 28-day treatment cycle.

Investigational medicinal product name

Dexamethasone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Solution for infusion

Routes of administration

Intravenous use, Oral use

Dosage and administration details

A dose of 8 mg dexamethasone oral tablet or IV infusion on Days 1, 2, and an optional 4 mg on Days 3 and 4 of each 28-day treatment cycle.

Number of subjects in period 1	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Started	4	7	6	6	39	13
Completed	1	0	1	0	15	2
Not completed	3	7	5	6	30	11
Consent withdrawn by subject	-	-	-	-	-	1
Disease progression	3	5	1	3	-	-
Study terminated with patient alive	-	-	-	-	1	-
Adverse event, non-fatal	-	1	4	3	-	-
Death	-	-	-	-	25	10
Unspecified	-	1	-	-	3	-
Lost to follow-up	-	-	-	-	1	-
Joined	0	0	0	0	6	0
Transferred in from Phase I: Melflufen 40 mg group	-	-	-	-	6	-

Baseline characteristics

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Reporting group title

Phase I: Melflufen 15 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I: Melflufen 25 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I: Melflufen 40 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I: Melflufen 55 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I + II: Melflufen 40 mg + Dexamethasone

Reporting group description

Reporting group title

Phase II: Melflufen 40 mg (Single Agent)

Reporting group description

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: 6 patients in the Phase I: Melflufen 40 mg + Dexamethasone reporting group were included in the analysis of the Phase IIa part of the study. So, these 6 patients were also included in the Phase I + II: Melflufen 40 mg + Dexamethasone reporting group.

Reporting group values	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)	Total
Number of subjects	4	7	6	6	45	13	75
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	1	3	3	2	20	8	34
From 65-84 years	3	4	3	4	25	5	41
85 years and over	0	0	0	0	0	0	0
Gender categorical
Units: Subjects
Female	2	4	2	3	15	5	29
Male	2	3	4	3	30	8	46
Race
Units: Subjects
Black or African American	1	1	0	0	3	3	8
Caucasian	3	6	6	6	41	10	66
Not collected as per local laws	0	0	0	0	1	0	1
Ethnicity
Units: Subjects
Hispanic or Latino	0	1	0	0	1	0	2
Not Hispanic or Latino	4	6	5	5	37	12	64
Not collected as per local laws	0	0	1	1	7	1	9

End points

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Reporting group title

Phase I: Melflufen 15 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I: Melflufen 25 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I: Melflufen 40 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I: Melflufen 55 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I + II: Melflufen 40 mg + Dexamethasone

Reporting group description

Reporting group title

Phase II: Melflufen 40 mg (Single Agent)

Reporting group description

Primary: Percentage of Patients Who Achieved Best Overall Disease Response

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End point title

Percentage of Patients Who Achieved Best Overall Disease Response ^[1]

End point description

The best overall disease response on treatment including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR, MR, stable disease (SD) or progressive disease (PD) were evaluated. Starting on completion of Cycle 2, response was assessed according to International Myeloma Working Group (IMWG) criteria based on Investigator's assessment for all patients at every cycle during treatment period. PD was defined as increase of ≥25% from lowest response value in any 1 of the following: serum M-component (absolute increase must be ≥0.5 gram/deciliter) and/or urine M-component (absolute increase must be ≥200 mg/24 hr); development of new bone lesions or soft tissue plasmacytomas or increase in size of existing bone lesions or soft tissue plasmacytomas or development of hypercalcemia that could be attributed solely to plasma cell proliferative disorder. SD was defined as not meeting criteria for CR, VGPR, PR or PD.

End point type

Primary

End point timeframe

Baseline (Cycle 1 Day 1) and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until end of trial (EOT) date of 29 October 2019; up to a maximum of approximately 76 months.

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 descriptive statistical analysis was performed for this endpoint.

