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Clinical Trial Results:
A randomized, open-label, Phase 2 study of nanoliposomal irinotecan (nal-IRI)-containing regimens versus nab-paclitaxel plus gemcitabine in patients with previously untreated, metastatic pancreatic adenocarcinoma

Summary
EudraCT number	2015-003086-28
Trial protocol	SE ES GB BE FR IT
Global end of trial date	15 Feb 2021

Results information
Results version number	v1(current)
This version publication date	06 Jun 2022
First version publication date	06 Jun 2022
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

MM-398-07-02-03

ISRCTN number

US NCT number

NCT02551991

WHO universal trial number (UTN)

Other trial identifiers

IND No. : 102799

Sponsor organisation name

Ipsen Bioscience, Inc.

Sponsor organisation address

650 East Kendall Street, Cambridge, Massachusetts, United States, 02142

Public contact

Medical Director, Ipsen Bioscience, Inc., clinical.trials@ipsen.com

Scientific contact

Medical Director, Ipsen Bioscience, Inc., clinical.trials@ipsen.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

15 Feb 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Feb 2021

Was the trial ended prematurely?

Main objective of the trial

• To evaluate the safety and tolerability of irinotecan liposome injection + 5-fluorouracil (5-FU)/leucovorin (LV) + oxaliplatin. • To characterize dose limiting toxicities (DLTs) associated with irinotecan liposome injection +5-FU/LV + oxaliplatin and determine the recommended dose of the triplet combination for future development.

Protection of trial subjects

The study was conducted under the provisions of the Declaration of Helsinki, in accordance with the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice and in compliance with Independent Ethics Committees/Institutional Review Boards and informed consent regulations.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Oct 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 17

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

United States: 33

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 Phase 2 non-comparative, open-label study was conducted in previously untreated metastatic pancreatic cancer participants at 15 investigational sites.

Screening details

This study was divided into 2 parts: Part 1 (dose exploration [Part 1A] followed by dose expansion [Part 1B] of irinotecan liposome injection + 5-FU/LV + oxaliplatin regimen) and Part 2 (comparison of irinotecan liposome injection-containing regimen versus [vs] nab-paclitaxel plus gemcitabine). Overall, 56 participants were enrolled in this study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Dose Exploration: Cohort 1

Arm description

Participants received irinotecan liposome injection 70 milligram per square meter (mg/m^2) followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

Irinotecan liposome injection

Investigational medicinal product code

MM-398

Other name

Nal-IRI, BAX2398, PEP02, Onivyde

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan liposome injection was administered as an IV infusion over 90 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was administered as an IV infusion over 120 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

LV was administered as an IV infusion over 30 minutes (±5 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

5-FU

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

5-FU was administered as an IV infusion over 46-hours (±60 minutes) on Days 1 and 15 of each 28-day cycle.

Dose Exploration: Cohort -1

Arm description

Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

Irinotecan liposome injection

Investigational medicinal product code

MM-398

Other name

Nal-IRI, BAX2398, PEP02, Onivyde

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan liposome injection was administered as an IV infusion over 90 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was administered as an IV infusion over 120 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

LV was administered as an IV infusion over 30 minutes (±5 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

5-FU

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

5-FU was administered as an IV infusion over 46-hours (±60 minutes) on Days 1 and 15 of each 28-day cycle.

Dose Exploration: Cohort -2B

Arm description

Participants received irinotecan liposome injection 50 mg/m^2 followed by oxaliplatin 85 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

Irinotecan liposome injection

Investigational medicinal product code

MM-398

Other name

Nal-IRI, BAX2398, PEP02, Onivyde

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan liposome injection was administered as an IV infusion over 90 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was administered as an IV infusion over 120 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

LV was administered as an IV infusion over 30 minutes (±5 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

5-FU

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

5-FU was administered as an IV infusion over 46-hours (±60 minutes) on Days 1 and 15 of each 28-day cycle.

Dose Exploration: Cohort -3

Arm description

Participants received irinotecan liposome injection 55 mg/m^2 followed by oxaliplatin 70 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Arm type

Experimental

Investigational medicinal product name

Irinotecan liposome injection

Investigational medicinal product code

MM-398

Other name

Nal-IRI, BAX2398, PEP02, Onivyde

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan liposome injection was administered as an IV infusion over 90 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was administered as an IV infusion over 120 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

LV was administered as an IV infusion over 30 minutes (±5 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

5-FU

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

5-FU was administered as an IV infusion over 46-hours (±60 minutes) on Days 1 and 15 of each 28-day cycle.

