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Clinical Trial Results:
An Open-Label, Multicenter, Phase 1/2 Study of Poly(ADP-Ribose) Polymerase (PARP) Inhibitor E7449 as Single Agent in Subjects With Advanced Solid Tumours or With B-cell Malignancies and in Combination With Temozolomide(TMZ) or With Carboplatin and Paclitaxel in Subjects With Advanced Solid Tumors

Summary
EudraCT number	2011-001959-37
Trial protocol	GB
Global end of trial date	14 Jul 2015

Results information
Results version number	v1(current)
This version publication date	23 May 2019
First version publication date	23 May 2019
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

E7449-E044-101

ISRCTN number

US NCT number

NCT01618136

WHO universal trial number (UTN)

Other trial identifiers

PACT: E7449

Sponsor organisation name

Eisai Ltd, European Knowledge Centre, Mosquito Way

Sponsor organisation address

AL10 9SN, Hatfield, Hertfordshire, United Kingdom,

Public contact

Medical Information, Eisai Limited, +44 2086001400, eumedinfo@eisai.net

Scientific contact

Medical Information, Eisai Limited, +44 2086001400, eumedinfo@eisai.net

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

14 Jul 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Jul 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

The Primary objective of the trial was to determine maximum tolerated dose (MTD) as single agent, administered once daily (QD) continuously in 28-day cycles in subjects with advanced solid tumors or B-cell lymphoma.

Protection of trial subjects

This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Jan 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 41

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

Enrollment to the study was stopped after Phase 1 single agent arm was completed and the Phase 1 combination arms and the Phase 2 part of the study were cancelled.

Screening details

Extension Phase: of the 33 participants who completed the Treatment Phase, 32 entered the Extension Phase. Of these 32 participants; 27 discontinued due to disease progression (defined as treatment completion) and 5 discontinued due to; choice, withdrew consent, adverse event, physician choice, and biopsy procedure not done due to comorbidities.

Period 1 title

Treatment Phase

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

50 mg E7449

Arm description

E7449 (50 mg) was administered orally once on Day 2 in the single-dose pharmacokinetic (PK) period (dose escalation cohorts only) and once a day (QD) continuously starting on Cycle 1 Day 1 in 28-day treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent. E7449 had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Arm type

Experimental

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 50 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

100 mg E7449

Arm description

E7449 (100 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent. E7449 had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Arm type

Experimental

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 100 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

200 mg E7449

Arm description

E7449 (200 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent. E7449 had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Arm type

Single agent

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 200 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

400 mg E7449

Arm description

E7449 (400 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent. E7449 inhibitor had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Arm type

Single agent

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 400 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

600 mg E7449 Overall

Arm description

E7449 (600 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent. E7449 had to be taken at least 2 hours before or 2 hours after food. Also, participants in the MTD expansion cohort were randomized to receive E7449 either with or without food after an overnight fast on Cycle 1 Day 7. Participants randomized to fed condition received E7449 immediately after consuming a high fat breakfast. On Cycle 1 Day 15, participants crossed over to the other food regimen, according to the randomization scheme (with or without food). Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Arm type

Single agent

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 600 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

800 mg E7449

Arm description

E7449 (800 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent. E7449 had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Arm type

Single agent

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 800 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

Number of subjects in period 1	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Started	3	3	4	4	21	6
Completed	3	3	4	3	15	5
Not completed	0	0	0	1	6	1
Consent withdrawn by subject	-	-	-	-	1	-
Participant choice	-	-	-	-	2	-
Adverse event, non-fatal	-	-	-	-	1	-
Not specified	-	-	-	-	2	1
Lost to follow-up	-	-	-	1	-	-

Period 2 title

Extension Phase

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

50 mg E7449

Arm description

Arm type

Experimental

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 50 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

100 mg E7449

Arm description

Arm type

Experimental

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 100 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

200 mg E7449

Arm description

Arm type

Single agent

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 200 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

400 mg E7449

Arm description

Arm type

Single agent

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 400 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

600 mg E7449 Overall

Arm description

Arm type

Single agent

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 600 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

800 mg E7449

Arm description

Arm type

Single agent

Investigational medicinal product name

Poly(ADP-Ribose) Polymerase (PARP) Inhibitor

Investigational medicinal product code

E7449

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

E7449 800 mg was administered as oral Capsule taken at least 2 hours before or 2 hours after food.

Number of subjects in period 2 ^[1]	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Started	3	3	4	3	14	5
Completed	2	3	4	3	11	4
Not completed	1	0	0	0	3	1
withdrawal of consent from study	-	-	-	-	-	1
Adverse event, non-fatal	-	-	-	-	1	-
Other	1	-	-	-	1	-
Subject choice	-	-	-	-	1	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all subjects who completed treatment period in 600 mg E7449 overall arm entered in the extension phase.