End point values	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	4 ^[2]	7 ^[3]	6 ^[4]	6 ^[5]	45 ^[6]	13 ^[7]
Units: percentage of patients
number (confidence interval 95%)
sCR	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	0.0 (0.0 to 45.9)	0.0 (0.0 to 45.9)	0.0 (0.0 to 7.9)	0.0 (0.0 to 24.7)
CR	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	0.0 (0.0 to 45.9)	0.0 (0.0 to 45.9)	0.0 (0.0 to 7.9)	0.0 (0.0 to 24.7)
VGPR	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	16.7 (0.4 to 64.1)	16.7 (0.4 to 64.1)	11.1 (3.7 to 24.1)	0.0 (0.0 to 24.7)
PR	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	50.0 (11.8 to 88.2)	0.0 (0.0 to 45.9)	20.0 (9.6 to 34.6)	7.7 (0.2 to 36.0)
MR	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	0.0 (0.0 to 45.9)	0.0 (0.0 to 45.9)	17.8 (8.0 to 32.1)	15.4 (1.9 to 45.4)
SD	75.0 (19.4 to 99.4)	42.9 (9.9 to 81.6)	16.7 (0.4 to 64.1)	66.7 (22.3 to 95.7)	26.7 (14.6 to 41.9)	69.2 (38.6 to 90.9)
PD	25.0 (0.6 to 80.6)	57.1 (18.4 to 90.1)	16.7 (0.4 to 64.1)	16.7 (0.4 to 64.1)	15.6 (6.5 to 29.5)	7.7 (0.2 to 36.0)
Missing	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	0.0 (0.0 to 45.9)	0.0 (0.0 to 45.9)	8.9 (2.5 to 21.2)	0.0 (0.0 to 24.7)
sCR + CR	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	0.0 (0.0 to 45.9)	0.0 (0.0 to 45.9)	0.0 (0.0 to 7.9)	0.0 (0.0 to 24.7)
sCR + CR + VGPR	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	16.7 (0.4 to 64.1)	16.7 (0.4 to 64.1)	11.1 (3.7 to 24.1)	0.0 (0.0 to 24.7)

Notes
[2] - Safety Analysis Set.
[3] - Safety Analysis Set.
[4] - Safety Analysis Set.
[5] - Safety Analysis Set.
[6] - Modified Intent-to-Treat (mITT) Analysis Set.
[7] - mITT Analysis Set.

No statistical analyses for this end point

Primary: Overall Response Rate

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End point title

Overall Response Rate ^[8]

End point description

ORR was defined as percentage of patients with an overall response (OR), defined as first occurrence of confirmed disease response including PR or better (i.e, PR, VGPR, CR or sCR). Starting on completion of Cycle 2, response was assessed according to IMWG criteria based on Investigator's assessment for all patients at every cycle during treatment period. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum plus urine M-protein level <100 mg/24hr and >90% decrease in difference between involved and uninvolved free light chain (FLC) levels (only in FLC diseased patients). CR was defined as negative immunofixation on serum and urine, loss of any soft tissue plasmacytomas, <5% plasma cells in bone marrow and normal FLC ratio of 0.26 to 1.65 (only in FLC diseased patients). sCR was defined as CR plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or 2 to 4 color flow cytometry.

End point type

Primary

End point timeframe

Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Notes
[8] - 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 descriptive statistical analysis was performed for this endpoint.

End point values	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	4 ^[9]	7 ^[10]	6 ^[11]	6 ^[12]	45 ^[13]	13 ^[14]
Units: percentage of patients
number (confidence interval 95%)	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	66.7 (22.3 to 95.7)	16.7 (0.4 to 64.1)	31.1 (18.2 to 46.6)	7.7 (0.2 to 36.0)

Notes
[9] - Safety Analysis Set.
[10] - Safety Analysis Set.
[11] - Safety Analysis Set.
[12] - Safety Analysis Set.
[13] - mITT Analysis Set.
[14] - mITT Analysis Set.