Dose Expansion: Cohort -1

Arm description

Arm type

Experimental

Investigational medicinal product name

Irinotecan liposome injection

Investigational medicinal product code

MM-398

Other name

Nal-IRI, BAX2398, PEP02, Onivyde

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Irinotecan liposome injection was administered as an IV infusion over 90 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin was administered as an IV infusion over 120 minutes (±10 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

LV was administered as an IV infusion over 30 minutes (±5 minutes) on Days 1 and 15 of each 28-day cycle.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

5-FU

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

5-FU was administered as an IV infusion over 46-hours (±60 minutes) on Days 1 and 15 of each 28-day cycle.

Number of subjects in period 1	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1
Started	7	7	10	7	25
Completed	0	0	0	0	0
Not completed	7	7	10	7	25
Consent withdrawn by subject	1	-	-	-	2
Death	5	7	8	7	17
Sponsor Decision	1	-	1	-	5
Unspecified	-	-	-	-	1
Lost to follow-up	-	-	1	-	-

Baseline characteristics

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Reporting group title

Dose Exploration: Cohort 1

Reporting group description

Reporting group title

Dose Exploration: Cohort -1

Reporting group description

Reporting group title

Dose Exploration: Cohort -2B

Reporting group description

Reporting group title

Dose Exploration: Cohort -3

Reporting group description

Reporting group title

Dose Expansion: Cohort -1

Reporting group description

Reporting group values	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Total
Number of subjects	7	7	10	7	25	56
Age categorical
Units: Subjects
< 65 years	4	4	3	4	19	34
>= 65 years	3	3	7	3	6	22
Gender categorical
Units: Subjects
Female	6	4	2	2	14	28
Male	1	3	8	5	11	28
Race
Units: Subjects
White	6	7	9	7	21	50
Black or African American	0	0	0	0	2	2
Asian	1	0	1	0	1	3
Not Reportable	0	0	0	0	1	1
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	0	0	4	4
Not Hispanic or Latino	7	7	10	7	21	52

End points

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Reporting group title

Dose Exploration: Cohort 1

Reporting group description

Reporting group title

Dose Exploration: Cohort -1

Reporting group description

Reporting group title

Dose Exploration: Cohort -2B

Reporting group description

Reporting group title

Dose Exploration: Cohort -3

Reporting group description

Reporting group title

Dose Expansion: Cohort -1

Reporting group description

Subject analysis set title

Cohort -1: Pooled

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT)

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End point title

Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT) ^[1] ^[2]

End point description

Adverse events (AEs) were considered to be DLTs if they occurred during the safety evaluation period (i.e, 28 days of Cycle 1; or 14 days after the second dose of study treatment if there was a treatment delay) and were deemed related to the study treatment regimen. Any AE that was related to disease progression was not considered a DLT. Safety population included participants who received at least 1 dose of any study treatment.

End point type

Primary

End point timeframe

From the start of the first study treatment (Cycle 1 Day 1) up to 14 days after the second dose of study treatment, maximum of 42 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 descriptive statistical analysis was performed for the primary 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 participants treated in Part 1A (dose exploration) were analyzed for the primary endpoint.

End point values	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3
Number of subjects analysed	7	7	10	7
Units: participants	2	1	2	0

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)

End point description

The PFS was defined as the time from date of first study treatment to the first documented radiographical progression of disease (PD), per investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, or death from any cause, whichever comes first. The PFS was calculated using Kaplan-Meier technique. Safety population included participants who received at least 1 dose of any study treatment. 99999= Upper limit of confidence interval was not evaluable.

End point type

Secondary

End point timeframe

RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, end of treatment (EoT) visit, then every 2 months thereafter (maximum of 278 weeks).

