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Clinical Trial Results:
A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Gemcitabine and Nab-paclitaxel combined with Momelotinib in Subjects with Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma Preceded by a Dose-finding, Lead-in Phase

Summary
EudraCT number	2014-004480-20
Trial protocol	HU DE ES GB CZ IT
Global end of trial date	10 Apr 2017

Results information
Results version number	v2(current)
This version publication date	16 Jun 2018
First version publication date	22 Apr 2018
Other versions	v1
Version creation reason	Correction of full data set • Updating time frames for time-to-event outcome measures #2-7 • Deleting statistical analyses from outcome measures #3-5 (inadvertently entered - these are not statistical comparisons between groups) • Adding text to description for outcome measure #4 and 5

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

GS-US-370-1296

ISRCTN number

US NCT number

NCT02101021

WHO universal trial number (UTN)

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

333 Lakeside Drive, Foster City, CA, United States, 94404

Public contact

Gilead Clinical Study Information Center, Gilead Sciences International Ltd., GileadClinicalTrials@gilead.com

Scientific contact

Gilead Clinical Study Information Center, Gilead Sciences International Ltd., GileadClinicalTrials@gilead.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

10 Apr 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Apr 2017

Global end of trial reached?

Yes

Global end of trial date

10 Apr 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

There were two planned phases to this study. The lead-in phase evaluated the safety, pharmacokinetics, and define the maximum tolerated dose (MTD) of momelotinib (MMB) combined with nab-paclitaxel and gemcitabine (nab-P + G) in adults with previously untreated metastatic pancreatic ductal adenocarcinoma. The primary objectives of the randomized treatment phase were to evaluate the efficacy, safety, and tolerability of nab-P + G with either MMB administered at the MTD or placebo in adults with previously untreated metastatic pancreatic ductal adenocarcinoma. Participants were to continue study treatment until disease progression, unacceptable toxicity, consent withdrawal, or participant's refusal of treatment. Following treatment, participants were to be followed for safety for 30 days and for survival approximately every 3 months for up to 3 years.

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Jun 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 25

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled at study sites in the United States (US). The first participant was screened on 02 June 2014. The last study visit occurred on 10 April 2017.

Screening details

38 participants were screened. Data submitted represent analysis performed on data collected in the lead-in phase by the Study Termination Date, 10 April 2017. The study was discontinued before initiation of the randomized treatment phase, therefore no data were collected for the randomized treatment phase.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

MMB Dose Level 1

Arm description

Momelotinib (MMB) 100 mg tablet once daily + albumin-bound (nab)-paclitaxel plus gemcitabine (nab-P+G) (1000+1000 mg/m^2) intravenous (IV) infusion on Days 1, 8, and 15 of each 28-day cycle

Arm type

Experimental

Investigational medicinal product name

Momelotinib 100 mg

Investigational medicinal product code

Other name

GS-0387, CYT387

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

100 mg oral tablet (s)

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m^2 administered over approximately 30 to 40 minutes

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m^2 administered over approximately 30 to 40 minutes

MMB Dose Level 2

Arm description

MMB 150 mg tablet once daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Arm type

Experimental

Investigational medicinal product name

Momelotinib 150 mg

Investigational medicinal product code

Other name

GS-0387, CYT387

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

150 mg oral tablet (s)

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m^2 administered over approximately 30 to 40 minutes

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m^2 administered over approximately 30 to 40 minutes

MMB Dose Level 3

Arm description

MMB 200 mg tablet once daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Arm type

Experimental

Investigational medicinal product name

Momelotinib 200 mg

Investigational medicinal product code

Other name

GS-0387, CYT387

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200 mg oral tablet (s)

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg^m2 administered over approximately 30 to 40 minutes

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m^2 administered over approximately 30 to 40 minutes

MMB Dose Level 4

Arm description

MMB 150 mg tablet twice daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Arm type

Experimental

Investigational medicinal product name

Momelotinib 150 mg

Investigational medicinal product code

Other name

GS-0387, CYT387

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

150 mg oral tablet (s)

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m^2 administered over approximately 30 to 40 minutes

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m^2 administered over approximately 30 to 40 minutes

MMB Dose Level 5

Arm description

MMB 200 mg tablet twice daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Arm type

Experimental

Investigational medicinal product name

Momelotinib 200 mg

Investigational medicinal product code

Other name

GS-0387, CYT387

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

200 mg oral tablet (s)