No statistical analyses for this end point

Primary: Clinical Benefit Response Rate (CBRR)

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End point title

Clinical Benefit Response Rate (CBRR) ^[15]

End point description

The CBRR was defined as the percentage of patients with a CBR, defined as the first occurrence of confirmed disease response including MR or better (i.e, MR, PR, VGPR, CR, or sCR). Starting on completion of Cycle 2, response was assessed according to the IMWG criteria based on the Investigator's assessment for all patients at every cycle during the treatment period. MR was defined as ≥25% but <49% reduction of serum M-protein and reduction in 24 hour urine M-protein by 50 to 89%, which still exceeds 200 mg/24 hours. In addition to above; if present at baseline, 25 to 49% reduction in the size of soft tissue plasmacytomas is also required. No increase in size or number of lytic bone lesions (development of compression fractures does not exclude response). PR was defined as 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by ≥90% or to <200 mg/24 hour.

End point type

Primary

End point timeframe

Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 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 descriptive statistical analysis was performed for this endpoint.

End point values	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	4 ^[16]	7 ^[17]	6 ^[18]	6 ^[19]	45 ^[20]	13 ^[21]
Units: percentage of patients
number (confidence interval 95%)	0.0 (0.0 to 60.2)	0.0 (0.0 to 41.0)	66.7 (22.3 to 95.7)	16.7 (0.4 to 64.1)	48.9 (33.7 to 64.2)	23.1 (5.0 to 53.8)

Notes
[16] - Safety Analysis Set.
[17] - Safety Analysis Set.
[18] - Safety Analysis Set.
[19] - Safety Analysis Set.
[20] - mITT Analysis Set.
[21] - mITT Analysis Set.

No statistical analyses for this end point

Secondary: Duration of Disease Response (DOR)

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End point title

Duration of Disease Response (DOR) ^[22]

End point description

The DOR to treatment was defined as time from first response (PR or better) to disease progression or death, or date of last evaluable disease response assessment for those who had not progressed or died. DOR was estimated using Kaplan-Meier statistics. The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had achieved at least PR were evaluated. -9999 and 9999 = confidence interval could not be determined as only 1 patient was analysed.

End point type

Secondary

End point timeframe

Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 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 patients who were treated at the maximum tolerated dose (MTD) were analysed for this endpoint.

End point values	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	14	1
Units: months
median (confidence interval 95%)	8.4 (4.6 to 11.1)	7.2 (-9999 to 9999)

No statistical analyses for this end point

Secondary: Time to Disease Response in Patients Who Achieved OR and CBR

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End point title

Time to Disease Response in Patients Who Achieved OR and CBR ^[23]

End point description

Time to first OR was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of PR or better (first of 2 consecutive assessments-confirmed response). Time to first CBR was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of MR or better (first of 2 consecutive assessments-confirmed response). Time to disease response was estimated using Kaplan-Meier statistics. The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Here, 'n' was defined as patients who had achieved OR and CBR for each respective time to response parameter; -9999 and 9999 = confidence interval could not be determined as only 1 patient was analysed.

End point type

Secondary

End point timeframe

Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 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 patients who were treated at the MTD were analysed for this endpoint.

End point values	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	45	13
Units: months
median (confidence interval 95%)
OR (n= 14, 1)	2.8 (1.6 to 4.7)	6.7 (-9999 to 9999)
CBR (n= 22, 3)	2.4 (1.4 to 3.0)	2.8 (2.8 to 6.1)

No statistical analyses for this end point

Secondary: Time to Disease Progression

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End point title

Time to Disease Progression ^[24]

End point description

Time to disease progression was defined as the time from the date of the first dose of study drug (overall reference start date) to the date of the first occurrence of evaluable PD. Time to disease progression was estimated using Kaplan-Meier statistics. The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had experienced disease progression at the time of EOT (29 October 2019) were reported.

End point type

Secondary

End point timeframe

Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 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 patients who were treated at the MTD were analysed for this endpoint.

End point values	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	45	13
Units: months
median (confidence interval 95%)	6.5 (3.7 to 9.3)	4.4 (2.8 to 12.2)

No statistical analyses for this end point

Secondary: Median Progression-Free Survival (PFS)

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End point title

Median Progression-Free Survival (PFS) ^[25]

End point description

The PFS was defined as the time from the date of the first dose of melflufen (overall reference start date) to the date of the first occurrence of any disease response assessment available for PD or death. The PFS was estimated using Kaplan-Meier statistics. The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had information about PFS at the time of EOT (29 October 2019) were reported.