End point values	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Number of subjects analysed	7	7	10	7	25	32
Units: months
number (confidence interval 95%)	9.7 (2.96 to 99999)	32.3 (0.53 to 99999)	9.2 (0.46 to 99999)	3.8 (1.22 to 5.78)	9.2 (7.59 to 11.20)	9.2 (7.59 to 11.96)

No statistical analyses for this end point

Secondary: Best Overall Response (BOR)

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End point title

Best Overall Response (BOR)

End point description

The BOR was defined as the best response (complete response [CR] + partial response [PR] + stable disease [SD]) recorded from the start of study treatment until disease progression or start of new anticancer therapy. Safety population included participants who received at least 1 dose of any study treatment.

End point type

Secondary

End point timeframe

RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).

End point values	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Number of subjects analysed	7	7	10	7	25	32
Units: participants	2	6	4	4	20	26

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR)

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End point title

Overall Response Rate (ORR)

End point description

The ORR was defined as the percentage of participants with a BOR characterized as either a CR or PR relative to the total number of evaluable participants. Evaluable participants were defined as treated participants with measurable disease at baseline. Safety population included participants who received at least 1 dose of any study treatment.

End point type

Secondary

End point timeframe

RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).

End point values	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Number of subjects analysed	7	7	10	7	25	32
Units: percentage of participants
number (confidence interval 95%)	0 (0 to 41.0)	42.9 (9.9 to 81.6)	30.0 (6.7 to 65.2)	14.3 (0.4 to 57.9)	32.0 (14.9 to 53.5)	34.4 (18.6 to 53.2)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR)

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End point title

Disease Control Rate (DCR)

End point description

The DCR was defined as percentage of participants with CR or PR or SD, per RECIST Version 1.1 relative to total number of treated participants with measurable disease at baseline. Safety population included participants who received at least 1 dose of any study treatment.

End point type

Secondary

End point timeframe

At Week 16

End point values	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Number of subjects analysed	7	7	10	7	25	32
Units: percentage of participants
number (confidence interval 95%)	42.9 (9.9 to 81.6)	71.4 (29.0 to 96.3)	40.0 (12.2 to 73.8)	28.6 (3.7 to 71.0)	72.0 (50.6 to 87.9)	71.9 (53.3 to 86.3)

No statistical analyses for this end point

Secondary: Median Overall Survival (OS)

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End point title

Median Overall Survival (OS)

End point description

The OS was the time from date of first study treatment to the date of death from any cause. Participant survival data were collected from all available sources. The OS was calculated using Kaplan-Meier technique. Safety population included participants who received at least 1 dose of any study treatment.

End point type

Secondary

End point timeframe

RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).

End point values	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Number of subjects analysed	7	7	10	7	25	32
Units: months
median (confidence interval 95%)	12.6 (3.98 to 21.03)	12.5 (0.53 to 12.71)	16.6 (0.69 to 26.74)	5.8 (1.35 to 14.65)	12.7 (8.18 to 23.66)	12.6 (8.74 to 19.12)

No statistical analyses for this end point

Secondary: Median Duration of Response (DoR)

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End point title

Median Duration of Response (DoR)

End point description

The DoR was defined as the time from the first date of response (CR or PR) to first date of documented radiographical PD, per investigator using RECIST Version 1.1. This only applied to participants with CR or PR. If a participant was given a new anticancer therapy prior to first response, DoR was not calculated. The DoR was calculated using Kaplan-Meier technique. Safety population included participants who received at least 1 dose of any study treatment. Only participants with DoR events were analyzed for this outcome measure. -9999= Median was not evaluable, -99999= Lower limit of confidence interval was not evaluable, and 99999= Upper limit of confidence interval was not evaluable.

End point type

Secondary

End point timeframe

RECIST assessments performed at baseline (within 28 days before start of study treatment), every 8 weeks after first dose, EoT visit, then every 2 months thereafter (maximum of 278 weeks).

End point values	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1	Cohort -1: Pooled
Number of subjects analysed	0 ^[3]	2	1	0 ^[4]	4	6
Units: months
median (confidence interval 95%)	( to )	28.4 (3.52 to 99999)	-9999 (-99999 to 16.39)	( to )	9.4 (2.20 to 99999)	9.4 (3.52 to 99999)

Notes
[3] - No participants with DoR events.
[4] - No participants with DoR events.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Treatment-emergent adverse events are reported from the time of first study treatment administration (Day 1) up to 30 days after the date of last study treatment administration or until the start of alternative anticancer therapy, approximately 1008 days.