Baseline characteristics

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Reporting group title

50 mg E7449

Reporting group description

Reporting group title

100 mg E7449

Reporting group description

Reporting group title

200 mg E7449

Reporting group description

Reporting group title

400 mg E7449

Reporting group description

Reporting group title

600 mg E7449 Overall

Reporting group description

Reporting group title

800 mg E7449

Reporting group description

Reporting group values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449	Total
Number of subjects	3	3	4	4	21	6	41
Age categorical
Units: Subjects
In utero							0
Preterm newborn infants (gestational age < 37 wks)							0
Newborns (0-27 days)							0
Infants and toddlers (28 days-23 months)							0
Children (2-11 years)							0
Adolescents (12-17 years)							0
Adults (18-64 years)							0
From 65-84 years							0
85 years and over							0
Age continuous
Units: years
arithmetic mean (standard deviation)	62 ( 11.36 )	64.3 ( 11.06 )	56.8 ( 14.2 )	58 ( 22.67 )	60.7 ( 9.5 )	61.2 ( 15.66 )	-
Gender categorical
Units: Subjects
Female	1	1	2	2	10	3	19
Male	2	2	2	2	11	3	22
Race
Units: Subjects
White	3	3	4	4	21	5	40
Asian	0	0	0	0	0	1	1

End points

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Reporting group title

50 mg E7449

Reporting group description

Reporting group title

100 mg E7449

Reporting group description

Reporting group title

200 mg E7449

Reporting group description

Reporting group title

400 mg E7449

Reporting group description

Reporting group title

600 mg E7449 Overall

Reporting group description

Reporting group title

800 mg E7449

Reporting group description

Reporting group title

50 mg E7449

Reporting group description

Reporting group title

100 mg E7449

Reporting group description

Reporting group title

200 mg E7449

Reporting group description

Reporting group title

400 mg E7449

Reporting group description

Reporting group title

600 mg E7449 Overall

Reporting group description

Reporting group title

800 mg E7449

Reporting group description

Subject analysis set title

E7449 (single agent)

Subject analysis set type

Intention-to-treat

Subject analysis set description

During dose escalation, sequential cohorts of 3 to 6 participants (dose escalation cohorts) were administered increasing doses (starting at 50 mg) of E7449 orally, once daily in 28-day cycles to determine the MTD of E7449 as a single agent. Dose escalation proceeded in 100% increments (i.e. 100 mg, 200 mg, 400 mg, etc.) in subsequent cohorts unless 2 Grade 2 toxicities were assessed as related to the study drug. After which, dose escalation had to follow a modified scheme increasing in 50%, 33%, and 25% dose increments in subsequent cohorts.

Subject analysis set title

600 mg E7449 (Fed)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants in the MTD expansion cohort were randomized to receive E7449 with food after an overnight fast on Cycle 1 Day 7. Participants randomized to fed condition received PARP immediately after consuming a high fat breakfast. On Cycle 1 Day 15, participants crossed over to the other food regimen, according to the randomization scheme (with food).

Subject analysis set title

600 mg E7449 (Fasted)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants in the MTD expansion cohort were randomized to receive E7449 without food after an overnight fast on Cycle 1 Day 7. On Cycle 1 Day 15, participants crossed over to the other food regimen, according to the randomization scheme (without food).

Primary: Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose of E7449 when Administered as a Single Agent

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End point title

Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose of E7449 when Administered as a Single Agent ^[1]

End point description

The MTD was defined as the highest dose level at which no more than 1 out of 6 participants experienced dose-limiting toxicity (DLT). A DLT was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE v4.03): Any Grade 4 neutropenia for >=7 days or Grade 3 neutropenia with fever; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or lasting >7 days. Grade 3 fatigue, or a 2 point decline in Eastern Cooperative Oncology Group (ECOG) performance status that persists for >7days; Nausea, vomiting or diarrhea that persists at Grade 3 or 4 despite maximal medical therapy; Any Grade 3 or higher non-hematological laboratory abnormalities that require hospitalization. The RP2 dose was the same as the confirmed MTD and was to be used for the Phase 2 part of this study, however enrollment was stopped after Phase 1 was completed and the Phase 2 part of the study was cancelled.

End point type

Primary

End point timeframe

First dose of study drug (Day -2) to end of first 4 weeks of therapy (Cycle 1) (1 cycle = 28 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analysis was planned to be reported for this outcome measure.

End point values	E7449 (single agent)
Number of subjects analysed	41 ^[2]
Units: milligrams
number (not applicable)	600

Notes
[2] - Total participants treated in Arm 1 including all dose escalation cohorts and MTD expansion cohort.

No statistical analyses for this end point

Secondary: Phase 1: Number of Participants with DLT

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End point title

Phase 1: Number of Participants with DLT

End point description

A DLT was assessed according to the CTCAE v4.03: Any Grade 4 neutropenia for >=7 days or Grade 3 neutropenia with fever; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or lasting >7 days; Grade 3 fatigue, or a 2 point decline in ECOG performance status that persists for >7days; Nausea, vomiting or diarrhea that persists at Grade 3 or 4 despite maximal medical therapy; Any Grade 3 or higher non-hematological laboratory abnormalities that require hospitalization. DLT was assessed during the first 4 weeks of therapy (Cycle 1) for dose escalation purposes. Participants who failed to take at least 75% of the daily doses of E7449 during Cycle 1 (first 4 weeks of treatment), for reasons not related to toxicity, were not evaluable for DLTs and were replaced by a new participant in the same dose group.