End point type

Secondary

End point timeframe

Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 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 patients who were treated at the MTD were analysed for this endpoint.

End point values	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	45	13
Units: months
median (confidence interval 95%)	5.7 (3.7 to 9.2)	4.4 (2.8 to 7.6)

No statistical analyses for this end point

Secondary: Median Overall Survival (OS)

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End point title

Median Overall Survival (OS) ^[26]

End point description

The OS was defined as the time from the date of the first dose of melflufen (overall reference start date) to death. The OS was estimated using Kaplan-Meier statistics. The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had information about OS at the time of EOT (29 October 2019) were reported.

End point type

Secondary

End point timeframe

From baseline until death. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 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 patients who were treated at the MTD were analysed for this endpoint.

End point values	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	45	13
Units: months
median (confidence interval 95%)	20.7 (11.8 to 41.3)	15.5 (4.9 to 23.4)

No statistical analyses for this end point

Secondary: Time to First Subsequent Treatment

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End point title

Time to First Subsequent Treatment ^[27]

End point description

Time to first subsequent treatment start was defined as the time from the date of the actual end of treatment to the date of the first subsequent treatment. Time to first subsequent treatment was estimated using Kaplan-Meier statistics. The mITT Analysis Set included all patients considered to be valid for the Safety Analysis Set and who received at least 1 dose of study drug at the MTD as the initial dose. Only patients who had information about first subsequent treatment at the time of EOT (29 October 2019) were reported. 9999 = upper limit of confidence could not be calculated as it was not reached.

End point type

Secondary

End point timeframe

From baseline until start of first subsequent treatment. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 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 patients who were treated at the MTD were analysed for this endpoint.

End point values	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	45	13
Units: months
median (confidence interval 95%)	10.5 (7.9 to 12.2)	10.7 (5.3 to 9999)

No statistical analyses for this end point

Secondary: Number of Patients With Treatment Emergent Adverse Events (TEAEs)

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End point title

Number of Patients With Treatment Emergent Adverse Events (TEAEs)

End point description

An adverse event (AE) was any untoward medical occurrence in a study patient administered an investigational product and that does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was defined as any AE, occurring at any dose, that met any 1 or more of the following criteria: fatal or immediately life-threatening; persistent or significant disability/incapacity; congenital anomaly/birth defect; medically significant; requires inpatient hospitalization or prolongation of existing hospitalization; or other important medical event. TEAEs were defined as AEs that started or worsened on or after first dose of study drug (overall reference start date) up to and including actual EOT date. The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study drug. TESAEs = Treatment emergent serious adverse events. 99999 = not applicable.

End point type

Secondary

End point timeframe

From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months.

End point values	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Number of subjects analysed	4	7	6	6	45	13
Units: participants
TEAEs	4	7	6	6	45	13
TEAEs leading to death	0	1	0	0	3	0
TESAEs	3	4	2	4	17	9
DLT TEAEs	0	0	0	4	99999	99999
TEAEs related to melflufen and/or dexamethasone	4	7	6	6	45	13
TESAEs related to melflufen and/or dexamethasone	3	4	2	4	17	9

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months.

Adverse event reporting additional description

The Safety Analysis Set included all patients who received at least 1 dose, or part thereof, of study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Phase I: Melflufen 15 mg + Dexamethasone

Reporting group description

Patients were treated with 15 mg melflufen as IV infusion on Day 1 and 40 mg dexamethasone oral tablet or IV infusion on Days 1, 8 and 15 of each 21-day treatment cycle. Patients could continue receiving treatment for up to 8 cycles or until they experienced unacceptable toxicity, disease progression, withdrew consent, and/or the study drug was discontinued at the discretion of the Investigator.