Adverse event reporting additional description

Safety population included participants who received at least 1 dose of any study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Dose Exploration: Cohort 1

Reporting group description

Participants received irinotecan liposome injection 70 mg/m^2 followed by oxaliplatin 60 mg/m^2 followed by LV 400 mg/m^2 and then 5-FU 2400 mg/m^2 IV infusion on Days 1 and 15 of each 28-day cycle until disease progression, death, unacceptable study treatment-related toxicity or withdrawal of consent.

Reporting group title

Dose Exploration: Cohort -1

Reporting group description

Reporting group title

Dose Exploration: Cohort -2B

Reporting group description

Reporting group title

Dose Exploration: Cohort -3

Reporting group description

Reporting group title

Dose Expansion: Cohort -1

Reporting group description

Serious adverse events	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 7 (85.71%)	2 / 7 (28.57%)	7 / 10 (70.00%)	4 / 7 (57.14%)	15 / 25 (60.00%)
number of deaths (all causes)	5	7	8	7	17
number of deaths resulting from adverse events	0	1	1	1	2
Injury, poisoning and procedural complications
Subdural haematoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (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
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Hypotension
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (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
Orthostatic hypotension
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (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
Cardiac disorders
Arteriospasm coronary
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (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
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia of malignant disease
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (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
General disorders and administration site conditions
Disease progression
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Fatigue
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (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
Pyrexia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	1 / 10 (10.00%)	1 / 7 (14.29%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 10 (20.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	3 / 7 (42.86%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	2 / 7 (28.57%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Enterocolitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (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
Duodenal ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (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
Enteritis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (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
Intestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Large intestinal obstruction
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (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
Malignant gastrointestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Pancreatitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Stomatitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Biliary dilatation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Cholangitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (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
Nephrolithiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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 sepsis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (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
Neutropenic sepsis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (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
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Sepsis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
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
Hypokalaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	Dose Exploration: Cohort 1	Dose Exploration: Cohort -1	Dose Exploration: Cohort -2B	Dose Exploration: Cohort -3	Dose Expansion: Cohort -1
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	7 / 7 (100.00%)	10 / 10 (100.00%)	7 / 7 (100.00%)	25 / 25 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	2 / 7 (28.57%)	4 / 7 (57.14%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	5	8	0	0	0
Deep vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences all number	0	1	0	0	3
Hypotension
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 10 (20.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	1	0	3	1	0
Orthostatic hypotension
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	3	0	0	0	0
Embolism
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Vascular occlusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	5 / 7 (71.43%)	5 / 7 (71.43%)	7 / 10 (70.00%)	5 / 7 (71.43%)	16 / 25 (64.00%)
occurrences all number	9	10	13	6	21
Pyrexia
subjects affected / exposed	3 / 7 (42.86%)	1 / 7 (14.29%)	2 / 10 (20.00%)	1 / 7 (14.29%)	5 / 25 (20.00%)
occurrences all number	3	1	2	1	14
Asthenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	8 / 25 (32.00%)
occurrences all number	0	0	1	1	15
Oedema peripheral
subjects affected / exposed	3 / 7 (42.86%)	2 / 7 (28.57%)	1 / 10 (10.00%)	1 / 7 (14.29%)	2 / 25 (8.00%)
occurrences all number	3	2	3	1	2
Chills
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	3	0	1	0	2
Mucosal inflammation
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences all number	0	1	0	0	7
Malaise
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	2	0	0	1
Temperature intolerance
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	0	0	2
Axillary pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Catheter site erythema
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Catheter site extravasation