Investigational medicinal product name

Nab-paclitaxel

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m^2 administered over approximately 30 to 40 minutes

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Abraxane

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

1000 mg/m^2 administered over approximately 30 to 40 minutes

Number of subjects in period 1	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Started	7	4	7	3	4
Completed	0	0	0	0	0
Not completed	7	4	7	3	4
Withdrew Consent from study	1	1	-	2	-
Death	4	3	6	-	3
Study Terminated by Sponsor	1	-	1	1	1
Lost to follow-up	1	-	-	-	-

Baseline characteristics

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Reporting group title

MMB Dose Level 1

Reporting group description

Momelotinib (MMB) 100 mg tablet once daily + albumin-bound (nab)-paclitaxel plus gemcitabine (nab-P+G) (1000+1000 mg/m^2) intravenous (IV) infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 2

Reporting group description

MMB 150 mg tablet once daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 3

Reporting group description

MMB 200 mg tablet once daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 4

Reporting group description

MMB 150 mg tablet twice daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 5

Reporting group description

MMB 200 mg tablet twice daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group values	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5	Total
Number of subjects	7	4	7	3	4	25
Age categorical
Units: Subjects
Age continuous
All Enrolled Analysis Set: all participants who received a study participant identification number in the study after screening.
Units: years
arithmetic mean (standard deviation)	59.9 ± 12.32	63.5 ± 12.12	64.7 ± 8.79	52.0 ± 5.00	59.0 ± 9.13	-
Gender categorical
Units: Subjects
Female	2	3	2	0	1	8
Male	5	1	5	3	3	17
Race
Units: Subjects
Asian	0	0	1	0	0	1
White	6	3	6	3	4	22
Other	1	1	0	0	0	2
Ethnicity
Units: Subjects
Hispanic or Latino	1	0	0	0	0	1
Not Hispanic or Latino	6	4	7	3	4	24

End points

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Reporting group title

MMB Dose Level 1

Reporting group description

Momelotinib (MMB) 100 mg tablet once daily + albumin-bound (nab)-paclitaxel plus gemcitabine (nab-P+G) (1000+1000 mg/m^2) intravenous (IV) infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 2

Reporting group description

MMB 150 mg tablet once daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 3

Reporting group description

MMB 200 mg tablet once daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 4

Reporting group description

MMB 150 mg tablet twice daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 5

Reporting group description

MMB 200 mg tablet twice daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Primary: Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events

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End point title

Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events ^[1]

End point description

Dose limiting toxicities were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Dose limiting toxicities referred to toxicities experienced during the first 28 days (Cycle 1) of treatment that were judged to be clinically significant and related to study treatment. DLT-Evaluable Analysis Set: participants in the Safety Analysis Set who completed all treatment and safety procedures through Day 28, inclusive, or experienced a DLT prior to Day 29. Participants in the DLT-Evaluable Analysis Set with available data were analyzed.

End point type

Primary

End point timeframe

Up to 28 Days

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned or performed.

End point values	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Number of subjects analysed	6	3	6	3	3
Units: percentage of participants
number (not applicable)	16.7	0	16.7	0	0

No statistical analyses for this end point

Primary: Randomized Treatment Phase: Overall Survival (OS)

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End point title

Randomized Treatment Phase: Overall Survival (OS) ^[2]

End point description

End point type

Primary

End point timeframe

Baseline up to the Date of Death or Censoring, up to 3 years

Notes
[2] - 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: No statistical analysis was performed because the study was discontinued prior to initiation of randomized phase.

End point values	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Number of subjects analysed	0 ^[3]	0 ^[4]	0 ^[5]	0 ^[6]	0 ^[7]
Units: Months
median (inter-quartile range (Q1-Q3))	( to )	( to )	( to )	( to )	( to )

Notes
[3] - The study was discontinued before initiation of the randomized treatment phase.
[4] - The study was discontinued before initiation of the randomized treatment phase.
[5] - The study was discontinued before initiation of the randomized treatment phase.
[6] - The study was discontinued before initiation of the randomized treatment phase.
[7] - The study was discontinued before initiation of the randomized treatment phase.