End point type

Secondary

End point timeframe

First dose of study drug (Day -2) to end of first 4 weeks of therapy (Cycle 1) (1 cycle = 28 days)

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	3	3	4	4	8	6
Units: Percentage of participants
number (not applicable)
Any DLT during 1st Cycle	0	0	0	0	1	4
Treatment-related non-hematological AE Grade ≥3	0	0	0	0	1	1
Treatment-related toxicity	0	0	0	0	0	4

No statistical analyses for this end point

Secondary: Percentage of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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End point title

Percentage of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

End point description

TEAEs were defined as AEs that occurred after the first dose of treatment on Cycle 1 Day 1 and up to 30 days after the last dose of treatment. Participants with 2 or more TEAEs in a specific category were counted only once. Safety was assessed by monitoring and recording all AEs, including all CTCAE version 4.03 grades (both increasing and decreasing severity) and SAEs, regular monitoring of hematology, clinical chemistry, and urine values, measurement of weight, vital signs, and electrocardiograms. Treatment-related TEAEs included TEAEs that were considered by the investigatory to be possible or probably related to study treatment. Participants reporting AEs with different CTCAE grades were counted only once using the highest CTCAE grade. Participants may be counted in more than one category. Safety analysis set included all participants who received at least 1 dose of the study drug and had at least 1 postbaseline safety evaluation.

End point type

Secondary

End point timeframe

From date of administration of first dose up to 30 days after the last dose, or up to approximately 3 years 8 months.

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	3	3	4	4	21	6
Units: Percentage of participants
number (not applicable)
All TEAEs	100	100	100	100	100	100
Treatment-related TEAEs	100	100	75	75	100	100
TEAEs with CTCAE grade 3 or 4	66.7	0	100	50	76.2	66.7
Treatment-related TEAEs with CTCAE Grade 3 or 4	33.3	0	0	25	28.6	50
Serious Adverse Events	33.3	0	100	50	57.1	83.3
TEAEs leading to treatment withdrawal	33.3	0	0	0	19	33.3
TEAEs leading to dose reduction	0	0	0	25	9.5	50
TEAEs leading to dose interruption	33.3	33.3	75	75	47.6	100
TEAEs associated with skin rash	0	33.3	25	25	47.6	66.7

No statistical analyses for this end point

Secondary: Percentage of Subjects with Best Overall Response (BOR) for E7449

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End point title

Percentage of Subjects with Best Overall Response (BOR) for E7449

End point description

BOR was the best confirmed response of partial response (PR), progressive disease (PD), or stable disease (SD), recorded from the start of E7449 until disease progression/recurrence or death. Analysis was based on investigator review of computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, photographs, and bone scans, as appropriate to tumor type, utilizing Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. PR; at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD; 20% or greater increase in the sum of the longest diameter of measured lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions. SD; PR failed to be achieved in the overall response assessment and there was no PD observed at 7 weeks or later after starting E7449. 95% confidence interval was constructed using exact method of binomial distribution.

End point type

Secondary

End point timeframe

Baseline to first date of documented CR, PR, SD, or PD, assessed up to approximately 3 years 7 months

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	3	3	4	4	21	6
Units: Percentage of participants
number (not applicable)
Complete response	0	0	0	0	0	0
Partial response	0	0	0	0	4.8	16.7
Stable disease	66.7	33.3	25.0	50.0	23.8	33.3
Progressive disease	33.3	66.7	75.0	25.0	52.4	33.3

No statistical analyses for this end point

Secondary: Percentage of Subjects with Objective Response Rate (ORR) for E7449

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End point title

Percentage of Subjects with Objective Response Rate (ORR) for E7449

End point description

ORR was the percentage of participants with best overall response (BOR) of complete response (CR) and PR based on modified RECIST 1.1 for target lesions using MRI/CT scans, as determined by Independent Imaging Review (IIR). CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. ORR=CR+PR. The safety analysis set included all participants who received at least 1 dose of study drug and had at least 1 postbaseline safety evaluation. Here '99999' represents that none of the participants achieved ORR.

End point type

Secondary

End point timeframe

From date of treatment start until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice to stop study treatment, for up to approximately 3 years 7 months.

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	3	3	4	4	21	6
Units: Percentage of participants
number (not applicable)	99999	99999	99999	99999	4.8	16.7

No statistical analyses for this end point

Secondary: Preliminary Efficacy Assessment of Disease Control Rate (DCR) for E7449 when Administered as a Single Agent

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End point title

Preliminary Efficacy Assessment of Disease Control Rate (DCR) for E7449 when Administered as a Single Agent

End point description

DCR was the percentage of the participants who had BOR of CR, PR, and SD with the minimum duration of SD lasting greater than or equal to 7 weeks, based on assessments by IIR. The 95% CI was calculated using exact method of binomial distribution. DCR = CR + PR + SD greater than or equal to 23 weeks. The safety analysis set included all participants who received at least 1 dose of study drug and had at least 1 postbaseline safety evaluation.