Reporting group title

Phase I: Melflufen 25 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I: Melflufen 40 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I: Melflufen 55 mg + Dexamethasone

Reporting group description

Reporting group title

Phase I + II: Melflufen 40 mg + Dexamethasone

Reporting group description

Reporting group title

Phase II: Melflufen 40 mg (Single Agent)

Reporting group description

Serious adverse events	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 4 (75.00%)	4 / 7 (57.14%)	2 / 6 (33.33%)	4 / 6 (66.67%)	17 / 45 (37.78%)	9 / 13 (69.23%)
number of deaths (all causes)	3	5	2	5	30	10
number of deaths resulting from adverse events	0	1	0	0	3	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasmacytoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 45 (4.44%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
White blood cell count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Injury, poisoning and procedural complications
Spinal compression fracture
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Nervous system disorders
Spinal cord compression
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	3 / 6 (50.00%)	2 / 45 (4.44%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	2 / 13 (15.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	10 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 4 (25.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	1 / 1	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	0 / 0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Renal failure
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	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	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Bone lesion
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Spinal disorder
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Cystitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Pseudomonal sepsis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Sepsis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Pneumonia
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	5 / 45 (11.11%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2	4 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperphosphataemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Phase I: Melflufen 15 mg + Dexamethasone	Phase I: Melflufen 25 mg + Dexamethasone	Phase I: Melflufen 40 mg + Dexamethasone	Phase I: Melflufen 55 mg + Dexamethasone	Phase I + II: Melflufen 40 mg + Dexamethasone	Phase II: Melflufen 40 mg (Single Agent)
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 4 (100.00%)	7 / 7 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	45 / 45 (100.00%)	12 / 13 (92.31%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasmacytoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Vascular disorders
Flushing
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Haematoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Hypertension
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	3	0
Hypotension
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	2	1
Thrombophlebitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Venous thrombosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
General disorders and administration site conditions
Application site erosion
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Asthenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	14 / 45 (31.11%)	0 / 13 (0.00%)
occurrences all number	0	0	0	3	46	0
Chest pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	1	0
Chills
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Fatigue
subjects affected / exposed	1 / 4 (25.00%)	3 / 7 (42.86%)	3 / 6 (50.00%)	2 / 6 (33.33%)	13 / 45 (28.89%)	4 / 13 (30.77%)
occurrences all number	1	5	7	2	20	4
Feeling cold
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Hyperthermia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	1	1	1	0
Influenza like illness
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	4 / 45 (8.89%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	4	0
Mucosal inflammation
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 6 (16.67%)	6 / 45 (13.33%)	0 / 13 (0.00%)
occurrences all number	0	1	1	2	8	0
Mucous membrane disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Non-cardiac chest pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	2	1
Pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Pyrexia
subjects affected / exposed	2 / 4 (50.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	16 / 45 (35.56%)	0 / 13 (0.00%)
occurrences all number	2	0	2	1	19	0
Immune system disorders
Immune system disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Reproductive system and breast disorders
Erectile Dysfunction
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	8 / 45 (17.78%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	11	0
Dysphonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	2	0
Dyspnoea
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)	6 / 45 (13.33%)	1 / 13 (7.69%)
occurrences all number	1	0	2	2	6	1
Dyspnoea exertional
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	6 / 45 (13.33%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1	8	1
Oropharyngeal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	2	0
Pleural effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Productive cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	1	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	1	0
Confusional state
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	1	0
Depression
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Insomnia
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	6 / 45 (13.33%)	0 / 13 (0.00%)
occurrences all number	1	0	1	0	8	0
Mood altered
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	1	1
Nervousness
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	1	0
Restlessness
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Sleep disorder
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	1	1	0	2	0
Product issues
Device occlusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	2	0
Blood creatinine increased
subjects affected / exposed	0 / 4 (0.00%)	3 / 7 (42.86%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	3	0	0	1	0
Blood glucose increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
C-reactive protein increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	4 / 45 (8.89%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	5	0
CD4 lymphocytes decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	3	0
Cardiac murmur
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	1	0
Fibrin d dimer increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
International normalised ratio increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	4	0
Lymphocyte count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Protein total increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Red blood cell count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Urine output decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Vitamin B12 decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Weight decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	2	0
Weight increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
White blood cell count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	4 / 45 (8.89%)	3 / 13 (23.08%)
occurrences all number	0	0	1	1	4	3
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	3	0
Humerus fracture
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Infusion related reaction
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Joint dislocation
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Spinal compression fracture
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Thermal burn
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Cardiac disorders
Mitral valve disease mixed
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Palpitations
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0	3	0
Sinus tachycardia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Dizziness
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	4 / 45 (8.89%)	0 / 13 (0.00%)
occurrences all number	0	0	1	1	4	0
Headache