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Catheter site haemorrhage
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Catheter site pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Cyst
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Disease progression
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Localised oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Reproductive system and breast disorders
Vulvovaginal swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	2 / 10 (20.00%)	2 / 7 (28.57%)	2 / 25 (8.00%)
occurrences all number	2	0	3	2	2
Cough
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 10 (20.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	1	0	6	0	2
Pulmonary embolism
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	2 / 7 (28.57%)	2 / 25 (8.00%)
occurrences all number	0	0	1	3	2
Epistaxis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences all number	0	0	1	0	3
Hiccups
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	0	0	2
Nasal congestion
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	3	0	0	0
Sinus congestion
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	1	0	1
Catarrh
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Dysphonia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Dyspnoea exertional
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Haemoptysis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	0	0	1	0
Hypoxia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	0	0	2	0
Laryngeal oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	6
Nasal dryness
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Pharyngeal inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Pneumonitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Respiratory failure
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 7 (14.29%)	5 / 7 (71.43%)	1 / 10 (10.00%)	1 / 7 (14.29%)	2 / 25 (8.00%)
occurrences all number	1	6	1	1	2
Insomnia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 10 (10.00%)	2 / 7 (28.57%)	5 / 25 (20.00%)
occurrences all number	1	0	1	2	6
Anxiety
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 10 (10.00%)	2 / 7 (28.57%)	3 / 25 (12.00%)
occurrences all number	1	0	1	2	3
Confusional state
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	0	0	0	1
Hallucination
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Irritability
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Investigations
Weight decreased
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	4 / 10 (40.00%)	2 / 7 (28.57%)	5 / 25 (20.00%)
occurrences all number	2	3	6	4	7
Alanine aminotransferase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	9 / 25 (36.00%)
occurrences all number	0	0	1	1	17
Aspartate aminotransferase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 10 (20.00%)	0 / 7 (0.00%)	9 / 25 (36.00%)
occurrences all number	0	0	2	0	15
Platelet count decreased
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 10 (10.00%)	0 / 7 (0.00%)	5 / 25 (20.00%)
occurrences all number	2	2	2	0	17
White blood cell count decreased
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	2 / 10 (20.00%)	0 / 7 (0.00%)	4 / 25 (16.00%)
occurrences all number	1	1	2	0	10
Neutrophil count decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	4 / 25 (16.00%)
occurrences all number	1	0	7	1	12
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	4 / 25 (16.00%)
occurrences all number	0	0	1	0	17
Blood bilirubin increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	4 / 25 (16.00%)
occurrences all number	0	0	0	0	4
Lymphocyte count decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences all number	0	0	1	0	23
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	0	0	2
Alanine aminotransferase
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	4
Blood magnesium decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Cardiac murmur
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Liver function test increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	0	0	1	0
Lung diffusion test decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Urine output decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	4	1	1	0	0
Contusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	1	0	1
Tooth fracture
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	1	0	1	0
Animal scratch
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Ligament sprain
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Skin abrasion
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Subdural haematoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	0	0	0	1
Arteriospasm coronary
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Palpitations
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Sinus tachycardia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 7 (28.57%)	2 / 7 (28.57%)	3 / 10 (30.00%)	2 / 7 (28.57%)	8 / 25 (32.00%)
occurrences all number	5	2	6	2	9
Neuropathy peripheral
subjects affected / exposed	1 / 7 (14.29%)	3 / 7 (42.86%)	2 / 10 (20.00%)	2 / 7 (28.57%)	7 / 25 (28.00%)
occurrences all number	1	6	3	5	11
Dysgeusia
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	2 / 10 (20.00%)	2 / 7 (28.57%)	4 / 25 (16.00%)
occurrences all number	2	2	2	2	5
Headache
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	1 / 10 (10.00%)	0 / 7 (0.00%)	4 / 25 (16.00%)
occurrences all number	2	1	1	0	4
Peripheral sensory neuropathy
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	3 / 10 (30.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	2	1	5	0	7
Taste disorder
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	2	0	0	0	2
Lethargy
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	0	0	0	1
Neurotoxicity
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	0	0	3
Cognitive disorder
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Dysaesthesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Hyperaesthesia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	0	0	1	0