End point type

Secondary

End point timeframe

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	3	3	4	4	21	6
Units: Percentage of participants
number (not applicable)	33.3	33.3	0	50	19	33.3

No statistical analyses for this end point

Secondary: Preliminary Efficacy Assessment of Duration of Response (DoR) for E7449 when Administered as a Single Agent

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End point title

Preliminary Efficacy Assessment of Duration of Response (DoR) for E7449 when Administered as a Single Agent

End point description

DoR was calculated as 'end date minus date of first CR or PR plus 1', based on assessments by IIR. Participants without Progressive disease or death were censored at the date of last adequate tumor assessment according to the progression free survival (PFS) censoring rule. The safety analysis set included all participants who received at least 1 dose of study drug and had at least 1 postbaseline safety evaluation.

End point type

Secondary

End point timeframe

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	0 ^[3]	0 ^[4]	0 ^[5]	0 ^[6]	1 ^[7]	1 ^[8]
Units: Days
median (confidence interval 95%)	( to )	( to )	( to )	( to )	281 (281 to 281)	208 (208 to 208)

Notes
[3] - None of the participants achieved a complete or partial response.
[4] - None of the participants achieved a complete or partial response.
[5] - None of the participants achieved a complete or partial response.
[6] - None of the participants achieved a complete or partial response.
[7] - n=1
[8] - n=1

No statistical analyses for this end point

Secondary: Preliminary Efficacy Assessment of Duration of Stable Disease for E7449 when Administered as a Single Agent

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End point title

Preliminary Efficacy Assessment of Duration of Stable Disease for E7449 when Administered as a Single Agent

End point description

Tumor assessment was based on RECIST 1.1 criteria. Safety analysis set included Only participants with SD as their BOR were included. The safety analysis set included all participants who received at least 1 dose of study drug and had at least 1 postbaseline safety evaluation. Here '-99999' and '99999' represents lower and upper limit of the CI as only a single participant was analyzed and CI could not be estimated.

End point type

Secondary

End point timeframe

Date of first dose of study treatment until disease progression or death, whichever occurs first, or up to approximately 3 years 7 months.

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	2	1	1	2	5	2
Units: Weeks
median (confidence interval 95%)	184 (106 to 262)	332 (-99999 to 99999)	52 (-99999 to 99999)	190.5 (163 to 218)	148 (42 to 266)	109.5 (57 to 162)

No statistical analyses for this end point

Secondary: Preliminary Efficacy Assessment of Time to First Response for E7449 when Administered as a Single Agent

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End point title

Preliminary Efficacy Assessment of Time to First Response for E7449 when Administered as a Single Agent

End point description

Tumor assessment based on RECIST 1.1 criteria. Time to first response is defined as the time from first dose until the first documented evidence of CR or PR (whichever status is recorded first). For participants in the subset of non-responders, time to first response was censored. The safety analysis set included all participants who received at least 1 dose of study drug and had at least 1 postbaseline safety evaluation.

End point type

Secondary

End point timeframe

Date of first dose of study treatment until the first dose of documented evidence of CR or PR (whichever status is recorded first), up to approximately 3 years 7 months

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	0 ^[9]	0 ^[10]	0 ^[11]	0 ^[12]	1	1
Units: Weeks
median (confidence interval 95%)	( to )	( to )	( to )	( to )	51 (51 to 51)	108 (108 to 108)

Notes
[9] - no responders
[10] - no responders
[11] - no responders
[12] - no responders

No statistical analyses for this end point

Secondary: Time to Maximum Observed Concentration (Tmax) for E7449 when Administered as a Single Agent

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End point title

Time to Maximum Observed Concentration (Tmax) for E7449 when Administered as a Single Agent

End point description

Tmax for E7449 was the time it took after administration of study treatment on Day -2 and Cycle 1 Day 15 to reach the maximum concentration of E7449 in plasma. The PK analysis set included all participants who received at least one dose of E7449 and had at least one evaluable plasma concentration.

End point type

Secondary

End point timeframe

Day -2 (predose, 0 to 2 hours, 2 to 4 hours, 4 to 10 hours, 10 to 24 hours) and Cycle 1 Day 15 (0 to 4, 8, and 12 hours)

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	3	3	4 ^[13]	4 ^[14]	8 ^[15]	6 ^[16]
Units: Hours
median (full range (min-max))
Day -2	2 (0.58 to 2.03)	2.05 (1.08 to 3)	3.1 (1.03 to 4.18)	2.04 (1.03 to 4.05)	2.12 (0.5 to 24.3)	0.79 (0.5 to 2)
Cycle 1 Day 15	1 (0.5 to 2)	3 (1 to 4)	1 (1 to 2)	4 (0.5 to 4)	1.14 (0.5 to 4.05)	0.5 (0 to 1.97)

Notes
[13] - Cycle 1 Day 15 (n=3)
[14] - Cycle 1 Day 15 (n=3)
[15] - Cycle 1 Day 15 (n=6)
[16] - Cycle 1 Day 15 (n=5)

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of E7449 in Plasma when Administered as a Single Agent

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End point title

Maximum Concentration (Cmax) of E7449 in Plasma when Administered as a Single Agent

End point description

Cmax for E7449 was defined as the maximum observed concentration of E7449 in plasma following administration of study treatment on Day -2 and Cycle 1 Day 15 and was obtained directly from the measured plasma concentration-time curves. The PK analysis set included all participants who received at least one dose of E7449 and had at least one evaluable plasma concentration.