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	6 / 45 (13.33%)	0 / 13 (0.00%)
occurrences all number	0	0	1	2	8	0
Neuropathy peripheral
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	4 / 45 (8.89%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	4	0
Paraesthesia
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	1	0
Presyncope
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Somnolence
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Tremor
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 4 (75.00%)	4 / 7 (57.14%)	2 / 6 (33.33%)	3 / 6 (50.00%)	29 / 45 (64.44%)	5 / 13 (38.46%)
occurrences all number	3	5	4	6	96	14
Anaemia vitamin B12 deficiency
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Bone marrow failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Increased tendency to bruise
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0	0
Leukopenia
subjects affected / exposed	1 / 4 (25.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	2	1	0	0	1	0
Lymphopenia
subjects affected / exposed	1 / 4 (25.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 45 (6.67%)	1 / 13 (7.69%)
occurrences all number	2	1	1	0	3	3
Neutropenia
subjects affected / exposed	1 / 4 (25.00%)	3 / 7 (42.86%)	3 / 6 (50.00%)	6 / 6 (100.00%)	31 / 45 (68.89%)	9 / 13 (69.23%)
occurrences all number	1	7	12	26	115	25
Pancytopenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	1	0	1	1	0
Thrombocytopenia
subjects affected / exposed	2 / 4 (50.00%)	6 / 7 (85.71%)	4 / 6 (66.67%)	5 / 6 (83.33%)	33 / 45 (73.33%)	9 / 13 (69.23%)
occurrences all number	2	9	26	35	154	30
Ear and labyrinth disorders
Ear haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Eye disorders
Vision blurred
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	6	0
Abdominal hernia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Abdominal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	4	0
Abdominal pain upper
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	1	0	1	5	0
Aerophagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Constipation
subjects affected / exposed	2 / 4 (50.00%)	3 / 7 (42.86%)	1 / 6 (16.67%)	0 / 6 (0.00%)	7 / 45 (15.56%)	1 / 13 (7.69%)
occurrences all number	2	3	1	0	8	1
Diarrhoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	4 / 6 (66.67%)	9 / 45 (20.00%)	2 / 13 (15.38%)
occurrences all number	0	0	3	5	10	2
Dyspepsia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	3	0
Gastric disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	3	0
Gastrointestinal disorder
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Nausea
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	4 / 6 (66.67%)	4 / 6 (66.67%)	12 / 45 (26.67%)	2 / 13 (15.38%)
occurrences all number	1	0	6	5	14	3
Oral pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	1	0
Stomatitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	3	0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)	5 / 45 (11.11%)	1 / 13 (7.69%)
occurrences all number	0	0	2	2	5	1
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Blood blister
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Ecchymosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Erythema
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	1	0
Hyperhidrosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	1 / 13 (7.69%)
occurrences all number	0	0	1	0	1	1
Night sweats
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Petechiae
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	1	1	0	1	0
Rash
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	0	1	1	3	0
Skin lesion
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	2	0	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	1 / 13 (7.69%)
occurrences all number	0	0	1	0	1	1
Haematuria
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Renal failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	1	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	5 / 45 (11.11%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	5	0
Back pain
subjects affected / exposed	0 / 4 (0.00%)	3 / 7 (42.86%)	0 / 6 (0.00%)	1 / 6 (16.67%)	6 / 45 (13.33%)	2 / 13 (15.38%)
occurrences all number	0	3	0	1	9	2
Bone pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	6 / 45 (13.33%)	0 / 13 (0.00%)
occurrences all number	0	0	1	1	8	0
Bursitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Flank pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Muscle spasms
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	5 / 45 (11.11%)	0 / 13 (0.00%)
occurrences all number	0	1	1	0	5	0
Muscular weakness
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	2	0	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	4	0
Myalgia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	2	0
Myopathy
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Neck pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Osteoporosis
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Spinal pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	4	0
Synovial cyst
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Infections and infestations
Acarodermatitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Administration site infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Bronchitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0	2	0
Candida infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0	0
Conjunctivitis bacterial
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Cystitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Enterococcal infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Eye infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Furuncle
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastroenteritis viral
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Gingivitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Herpes virus infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Herpes zoster
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	2	0
Infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	4 / 45 (8.89%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	5	0
Influenza
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	1	0
Laryngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Lower respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Lung infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Mucosal infection
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	4	0
Oral candidiasis
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	0	0
Oral fungal infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	2	0
Oral herpes
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	2	1
Periodontitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 45 (6.67%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	3	1
Sinusitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Skin infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	2	0
Upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	5 / 45 (11.11%)	0 / 13 (0.00%)
occurrences all number	0	1	2	0	6	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	0	1
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	1	0
Decreased appetite
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	2 / 6 (33.33%)	1 / 6 (16.67%)	3 / 45 (6.67%)	1 / 13 (7.69%)
occurrences all number	0	1	4	1	5	1
Dehydration
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	2	0
Hyperglycaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	4 / 45 (8.89%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	13	0
Hyperuricaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	1 / 13 (7.69%)
occurrences all number	0	0	0	0	1	1
Hypoalbuminaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0	1	0
Hypocalcaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	4	0
Hypokalaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 45 (4.44%)	0 / 13 (0.00%)
occurrences all number	0	0	0	2	3	0
Hypomagnesaemia
subjects affected / exposed	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 45 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0	0	0
Hyponatraemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 45 (6.67%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	3	0
Hypercalcaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 45 (2.22%)	0 / 13 (0.00%)
occurrences all number	0	0	0	0	2	0