No statistical analyses for this end point

Secondary: Lead-In Phase: Overall Survival (OS)

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End point title

Lead-In Phase: Overall Survival (OS)

End point description

Overall survival was defined as the time interval from first dose date of MMB to death from any cause. Participants in the All Enrolled Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Baseline up to the Date of Death or Censoring, up to 3 years

End point values	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Number of subjects analysed	7	4	7	3	4
Units: Months
median (inter-quartile range (Q1-Q3))	12.4 (3.9 to 22.2)	5.1 (3.7 to 11.3)	8.7 (7.3 to 18.3)	5.6 (4.8 to 18.1)	7.1 (5.9 to 12.0)

No statistical analyses for this end point

Secondary: Lead-In Phase: Progression-Free Survival (PFS)

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End point title

Lead-In Phase: Progression-Free Survival (PFS)

End point description

Progression-free survival was defined as the time interval from the first dose of MMB to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression is progression based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria v1.1. Data from survival, non-progressing participants will be censored at the earliest of the time of initiation of anti-tumor therapy other than the study treatment or the last time that lack of definitive disease progression was objectively documented while on study. Participants in the All Enrolled Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Baseline up to the Date of Event or Censoring, up to 3 years

End point values	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Number of subjects analysed	7	4	7	3	4
Units: Months
median (inter-quartile range (Q1-Q3))	5.3 (1.4 to 7.4)	3.2 (1.9 to 4.8)	5.5 (5.3 to 7.2)	5.3 (0.0 to 13.0)	5.5 (4.5 to 10.1)

No statistical analyses for this end point

Secondary: Lead-In Phase: Overall Response Rate (ORR)

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End point title

Lead-In Phase: Overall Response Rate (ORR)

End point description

The ORR was defined as the proportion of participants who achieved a best overall response (BOR) during MMB therapy of complete response (CR) or partial response (PR) as assessed by RECIST v1.1. Participants in the All Enrolled Analysis Set were analyzed.

End point type

Secondary

End point timeframe

Baseline up to the Last Tumor Assessment Date, up to 3 years

End point values	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Number of subjects analysed	7	4	7	3	4
Units: participants
Complete Response (CR)	2	1	3	1	0
Partial Response (PR)	2	2	4	1	4

No statistical analyses for this end point

Secondary: Randomized Treatment Phase: Progression-Free Survival (PFS)

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End point title

Randomized Treatment Phase: Progression-Free Survival (PFS)

End point description

End point type

Secondary

End point timeframe

Baseline up to the Date of Event or Censoring, up to 3 years

End point values	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Number of subjects analysed	0 ^[8]	0 ^[9]	0 ^[10]	0 ^[11]	0 ^[12]
Units: Months
median (inter-quartile range (Q1-Q3))	( to )	( to )	( to )	( to )	( to )

Notes
[8] - The study was discontinued before initiation of the randomized treatment phase.
[9] - The study was discontinued before initiation of the randomized treatment phase.
[10] - The study was discontinued before initiation of the randomized treatment phase.
[11] - The study was discontinued before initiation of the randomized treatment phase.
[12] - The study was discontinued before initiation of the randomized treatment phase.

No statistical analyses for this end point

Secondary: Randomized Treatment Phase: Overall Response Rate (ORR)

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End point title

Randomized Treatment Phase: Overall Response Rate (ORR)

End point description

End point type

Secondary

End point timeframe

Baseline up to the Last Tumor Assessment Date, up to 3 years

End point values	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Number of subjects analysed	0 ^[13]	0 ^[14]	0 ^[15]	0 ^[16]	0 ^[17]
Units: participants

Notes
[13] - The study was discontinued before initiation of the randomized treatment phase.
[14] - The study was discontinued before initiation of the randomized treatment phase.
[15] - The study was discontinued before initiation of the randomized treatment phase.
[16] - The study was discontinued before initiation of the randomized treatment phase.
[17] - The study was discontinued before initiation of the randomized treatment phase.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to the last dose date plus 30 days (maximum exposure= 63.7 weeks)

Adverse event reporting additional description

Safety Analysis Set: all participants who were randomized and received at least 1 dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

MMB Dose Level 1

Reporting group description

Momelotinib (MMB) 100 mg tablet once daily + albumin-bound (nab)-paclitaxel plus gemcitabine (nab-P+G) (1000+1000 mg/m^2) intravenous (IV) infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 2

Reporting group description

MMB 150 mg tablet once daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 3

Reporting group description

MMB 200 mg tablet once daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 4

Reporting group description

MMB 150 mg tablet twice daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Reporting group title

MMB Dose Level 5

Reporting group description

MMB 200 mg tablet twice daily + nab-P+G (1000+1000 mg/m^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle

Serious adverse events	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 7 (57.14%)	3 / 4 (75.00%)	5 / 7 (71.43%)	2 / 3 (66.67%)	4 / 4 (100.00%)
number of deaths (all causes)	4	3	6	0	3
number of deaths resulting from adverse events
Investigations
Weight decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (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
Injury, poisoning and procedural complications
Rib fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (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
Nervous system disorders
Embolic stroke
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (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
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (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
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
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
Generalised oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
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
Mucosal inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
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
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (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
Small intestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
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%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (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 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (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
Haematemesis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (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
Large intestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (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 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (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
Pancreatitis acute
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (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
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
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
Cholecystitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
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
Dyspnoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
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%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (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 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	3 / 7 (42.86%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 0	0 / 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 / 4 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
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
Septic shock
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (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
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
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
Decreased appetite
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (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
Diabetic ketoacidosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (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 / 0	0 / 0	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (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 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	MMB Dose Level 1	MMB Dose Level 2	MMB Dose Level 3	MMB Dose Level 4	MMB Dose Level 5
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	4 / 4 (100.00%)	7 / 7 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Tumor pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	2 / 7 (28.57%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	2	1	2	3	10
Hypotension
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	2	0	1
Deep vein thrombosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	1	0	1
Embolism venous
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Subclavian vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Venous thrombosis limb
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	5 / 7 (71.43%)	3 / 4 (75.00%)	6 / 7 (85.71%)	2 / 3 (66.67%)	4 / 4 (100.00%)
occurrences all number	5	6	7	2	6
Oedema peripheral
subjects affected / exposed	4 / 7 (57.14%)	1 / 4 (25.00%)	2 / 7 (28.57%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	4	2	2	2	3
Pyrexia
subjects affected / exposed	3 / 7 (42.86%)	2 / 4 (50.00%)	3 / 7 (42.86%)	1 / 3 (33.33%)	3 / 4 (75.00%)
occurrences all number	3	3	4	1	6
Chills
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 7 (28.57%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	2	2	0
Malaise
subjects affected / exposed	1 / 7 (14.29%)	2 / 4 (50.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	2	1	0	0
Asthenia
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	1	1	0	0
Influenza like illness
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	1	1	1	0
Chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Early satiety
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Face oedema
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Gait disturbance
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Generalised oedema
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Peripheral swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Temperature intolerance
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Reproductive system and breast disorders
Prostatomegaly
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	2 / 7 (28.57%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	1	2	1	0
Cough
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	1	0	1	0	3
Epistaxis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	1	0	3
Hypoxia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	0	0	1	0	3
Dyspnoea exertional
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	0	0	0	0	3
Alveolitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Dysphonia
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Hiccups
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Pleural effusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Pleuritic pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Pneumonitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Productive cough
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Pulmonary embolism
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Pulmonary oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Respiratory distress
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Rhinorrhoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Wheezing
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Psychiatric disorders
Depression
subjects affected / exposed	2 / 7 (28.57%)	1 / 4 (25.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	2	1	2	0	2
Anxiety
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	1	1	0	1	1
Confusional state
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	2	0	0
Agitation
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Insomnia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	2	0
Mental status changes
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Panic attack
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Personality change
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Sleep disorder
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Investigations
Neutrophil count decreased
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	1	1	1	8	2
Platelet count decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 7 (28.57%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	2	2	0
Weight decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	0	0	1	2	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	2	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	1	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	3	0	1
Liver function test increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	1	0	1	0
Lymphocyte count decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	1	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Blood uric acid increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	3
Troponin increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Urine output decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
White blood cell count decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	1	0	0	1
Fall
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Head injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Joint injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Limb injury
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Transfusion reaction
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Cardiac disorders
Tachycardia
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	2	1	0
Acute myocardial infarction
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Atrial fibrillation
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Cardiac failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Intracardiac mass
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Sinus tachycardia