End point type

Secondary

End point timeframe

Day -2 (predose, 0 to 2 hours, 2 to 4 hours, 4 to 10 hours, 10 to 24 hours)and Cycle 1 Day 15 (0 to 4, 8, and 12 hours)

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	3	3	4 ^[17]	4 ^[18]	8 ^[19]	6 ^[20]
Units: nanograms per millilitre (ng/mL)
arithmetic mean (standard deviation)
Day -2	265 ( 99.8 )	284 ( 112 )	996 ( 676 )	999 ( 619 )	2250 ( 1330 )	4430 ( 2470 )
Cycle 1 Day 15	264 ( 227 )	404 ( 175 )	1430 ( 1080 )	1130 ( 1030 )	2230 ( 1570 )	4120 ( 2160 )

Notes
[17] - Cycle 1 Day 15 (n=3)
[18] - Cycle 1 Day 15 (n=3)
[19] - Cycle 1 Day 15 (n=6)
[20] - Cycle 1 Day 15 (n=5)

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours AUC(0-24) for E7449 when Administered as a Single Agent

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End point title

Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours AUC(0-24) for E7449 when Administered as a Single Agent

End point description

The PK analysis set included all participants who received at least one dose of E7449 and had at least one evaluable plasma concentration.

End point type

Secondary

End point timeframe

Day -2 (predose, 0 to 2 hours, 2 to 4 hours, 4 to 10 hours, 10 to 24 hours)and Cycle 1 Day 15 (0 to 4, 8, and 12 hours)

End point values	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449 Overall	800 mg E7449
Number of subjects analysed	3 ^[21]	3	4 ^[22]	4 ^[23]	21 ^[24]	6 ^[25]
Units: nanogram*hour per milliliter (ng·h/mL)
arithmetic mean (standard deviation)
Day -2	768 ( 99999 )	879 ( 104 )	3670 ( 1170 )	4690 ( 2400 )	7930 ( 4990 )	11300 ( 3230 )
Cycle 1 Day 15	714 ( 193 )	1100 ( 244 )	3690 ( 2230 )	4730 ( 2730 )	7900 ( 4730 )	12400 ( 5230 )

Notes
[21] - Day -2 (n=1)
[22] - Cycle 1 Day 15 (n = 3)
[23] - Cycle 1 Day 15 (n = 3)
[24] - Cycle 1 Day 15 (n = 6)
[25] - Cycle 1 Day 15 (n = 5)

No statistical analyses for this end point

Secondary: Effect of Food on Time to Maximum Concentration (Tmax) of E7449 when Administered as a Single Agent

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End point title

Effect of Food on Time to Maximum Concentration (Tmax) of E7449 when Administered as a Single Agent

End point description

The bioavailability of E7449 when administered as a single agent was explored under fast/fed conditions at the MTD during Cycle 1. The effect of food was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters (Cmax, AUC(0-24)) with fixed effects for treatment, period and sequence and a random effect of participant. Ratios of geometric means and associated 2-sided 90% CIs were presented. The PK analysis set included all participants who received at least one dose of E7449 and had at least one evaluable plasma concentration.

End point type

Secondary

End point timeframe

Cycle 1 Day 7 (predose) and Cycle 1 Day 15 (predose, 0.5 hours, 1 to 4 hours, 4, 6, 8, 10, 12, and 24 hours (Day 16)

End point values	600 mg E7449 (Fed)	600 mg E7449 (Fasted)
Number of subjects analysed	11	10
Units: Hours
median (full range (min-max))	4.05 (1.07 to 8.18)	2.01 (0.97 to 3)

No statistical analyses for this end point

Secondary: Effect of Food on the Maximum Plasma Concentration (Cmax) of E7449 when Administered as a Single Agent

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End point title

Effect of Food on the Maximum Plasma Concentration (Cmax) of E7449 when Administered as a Single Agent

End point description

The bioavailability of E7449 when administered as a single agent was explored under fast/fed conditions at the MTD during Cycle 1. The effect of food was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters (Cmax, AUC(0-24)) with fixed effects for treatment, period and sequence and a random effect of participant. Ratios of geometric means and associated 2-sided 90% confidence intervals (CIs) were presented. The PK analysis set included all participants who received at least one dose of E7449 and had at least one evaluable plasma concentration.

End point type

Secondary

End point timeframe

Cycle 1 Day 7 (predose) and Cycle 1 Day 15 (predose, 0.5 hours, 1 to 4 hours, 4, 6, 8, 10, 12, and 24 hours (Day 16)

End point values	600 mg E7449 (Fed)	600 mg E7449 (Fasted)
Number of subjects analysed	11	10
Units: ng/mL
arithmetic mean (standard deviation)	863 ( 563 )	1470 ( 697 )

No statistical analyses for this end point

Secondary: Effect of Food on the Area Under the Plasma Concentration-Time Curve from 0 to 24 Hours (AUC(0-24)) for E7449 when Administered as a Single Agent

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End point title

Effect of Food on the Area Under the Plasma Concentration-Time Curve from 0 to 24 Hours (AUC(0-24)) for E7449 when Administered as a Single Agent

End point description

The bioavailability of E7449 when administered as a single agent was explored under fast/fed conditions at the MTD during Cycle 1. The effect of food was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters (Cmax, AUC(0-24)) with fixed effects for treatment, period and sequence and a random effect of participant. Ratios of geometric means and associated 2-sided 90% confidence intervals (CIs) were presented. The PK analysis set included all participants who received at least one dose of E7449 and had at least one evaluable plasma concentration.