Lhermitte's sign
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	2	0	0	0
Memory impairment
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	0	0	0
Syncope
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	2 / 7 (28.57%)	3 / 7 (42.86%)	5 / 10 (50.00%)	1 / 7 (14.29%)	10 / 25 (40.00%)
occurrences all number	4	13	6	2	29
Thrombocytopenia
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	4 / 10 (40.00%)	0 / 7 (0.00%)	9 / 25 (36.00%)
occurrences all number	0	10	4	0	18
Anaemia
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	3 / 10 (30.00%)	2 / 7 (28.57%)	7 / 25 (28.00%)
occurrences all number	2	1	5	2	35
Febrile neutropenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences all number	0	1	0	0	4
Leukocytosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences all number	0	0	0	0	3
Leukopenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	1 / 25 (4.00%)
occurrences all number	0	0	2	1	1
Neutrophilia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	0	0	2
Anaemia of malignant disease
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	0	0	1	0
Cytopenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Splenic infarction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Splenic vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	0	0	1	0
Eye disorders
Eye disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Eyelid oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Vision blurred
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	5 / 7 (71.43%)	6 / 7 (85.71%)	9 / 10 (90.00%)	5 / 7 (71.43%)	23 / 25 (92.00%)
occurrences all number	9	7	19	6	49
Diarrhoea
subjects affected / exposed	6 / 7 (85.71%)	5 / 7 (71.43%)	6 / 10 (60.00%)	6 / 7 (85.71%)	22 / 25 (88.00%)
occurrences all number	18	22	14	14	54
Vomiting
subjects affected / exposed	5 / 7 (71.43%)	4 / 7 (57.14%)	5 / 10 (50.00%)	3 / 7 (42.86%)	14 / 25 (56.00%)
occurrences all number	12	7	8	4	28
Constipation
subjects affected / exposed	3 / 7 (42.86%)	4 / 7 (57.14%)	4 / 10 (40.00%)	1 / 7 (14.29%)	13 / 25 (52.00%)
occurrences all number	3	9	5	2	22
Abdominal pain
subjects affected / exposed	2 / 7 (28.57%)	3 / 7 (42.86%)	3 / 10 (30.00%)	4 / 7 (57.14%)	8 / 25 (32.00%)
occurrences all number	5	5	3	6	16
Stomatitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	2 / 10 (20.00%)	1 / 7 (14.29%)	7 / 25 (28.00%)
occurrences all number	0	1	7	1	9
Abdominal distension
subjects affected / exposed	3 / 7 (42.86%)	2 / 7 (28.57%)	2 / 10 (20.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences all number	3	2	2	0	3
Dry mouth
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	1 / 10 (10.00%)	3 / 7 (42.86%)	3 / 25 (12.00%)
occurrences all number	4	1	1	3	3
Flatulence
subjects affected / exposed	0 / 7 (0.00%)	4 / 7 (57.14%)	2 / 10 (20.00%)	1 / 7 (14.29%)	1 / 25 (4.00%)
occurrences all number	0	5	2	1	1
Abdominal pain upper
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	1 / 10 (10.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	2	1	1	0	2
Haemorrhoids
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	0 / 10 (0.00%)	1 / 7 (14.29%)	2 / 25 (8.00%)
occurrences all number	1	3	0	1	2
Pancreatic failure
subjects affected / exposed	0 / 7 (0.00%)	3 / 7 (42.86%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 25 (4.00%)
occurrences all number	0	3	0	1	1
Colitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	2 / 7 (28.57%)	1 / 25 (4.00%)
occurrences all number	1	0	0	3	1
Dyspepsia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	4 / 25 (16.00%)
occurrences all number	0	0	0	0	6
Anal fissure
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	2 / 10 (20.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	3	0	0
Small intestinal obstruction
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 25 (4.00%)
occurrences all number	1	0	0	1	2
Toothache
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	1	0	0	2
Anal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	0	1	1	0
Dysphagia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	1	0	0	1	0
Enterocolitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	1	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	3	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	2	0	0	0
Proctalgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 10 (20.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	4	0	0
Abdominal pain lower
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Abdominal rigidity
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	4
Anal incontinence
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Anal inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Angular cheilitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Ascites
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	2	0	0
Duodenal ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	2	0	0
Enteritis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Epigastric discomfort
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	2	0	0	0
Eructation
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Faeces discoloured
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Gastritis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Gastrointestinal oedema
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Haematemesis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Intestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Large intestinal obstruction
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Large intestine perforation
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Malignant gastrointestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Odynophagia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Oesophageal ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	2
Oesophagitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Oral pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Pancreatitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Rectal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	2
Steatorrhoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Tongue discolouration
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Varices oesophageal
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Biliary dilatation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Cholangitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Cholecystitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Hepatotoxicity
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Portal vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 7 (14.29%)	3 / 7 (42.86%)	0 / 10 (0.00%)	1 / 7 (14.29%)	4 / 25 (16.00%)
occurrences all number	1	3	0	1	5
Dry skin
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	1	1	0	1
Rash
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	1	0	2
Pruritus
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	1	0	2
Decubitus ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	0	0	1	0
Ingrowing nail
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Nail discolouration
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Nail ridging
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Pain of skin
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Petechiae
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Prurigo
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	2 / 7 (28.57%)	0 / 25 (0.00%)
occurrences all number	0	0	0	2	0
Micturition urgency
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	0	0	0	1
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Nephrolithiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Oliguria
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Pollakiuria
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Ureterolithiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Urinary incontinence
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Urinary retention
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	0	0	0	1	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 10 (10.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	1	2	1	0	6
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences all number	0	0	0	0	3
Muscular weakness
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 25 (4.00%)
occurrences all number	1	0	0	1	1
Myalgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	3 / 25 (12.00%)
occurrences all number	0	0	0	0	3
Arthritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 25 (4.00%)
occurrences all number	0	0	0	1	1
Flank pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Joint stiffness
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Muscle spasms
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Neck pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Pain in extremity
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Periarthritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Infections and infestations
Oral candidiasis
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 10 (10.00%)	1 / 7 (14.29%)	2 / 25 (8.00%)
occurrences all number	1	2	1	1	2
Pneumonia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 10 (20.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	1	0	2	0	1
Nasopharyngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	1	0	1
Bacterial sepsis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Candida infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Clostridium difficile colitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Fungal infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Gingivitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	1	0	0	0
Helicobacter infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Herpes zoster
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	0	0	1	0	0
Neutropenic infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	2	0	0	0	0
Neutropenic sepsis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Paronychia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Pharyngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Sepsis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	2
Septic shock
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Tooth infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	2
Vulvovaginitis trichomonal
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	5 / 7 (71.43%)	6 / 7 (85.71%)	4 / 10 (40.00%)	3 / 7 (42.86%)	12 / 25 (48.00%)
occurrences all number	10	9	8	4	15
Hypokalaemia
subjects affected / exposed	4 / 7 (57.14%)	2 / 7 (28.57%)	5 / 10 (50.00%)	3 / 7 (42.86%)	12 / 25 (48.00%)
occurrences all number	5	3	6	11	34
Dehydration
subjects affected / exposed	4 / 7 (57.14%)	3 / 7 (42.86%)	3 / 10 (30.00%)	2 / 7 (28.57%)	5 / 25 (20.00%)
occurrences all number	5	3	4	2	7
Hypomagnesaemia
subjects affected / exposed	3 / 7 (42.86%)	0 / 7 (0.00%)	2 / 10 (20.00%)	2 / 7 (28.57%)	4 / 25 (16.00%)
occurrences all number	4	0	3	2	21
Hypoalbuminaemia
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	2 / 10 (20.00%)	1 / 7 (14.29%)	3 / 25 (12.00%)
occurrences all number	4	0	3	1	9
Hypocalcaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 10 (20.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	2	0	10
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	2 / 25 (8.00%)
occurrences all number	0	0	1	0	18
Hyponatraemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	2 / 25 (8.00%)
occurrences all number	0	0	0	1	18
Hypophosphataemia
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 25 (0.00%)
occurrences all number	1	1	0	1	0
Hyperphosphataemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 25 (4.00%)
occurrences all number	0	0	0	0	1
Hypovolaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0
Metabolic acidosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 25 (0.00%)
occurrences all number	1	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