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Were there any global substantial amendments to the protocol? Yes

02 Oct 2013

MR was included in the OR assessment for evaluable patients. Lymphopenia was excluded from the definition of DLT. Criteria for assessment of renal function was clarified. Clarified the acceptable infusion devices permitted for melflufen infusion and that initially a patient would receive a screening number and treatment assignment would be communicated via email and/or fax. To be evaluable for response, patients were to have received at least 2 cycles of therapy defined as at least 2 doses of melflufen. Study drug would not be modified based on QTcF evaluations collected by the Holter Monitor. A typographical error for the duration of Holter monitoring was corrected from 210 minutes to 120 minutes. Instruction was added for preparing the study drug to shake the vial to disintegrate the freeze dried powder cake to a powder before adding the glucose solution. Table of assessments was updated to distinguish which evaluations of bone marrow aspirate would be conducted by the contract research organization and which would be performed locally. Also, results of the local laboratory could be used for entry criteria and treatment decisions while the central laboratory results were awaited. Serum sample for correlative testing was removed. Reporting timelines for AEs and SAEs were clarified.

07 May 2014

Platelet transfusion in absence of clinically significant bleeding or an urgent need to prevent bleeding (Grade 4 that required a platelet transfusion) was not considered DLT. Platelet transfusion within 7 days of registration was allowed (which previously was 14 days). To facilitate retreatment, use of growth factors was allowed in Cycle 1. To begin the treatment, Cycle 1, Day 1 values were required within the guidelines of entry criteria. Retreatment of patients with a platelet count of 50,000 per cube millimeter regardless of level of plasma cell infiltration in the bone marrow at baseline was allowed. Following Cycle 2 Day 1, clinic visits were made optional at the Investigator’s discretion as long as the complete blood count and toxicity were reviewed by the Investigator on Days 8 and 15 of the cycle (that is, local laboratory could be used by the patients). Patients continuing beyond Cycle 8 were to follow the same schedule of assessments as required from Cycle 2 to Cycle 8. The additional dose level of 70 mg of melflufen was added to the Phase I in the study. In case a 70 mg dose would be needed, it would be prepared from 2 boxes of 40 mg (volume would be calculated to ensure correct dose is given). The term ‘patient registration’ was changed to ‘initiation of therapy’. The study timeline was extended and 1 more site for pharmacokinetic sampling was added.