End point type

Secondary

End point timeframe

Cycle 1 Day 7 (predose) and Cycle 1 Day 15 (predose, 0.5 hours, 1 to 4 hours, 4, 6, 8, 10, 12, and 24 hours (Day 16)

End point values	600 mg E7449 (Fed)	600 mg E7449 (Fasted)
Number of subjects analysed	11	9
Units: ng·hr/mL
median (standard deviation)	6150 ( 3280 )	5510 ( 1730 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From date of administration of first dose up to 30 days after the last dose, or up to approximately 3 years 8 months.

Adverse event reporting additional description

Treatment-emergent adverse events were reported and were defined as AEs that occurred after the first dose of treatment on Cycle 1 Day 1 and up to 30 days after the last dose of study treatment. Adverse events were graded using CTCAE version 4.03.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

50 mg E7449

Reporting group description

E7449 (50 mg) was administered orally once on Day 2 in the single-dose pharmacokinetic (PK) period (dose escalation cohorts only) and once a day (QD) continuously starting on Cycle 1 Day 1 in 28-day treatment cycles. E7449 had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Reporting group title

100 mg E7449

Reporting group description

E7449 (100 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles. E7449 had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Reporting group title

200 mg E7449

Reporting group description

E7449 (200 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles. E7449 had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Reporting group title

400 mg E7449

Reporting group description

E7449 (400 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles. E7449 inhibitor had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Reporting group title

600 mg E7449

Reporting group description

E7449 (600 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles. E7449 had to be taken at least 2 hours before or 2 hours after food. Also, participants in the MTD expansion cohort were randomized to receive E7449 either with or without food after an overnight fast on Cycle 1 Day 7. Participants randomized to fed condition received E7449 immediately after consuming a high fat breakfast. On Cycle 1 Day 15, participants crossed over to the other food regimen, according to the randomization scheme (with or without food). Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Reporting group title

800 mg E7449

Reporting group description

E7449 (800 mg) was administered orally once on Day 2 in the single-dose PK period (dose escalation cohorts only) and QD continuously starting on Cycle 1 Day 1 in 28-day treatment cycles. E7449 had to be taken at least 2 hours before or 2 hours after food. Dose interruption, dose reduction, or treatment discontinuation was applied for participants who experienced E7449-related toxicity in accordance with protocol-specified instructions.