24 Mar 2016

To address changes to the planned statistical analyses and to incorporate the addition of ECG studies paired with time-matched PK sampling to assess possible changes in QTC intervals.

28 Dec 2016

To amend the original evaluation plan when dose levels 1 and -1 had been evaluated. The next dose level to be evaluated was to be level -2B, and dose levels 2 and -2A were not to be evaluated in the study. Therefore, the starting dose of irinotecan liposome injection in Part 2 would be 50 mg/m^2 and starting dose for oxaliplatin would be either 60 mg/m^2 or 85 mg/m^2 depending on findings from dose level -2B. Final determination of Part 2 dose of oxaliplatin for reporting group 1 would be made by the DLT review committee (i.e. the Part 1 Investigators, the Medical Monitor, and the Sponsor) and would be based upon careful review of DLTs, SAEs, and Grade 3-4 AEs which occurred in Part 1. To amend exclusion criteria to align with most stringent comparator drug.

03 Apr 2017

To change the study sponsor from Merrimack to Ipsen Bioscience.

29 Sep 2017

To divide Part 1 of the study into 2 phases: Part 1A (dose escalation phase enrolling small cohorts of participants progressively) and Part 1B (dose expansion intended to enroll 24 additional participants). To optimize the NAPOX regimen (irinotecan liposome injection +5-FU/LV + oxaliplatin) in participants with metastatic pancreatic adenocarcinoma by assessing an additional dose for the combination regimen (Part 1A). A new dose level cohort -3 (oxaliplatin 70 mg/m^2 + irinotecan liposome injection 55 mg/m^2) was introduced for evaluation in Part 1A following the completion of 3 dose level cohorts (1, -1 and -2B). To add another secondary objective for the Part 1 evaluation: To evaluate efficacy signals with irinotecan liposome injection in combination with 5-FU/LV + oxaliplatin using ORR (CR + PR, per RECIST v1.1), DCR (CR + PR + SD, per RECIST v1.1), DOR, PFS and OS. To expand the study sample size (Part 1B), once the dose was selected from Part 1A, to further evaluate the safety and efficacy signals and update the study design accordingly: to increase the number of participants enrolled in Part 1 from 6-18 to 54 participants. Therefore, the total enrolment for the study was increased from approximately 156-168 to 204 participants. To provide further details and add that the starting dose for all participants in Part 1 would be as per the dosing table regardless of UGT1A1*28, whereas previously participants receiving 70 mg/m^2 of irinotecan liposome injection could have the dose reduced depending on the overall safety profile seen after the first dose. In addition to the ECOG performance status, KPS was also to be recorded at Screening and within 72 hours of enrolment/randomization. An additional Appendix 3 was added for evaluating the KPS.

11 Apr 2018

To remove the comparative Part 2, which consisted of the comparison of irinotecan liposome injection-containing regimens versus nab-paclitaxel plus gemcitabine and all related information (example, comparison versus nab-paclitaxel plus gemcitabine; reporting groups 1, 2 and 3, randomization). The primary objective was then amended from determination of the Part 2 dose of the triplet combination to determination of the recommended dose of the triplet combination for future development. To add or modify inclusion criteria; To add, remove or modify exclusion criteria; To add clinical data in UGT1A1*28 homozygous participants; To update dose modification rules; To modify granulocyte Colony Stimulating Factors; To specify treatment infusion of 5-FU continued at home; and to remove QTcF assessments and Appendix 5 (QT specific), which were specific to Part 2.

27 Sep 2019

To provide details following fulfilment of analysis requirements for the primary and/or secondary endpoints. Participants still receiving treatment or being followed for OS could transition to an extension phase of the study, continue to be followed for OS and safety, which was completed once all participants had died, withdrew consent, or were lost to follow-up after two attempts on OS follow-up.

Were there any global interruptions to the trial? No

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

The comparative Part 2 was removed in a protocol amendment, dated 11 April 2018, before it was initiated, as this comparative part of the study is being undertaken as a stand-alone Phase 3 study D-US-60010-001.

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Clinical Trial Results:
A randomized, open-label, Phase 2 study of nanoliposomal irinotecan (nal-IRI)-containing regimens versus nab-paclitaxel plus gemcitabine in patients with previously untreated, metastatic pancreatic adenocarcinoma

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Primary: Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT)

Primary: Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT)

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Clinical trials

Clinical Trial Results: A randomized, open-label, Phase 2 study of nanoliposomal irinotecan (nal-IRI)-containing regimens versus nab-paclitaxel plus gemcitabine in patients with previously untreated, metastatic pancreatic adenocarcinoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT)

Primary: Part 1A: Number of Participants With Dose-Limiting Toxicities (DLT)

Secondary: Median Progression Free Survival (PFS)

Secondary: Median Progression Free Survival (PFS)

Secondary: Best Overall Response (BOR)

Secondary: Best Overall Response (BOR)

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Secondary: Median Duration of Response (DoR)

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A randomized, open-label, Phase 2 study of nanoliposomal irinotecan (nal-IRI)-containing regimens versus nab-paclitaxel plus gemcitabine in patients with previously untreated, metastatic pancreatic adenocarcinoma