27 Jan 2015

For the Phase IIa, patient sample size was increased to 55. The response analysis was changed to assume an ORR of 50%. Disease assessment was added to Cycle 1 Day 1. The difference between ORR (≥ PR) and CBR (≥ MR) was clarified. Inclusion criteria that prior therapy must include both lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of therapy was added.

20 Jun 2015

The cycle of melflufen was increased from 21 to 28 days. The dose of dexamethasone was reduced from 40 mg weekly to a maximum of 24 mg per cycle in a single agent cohort.

06 Jul 2016

In addition to the vials available, a 20 mg vial was introduced in the ongoing study. It was clarified that the Data Safety Monitoring Committee was continuously reviewing the data and could make recommendations at any time to continue to treat patients with single agent melflufen or recommend that melflufen be given in combination with 40 mg dexamethasone weekly.

02 Nov 2018

The follow up period was extended beyond 24 months to allow an additional assessment of OS.

Were there any global interruptions to the trial? No

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

Study is terminated and long-term follow-up ended due to Sponsor decision.

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Clinical trials

Clinical Trial Results:
An Open-Label Phase I/IIa Study of the Safety and Efficacy of Melphalan-flufenamide (Melflufen) and Dexamethasone Combination for Patients with Relapsed and/or Relapsed-Refractory Multiple Myeloma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Patients Who Achieved Best Overall Disease Response

Primary: Percentage of Patients Who Achieved Best Overall Disease Response

Primary: Overall Response Rate

Primary: Overall Response Rate

Primary: Clinical Benefit Response Rate (CBRR)

Primary: Clinical Benefit Response Rate (CBRR)

Secondary: Duration of Disease Response (DOR)

Secondary: Duration of Disease Response (DOR)

Secondary: Time to Disease Response in Patients Who Achieved OR and CBR

Secondary: Time to Disease Response in Patients Who Achieved OR and CBR

Secondary: Time to Disease Progression

Secondary: Time to Disease Progression

Secondary: Median Progression-Free Survival (PFS)

Secondary: Median Progression-Free Survival (PFS)

Secondary: Median Overall Survival (OS)

Secondary: Median Overall Survival (OS)

Secondary: Time to First Subsequent Treatment

Secondary: Time to First Subsequent Treatment

Secondary: Number of Patients With Treatment Emergent Adverse Events (TEAEs)

Secondary: Number of Patients With Treatment Emergent Adverse Events (TEAEs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: An Open-Label Phase I/IIa Study of the Safety and Efficacy of Melphalan-flufenamide (Melflufen) and Dexamethasone Combination for Patients with Relapsed and/or Relapsed-Refractory Multiple Myeloma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Patients Who Achieved Best Overall Disease Response

Primary: Percentage of Patients Who Achieved Best Overall Disease Response

Primary: Overall Response Rate

Primary: Overall Response Rate

Primary: Clinical Benefit Response Rate (CBRR)

Primary: Clinical Benefit Response Rate (CBRR)

Secondary: Duration of Disease Response (DOR)

Secondary: Duration of Disease Response (DOR)

Secondary: Time to Disease Response in Patients Who Achieved OR and CBR

Secondary: Time to Disease Response in Patients Who Achieved OR and CBR

Secondary: Time to Disease Progression

Secondary: Time to Disease Progression

Secondary: Median Progression-Free Survival (PFS)

Secondary: Median Progression-Free Survival (PFS)

Secondary: Median Overall Survival (OS)

Secondary: Median Overall Survival (OS)

Secondary: Time to First Subsequent Treatment

Secondary: Time to First Subsequent Treatment

Secondary: Number of Patients With Treatment Emergent Adverse Events (TEAEs)

Secondary: Number of Patients With Treatment Emergent Adverse Events (TEAEs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An Open-Label Phase I/IIa Study of the Safety and Efficacy of Melphalan-flufenamide (Melflufen) and Dexamethasone Combination for Patients with Relapsed and/or Relapsed-Refractory Multiple Myeloma