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Nervous system disorders
Dysgeusia
subjects affected / exposed	3 / 7 (42.86%)	0 / 4 (0.00%)	3 / 7 (42.86%)	2 / 3 (66.67%)	2 / 4 (50.00%)
occurrences all number	3	0	4	2	2
Neuropathy peripheral
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	3 / 7 (42.86%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	0	1	3	2	3
Peripheral sensory neuropathy
subjects affected / exposed	3 / 7 (42.86%)	1 / 4 (25.00%)	2 / 7 (28.57%)	2 / 3 (66.67%)	1 / 4 (25.00%)
occurrences all number	4	1	2	2	1
Headache
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	3 / 7 (42.86%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	1	4	0	0
Dizziness
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	0	1	1	0	2
Paraesthesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	1	0	1
Peripheral motor neuropathy
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	0	1	0
Peripheral sensorimotor neuropathy
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	1	0	0	0
Akathisia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Balance disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Cerebrovascular accident
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Cognitive disorder
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Dizziness exertional
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Dizziness postural
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Dysaesthesia
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Extrapyramidal disorder
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Facial paresis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Hemiparesis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Lethargy
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Peroneal nerve palsy
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Syncope
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Tremor
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 7 (85.71%)	2 / 4 (50.00%)	4 / 7 (57.14%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	6	4	4	2	5
Neutropenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	0	2	7	4	6
Thrombocytopenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	2 / 4 (50.00%)
occurrences all number	1	0	1	2	3
Disseminated intravascular coagulation
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Leukocytosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Leukopenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Thrombocytosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	5 / 7 (71.43%)	4 / 4 (100.00%)	4 / 7 (57.14%)	3 / 3 (100.00%)	3 / 4 (75.00%)
occurrences all number	7	5	8	3	8
Diarrhoea
subjects affected / exposed	3 / 7 (42.86%)	3 / 4 (75.00%)	3 / 7 (42.86%)	3 / 3 (100.00%)	3 / 4 (75.00%)
occurrences all number	3	4	5	5	4
Constipation
subjects affected / exposed	2 / 7 (28.57%)	3 / 4 (75.00%)	3 / 7 (42.86%)	2 / 3 (66.67%)	3 / 4 (75.00%)
occurrences all number	2	3	5	4	3
Vomiting
subjects affected / exposed	3 / 7 (42.86%)	3 / 4 (75.00%)	4 / 7 (57.14%)	0 / 3 (0.00%)	3 / 4 (75.00%)
occurrences all number	4	5	5	0	6
Abdominal pain
subjects affected / exposed	2 / 7 (28.57%)	1 / 4 (25.00%)	3 / 7 (42.86%)	1 / 3 (33.33%)	3 / 4 (75.00%)
occurrences all number	2	1	4	1	4
Dyspepsia
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	1	1	1	0
Abdominal pain upper
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	1	1	0	0
Abdominal distension
subjects affected / exposed	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	1	0	0	0
Ascites
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	0	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	1	0
Haematochezia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	1	0	1
Abdominal pain lower
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Abdominal tenderness
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Duodenal ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Gastritis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Gastrointestinal pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Ileus
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Melaena
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Pancreatic failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Paraesthesia oral
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Rectal haemorrhage
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Small intestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Stomatitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Varices oesophageal
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	1	0
Biliary dilatation
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Portal hypertension
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	3 / 7 (42.86%)	2 / 4 (50.00%)	3 / 7 (42.86%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	3	2	3	2	0
Rash
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	3 / 7 (42.86%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	2	0	3	0	2
Decubitus ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	2	0	0
Rash macular
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	1	0	0
Nail bed disorder
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Rash erythematous
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Rash papular
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Skin hypopigmentation
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Swelling face
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Renal and urinary disorders
Acute prerenal failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Dysuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Nephrolithiasis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Urinary retention
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 7 (28.57%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)
occurrences all number	2	0	0	0	2
Muscular weakness
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	2 / 4 (50.00%)
occurrences all number	0	0	1	1	2
Myalgia
subjects affected / exposed	3 / 7 (42.86%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	3	0	1	0	0
Pain in extremity
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	1	0	0
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	1	0
Arthritis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Bone pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Groin pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Joint swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Muscle fatigue
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Muscle spasms
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Musculoskeletal pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	2 / 7 (28.57%)	2 / 4 (50.00%)	3 / 7 (42.86%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	2	3	0	0
Oral candidiasis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	3 / 7 (42.86%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	4	1	0
Candida infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	0	0	1	1	1
Cellulitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	0	0	1
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	1	0	0	1
Bronchiolitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0	0
Bronchitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Catheter site infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Ear infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Endocarditis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Gastroenteritis viral
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Oesophageal candidiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Pulmonary tuberculosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Soft tissue infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Viral infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 7 (28.57%)	2 / 4 (50.00%)	2 / 7 (28.57%)	2 / 3 (66.67%)	1 / 4 (25.00%)
occurrences all number	2	2	4	2	1
Hypokalaemia
subjects affected / exposed	2 / 7 (28.57%)	2 / 4 (50.00%)	3 / 7 (42.86%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	2	2	3	2	0
Dehydration
subjects affected / exposed	2 / 7 (28.57%)	0 / 4 (0.00%)	3 / 7 (42.86%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	2	0	4	0	1
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	4 / 7 (57.14%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	5	0	0
Hypoalbuminaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	2	0	1
Hypomagnesaemia
subjects affected / exposed	2 / 7 (28.57%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	1	0	0
Hyponatraemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 7 (28.57%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	2	0	1
Hypoglycaemia
subjects affected / exposed	2 / 7 (28.57%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0	0
Cachexia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Hyperkalaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Hypernatraemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Hyperuricaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	0	1
Hypophosphataemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0
Malnutrition
subjects affected / exposed	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0	0