Serious adverse events	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449	800 mg E7449
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 4 (100.00%)	2 / 4 (50.00%)	12 / 21 (57.14%)	5 / 6 (83.33%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events
Investigations
Transaminases increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal spasm
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	2 / 6 (33.33%)
occurrences causally related to treatment / all	0 / 5	0 / 5	0 / 5	0 / 5	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Female genital tract fistula
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 3	0 / 3	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Lower respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 3	0 / 3	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 2	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colonic fistula
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	50 mg E7449	100 mg E7449	200 mg E7449	400 mg E7449	600 mg E7449	800 mg E7449
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	4 / 4 (100.00%)	21 / 21 (100.00%)	6 / 6 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 4 (25.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	8	8	8	8	8	8
Cancer pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Vascular disorders
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	2 / 6 (33.33%)
occurrences all number	4	4	4	4	4	4
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Superior vena cava stenosis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 3 (66.67%)	2 / 3 (66.67%)	3 / 4 (75.00%)	4 / 4 (100.00%)	17 / 21 (80.95%)	6 / 6 (100.00%)
occurrences all number	85	85	85	85	85	85
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 21 (14.29%)	0 / 6 (0.00%)
occurrences all number	3	3	3	3	3	3
Pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	4	4	4	4	4	4
Catheter site erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Catheter site swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	2	2	2	2	2
Early satiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Local swelling
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Non-cardiac chest pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Performance status decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	3	3	3	3	3	3
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	5 / 21 (23.81%)	2 / 6 (33.33%)
occurrences all number	14	14	14	14	14	14
Cough
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)	1 / 4 (25.00%)	1 / 21 (4.76%)	1 / 6 (16.67%)
occurrences all number	10	10	10	10	10	10
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Pleuritic pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Haemoptysis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Psychiatric disorders
Depression
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	2 / 4 (50.00%)	1 / 21 (4.76%)	1 / 6 (16.67%)
occurrences all number	13	13	13	13	13	13
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 21 (14.29%)	2 / 6 (33.33%)
occurrences all number	6	6	6	6	6	6
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	2 / 6 (33.33%)
occurrences all number	4	4	4	4	4	4
Confusional state
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	3	3	3	3	3	3
Agitation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Depressed mood
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Abnormal dreams
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Euphoric mood
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Hallucination
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Panic disorder
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Sleep disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Investigations
Weight decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 4 (75.00%)	2 / 4 (50.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	13	13	13	13	13	13
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	3 / 21 (14.29%)	0 / 6 (0.00%)
occurrences all number	8	8	8	8	8	8
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 21 (14.29%)	0 / 6 (0.00%)
occurrences all number	4	4	4	4	4	4
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	5	5	5	5	5	5
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	5	5	5	5	5	5
Blood creatinine increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	3	3	3	3	3	3
Body temperature increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	3	3	3	3	3
Blood cholesterol increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Blood glucose increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	3	3	3	3	3
Transaminases increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
White blood cell count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Muscle strain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Wound
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Cardiac disorders
Tachycardia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	1 / 6 (16.67%)
occurrences all number	5	5	5	5	5	5
Atrial flutter
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	4 / 21 (19.05%)	2 / 6 (33.33%)
occurrences all number	8	8	8	8	8	8
Paraesthesia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	7	7	7	7	7	7
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 21 (14.29%)	0 / 6 (0.00%)
occurrences all number	3	3	3	3	3	3
Headache
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	4	4	4	4	4	4
Aphasia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Lethargy
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Balance disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Dysarthria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Migraine
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Myoclonus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Restless legs syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Speech disorder
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Tremor
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	4 / 21 (19.05%)	1 / 6 (16.67%)
occurrences all number	22	22	22	22	22	22
Eye disorders
Periorbital oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	4 / 21 (19.05%)	0 / 6 (0.00%)
occurrences all number	6	6	6	6	6	6
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Eyelid oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Eye pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Pinguecula
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)	3 / 4 (75.00%)	9 / 21 (42.86%)	2 / 6 (33.33%)
occurrences all number	29	29	29	29	29	29
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)	2 / 4 (50.00%)	6 / 21 (28.57%)	4 / 6 (66.67%)
occurrences all number	23	23	23	23	23	23
Constipation
subjects affected / exposed	1 / 3 (33.33%)	3 / 3 (100.00%)	3 / 4 (75.00%)	1 / 4 (25.00%)	5 / 21 (23.81%)	2 / 6 (33.33%)
occurrences all number	20	20	20	20	20	20
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 4 (50.00%)	3 / 4 (75.00%)	5 / 21 (23.81%)	3 / 6 (50.00%)
occurrences all number	19	19	19	19	19	19
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 4 (50.00%)	1 / 4 (25.00%)	1 / 21 (4.76%)	1 / 6 (16.67%)
occurrences all number	19	19	19	19	19	19
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	5	5	5	5	5	5
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	4	4	4	4	4	4
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	1 / 6 (16.67%)
occurrences all number	3	3	3	3	3	3
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	3	3	3	3	3	3
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	3	3	3	3	3	3
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	3	3	3	3	3	3
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Toothache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	1 / 4 (25.00%)	7 / 21 (33.33%)	1 / 6 (16.67%)
occurrences all number	20	20	20	20	20	20
Photosensitivity reaction
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 4 (25.00%)	5 / 21 (23.81%)	2 / 6 (33.33%)
occurrences all number	20	20	20	20	20	20
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 4 (0.00%)	4 / 21 (19.05%)	0 / 6 (0.00%)
occurrences all number	7	7	7	7	7	7
Skin hyperpigmentation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	2 / 6 (33.33%)
occurrences all number	10	10	10	10	10	10
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	2 / 6 (33.33%)
occurrences all number	5	5	5	5	5	5
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 21 (14.29%)	1 / 6 (16.67%)
occurrences all number	8	8	8	8	8	8
Night sweats
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	5	5	5	5	5	5
Onycholysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	3	3	3	3	3	3
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	1 / 6 (16.67%)
occurrences all number	2	2	2	2	2	2
Skin discolouration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Acne
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Blister
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Dermatitis contact
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Nail discolouration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Nail disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Nail ridging
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Swelling face
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Renal and urinary disorders
Chromaturia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 4 (50.00%)	14 / 21 (66.67%)	5 / 6 (83.33%)
occurrences all number	25	25	25	25	25	25
Nephrolithiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Nocturia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	3 / 21 (14.29%)	0 / 6 (0.00%)
occurrences all number	10	10	10	10	10	10
Back pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	1 / 4 (25.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	5	5	5	5	5	5
Musculoskeletal pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	2 / 6 (33.33%)
occurrences all number	4	4	4	4	4	4
Muscular weakness
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	2 / 21 (9.52%)	0 / 6 (0.00%)
occurrences all number	6	6	6	6	6	6
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	1 / 6 (16.67%)
occurrences all number	7	7	7	7	7	7
Pain in extremity
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Musculoskeletal stiffness
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Myalgia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Neck mass
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Infections and infestations
Lower respiratory tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 4 (50.00%)	5 / 21 (23.81%)	2 / 6 (33.33%)
occurrences all number	10	10	10	10	10	10
Oral candidiasis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	3 / 21 (14.29%)	1 / 6 (16.67%)
occurrences all number	7	7	7	7	7	7
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 4 (25.00%)	2 / 21 (9.52%)	1 / 6 (16.67%)
occurrences all number	4	4	4	4	4	4
Nasopharyngitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	2	2	2	2	2
Tooth infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	1	1
Viral infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Wound infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 3 (100.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	2 / 4 (50.00%)	7 / 21 (33.33%)	4 / 6 (66.67%)
occurrences all number	33	33	33	33	33	33
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	1 / 6 (16.67%)
occurrences all number	2	2	2	2	2	2
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	5	5	5	5	5	5
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	2	2	2	2	2	2
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	2	2	2	2	2
Fluid overload
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 21 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 21 (4.76%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1

More information

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Were there any global substantial amendments to the protocol? Yes

14 Sep 2011

Addition of a communication strategy among the study sites so that the drug escalation rules can be followed to comply with the local regulatory and health authority based on a request from the Medicines and Healthcare products Regulatory Agency (MHRA).