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Were there any global substantial amendments to the protocol? Yes

14 Mar 2014

The protocol was revised to address administrative changes and to respond to the clinical questions posted by the FDA on the Solid Tumor IND received by Gilead Sciences, Inc.

25 Aug 2014

The protocol was revised to specify stratification and eligibility criteria for the randomized phase and to incorporate new emerging risk and drug-drug interaction data.

16 Feb 2015

Biostatistical changes were made to the sample size in this protocol to enable this single study to serve as a registrational trial, if safety and effectiveness of the combination is demonstrated in support of a potential new drug application (NDA) for the frontline treatment of metastatic pancreatic cancer. An optional intensive pharmacokinetic (PK) substudy was also incorporated for evaluation of drugdrug interactions between MMB and nab-paclitaxel or gemcitabine as requested by the Agency.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
10 Apr 2017	Following internal review, Gilead Sciences, Inc. decided not to move forward into the randomized treatment phase of this study given the minimal treatment effect, the low likelihood of improved outcome in patients with pancreatic cancer, and a similar lack of efficacy reported in another Janus kinase (JAK) program for a similar indication. Gilead decided to discontinue the 3-year long-term survival follow-up period following completion of study treatment for all participants in the lead-in phase. The study was formally closed once all participants completed the 30-day safety follow-up visit. An Administrative Letter dated 11 April 2016 the decision not to initiate the randomized treatment phase was distributed to the European and non-European sites.	-

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

None reported

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Clinical trials

Clinical Trial Results:
A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Gemcitabine and Nab-paclitaxel combined with Momelotinib in Subjects with Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma Preceded by a Dose-finding, Lead-in Phase

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events

Primary: Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events

Primary: Randomized Treatment Phase: Overall Survival (OS)

Primary: Randomized Treatment Phase: Overall Survival (OS)

Secondary: Lead-In Phase: Overall Survival (OS)

Secondary: Lead-In Phase: Overall Survival (OS)

Secondary: Lead-In Phase: Progression-Free Survival (PFS)

Secondary: Lead-In Phase: Progression-Free Survival (PFS)

Secondary: Lead-In Phase: Overall Response Rate (ORR)

Secondary: Lead-In Phase: Overall Response Rate (ORR)

Secondary: Randomized Treatment Phase: Progression-Free Survival (PFS)

Secondary: Randomized Treatment Phase: Progression-Free Survival (PFS)

Secondary: Randomized Treatment Phase: Overall Response Rate (ORR)

Secondary: Randomized Treatment Phase: Overall Response Rate (ORR)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Gemcitabine and Nab-paclitaxel combined with Momelotinib in Subjects with Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma Preceded by a Dose-finding, Lead-in Phase

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events

Primary: Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events

Primary: Randomized Treatment Phase: Overall Survival (OS)

Primary: Randomized Treatment Phase: Overall Survival (OS)

Secondary: Lead-In Phase: Overall Survival (OS)

Secondary: Lead-In Phase: Overall Survival (OS)

Secondary: Lead-In Phase: Progression-Free Survival (PFS)

Secondary: Lead-In Phase: Progression-Free Survival (PFS)

Secondary: Lead-In Phase: Overall Response Rate (ORR)

Secondary: Lead-In Phase: Overall Response Rate (ORR)

Secondary: Randomized Treatment Phase: Progression-Free Survival (PFS)

Secondary: Randomized Treatment Phase: Progression-Free Survival (PFS)

Secondary: Randomized Treatment Phase: Overall Response Rate (ORR)

Secondary: Randomized Treatment Phase: Overall Response Rate (ORR)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Gemcitabine and Nab-paclitaxel combined with Momelotinib in Subjects with Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma Preceded by a Dose-finding, Lead-in Phase