08 Oct 2012

• Clarified the type of B-cell malignancy (ie, B-cell lymphoma) for subject who will be enrolled in Phase 1 Arm 1. • Revised inclusion criteria: to include radiotherapy (5b) and update contraceptive use language (12) • Revised Exclusion Criterion 5 to allow subjects with squamous cell carcinoma of the skin, carcinoma in situ cervix, adequately treated Stage I or II cancer currently in complete remission, or any other cancer from which the subject has been disease-free for 5 years. • Revised dose reduction and interruption instructions table to exclude Grade 2 and Grade 3 laboratory abnormalities that are considered to be not clinically relevant by the investigator, and to discontinue E7449 and discuss with the sponsor any Grade 4 occurrences. • PK sampling schedule was revised to omit time points that were considered unnecessary without compromising results.

08 Jul 2013

• Added advisory to avoid sunlight, information to minimize sunlight exposure, and instructions on what to do in the event of a rash. • Revised alcohol and caffeine restrictions to allow for moderate use. Added advice regarding what constitutes moderate use.

20 Sep 2013

Amendment 04 was approved internally by the sponsor; however it was not implemented at the study sites due to logistical challenges associated with the proposed changes to explore BID dosing. Hence, BID dosing was not explored in this study. Not implemented.

30 Oct 2013

• Added information pertaining to the reporting of skin rash as an AE of special interest to allow collection of information related to skin rash.

Were there any global interruptions to the trial? No

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

Study was terminated early by the sponsor.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose of E7449 when Administered as a Single Agent

Primary: Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose of E7449 when Administered as a Single Agent

Secondary: Phase 1: Number of Participants with DLT

Secondary: Phase 1: Number of Participants with DLT

Secondary: Percentage of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Secondary: Percentage of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Secondary: Percentage of Subjects with Best Overall Response (BOR) for E7449

Secondary: Percentage of Subjects with Best Overall Response (BOR) for E7449

Secondary: Percentage of Subjects with Objective Response Rate (ORR) for E7449

Secondary: Percentage of Subjects with Objective Response Rate (ORR) for E7449

Secondary: Preliminary Efficacy Assessment of Disease Control Rate (DCR) for E7449 when Administered as a Single Agent

Secondary: Preliminary Efficacy Assessment of Disease Control Rate (DCR) for E7449 when Administered as a Single Agent

Secondary: Preliminary Efficacy Assessment of Duration of Response (DoR) for E7449 when Administered as a Single Agent

Secondary: Preliminary Efficacy Assessment of Duration of Response (DoR) for E7449 when Administered as a Single Agent

Secondary: Preliminary Efficacy Assessment of Duration of Stable Disease for E7449 when Administered as a Single Agent

Secondary: Preliminary Efficacy Assessment of Duration of Stable Disease for E7449 when Administered as a Single Agent

Secondary: Preliminary Efficacy Assessment of Time to First Response for E7449 when Administered as a Single Agent

Secondary: Preliminary Efficacy Assessment of Time to First Response for E7449 when Administered as a Single Agent

Secondary: Time to Maximum Observed Concentration (Tmax) for E7449 when Administered as a Single Agent

Secondary: Time to Maximum Observed Concentration (Tmax) for E7449 when Administered as a Single Agent

Secondary: Maximum Concentration (Cmax) of E7449 in Plasma when Administered as a Single Agent

Secondary: Maximum Concentration (Cmax) of E7449 in Plasma when Administered as a Single Agent

Secondary: Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours AUC(0-24) for E7449 when Administered as a Single Agent

Secondary: Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours AUC(0-24) for E7449 when Administered as a Single Agent

Secondary: Effect of Food on Time to Maximum Concentration (Tmax) of E7449 when Administered as a Single Agent

Secondary: Effect of Food on Time to Maximum Concentration (Tmax) of E7449 when Administered as a Single Agent

Secondary: Effect of Food on the Maximum Plasma Concentration (Cmax) of E7449 when Administered as a Single Agent

Secondary: Effect of Food on the Maximum Plasma Concentration (Cmax) of E7449 when Administered as a Single Agent

Secondary: Effect of Food on the Area Under the Plasma Concentration-Time Curve from 0 to 24 Hours (AUC(0-24)) for E7449 when Administered as a Single Agent

Secondary: Effect of Food on the Area Under the Plasma Concentration-Time Curve from 0 to 24 Hours (AUC(0-24)) for E7449 when Administered as a Single Agent

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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