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Clinical Trial Results:
A Phase 2a Randomized, Open-Label Study to Assess the Safety, Tolerability, and Efficacy of BAX69 in Combination with 5 FU/Leucovorin or Panitumumab versus Standard of Care in Subjects with Metastatic Colorectal Cancer

Summary
EudraCT number	2015-000896-28
Trial protocol	GB DE ES
Global end of trial date	15 Feb 2017

Results information
Results version number	v1(current)
This version publication date	03 Mar 2018
First version publication date	03 Mar 2018
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

391401

ISRCTN number

US NCT number

NCT02448810

WHO universal trial number (UTN)

Sponsor organisation name

Shire

Sponsor organisation address

300 Shire Way, Lexington, MA,, United States, 02421

Public contact

Study Physician, Shire, 1 866-842-5335, ClinicalTransparency@shire.com

Scientific contact

Study Physician, Shire, 1 866-842-5335, ClinicalTransparency@shire.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

15 Feb 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Feb 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of the trial was to determine the recommended Phase 2 dose (RP2D) of imalumab in combination with 5 Fluorouracil (5 FU)/Leucovorin (LV) or panitumumab (Part 1) and to compare progression free survival (PFS) between imalumab in combination with 5 FU/LV for subjects with mutated kirsten rat sarcoma viral oncogene homolog, mutated neuroblastoma rat sarcoma viral oncogene homolog (KRAS mut and/or NRAS mut tumors) or in combination with panitumumab for subjects with wild type kirsten rat sarcoma viral oncogene homolog, wild type neuroblastoma rat sarcoma viral oncogene homolog (KRAS wt and NRAS wt tumors), versus standard of care ([SoC] investigator choice), as third or fourth treatment line (Part 2).

Protection of trial subjects

This study was conducted in accordance with current applicable regulations, International Council for Harmonisation (ICH) of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Jun 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

Spain: 31

Country: Number of subjects enrolled

United States: 44

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

The study was conducted at 21 centers in the United States, the United Kingdom and Spain between 15 June 2015 (first subject first visit) and 15 February 2017 (last subject last visit).

Screening details

A total of 115 subjects were screened (17 and 98 for part 1 and part 2). Of them, 5 subjects failed screening and 12 received treatment in part 1 and 17 failed screening and 8 signed informed consent but were not enrolled due to over screening, thus 73 subjects were enrolled, of which 67 subjects received treatment in part 2.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1: Imalumab 7.5 mg/kg + 5 FU/LV

Arm description

Subjects with mutated tumors (mutated kirsten rat sarcoma viral oncogene homolog, mutated neuroblastoma rat sarcoma viral oncogene homolog [KRAS mut, NRAS mut]) received 7.5 milligram per kilogram (mg/kg) dose of imalumab every week (QW) in combination with 5-Fluorouracil/Leucovorin ([FU/LV] LV 400 milligram per square meter [mg/m^2] intravenous [IV] infusion over 2 hours, followed by 5 FU 2400 mg/m^2 IV infusion over 46 hours) for every two weeks (Q2W) IV infusion as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

5 Fluorouracil (FU)/Leucovorin (LV)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received LV 400 mg/m^2 IV infusion over 2 hours, followed by 5 FU 2400 mg/m^2 IV infusion over 46 hours as part of a 4-week /28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Investigational medicinal product name

Imalumab

Investigational medicinal product code

BAX69

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received 7.5 mg/kg or 10 mg/kg of imalumab IV infusion QW as part of a 4-week /28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Part 1: Imalumab 7.5 mg/kg + Panitumumab

Arm description

Subjects with wild-type tumors (wild type Kirsten rat sarcoma viral oncogene homolog, wild neuroblastoma rat sarcoma viral oncogene homolog [KRAS wt, NRAS wt]) received 7.5 mg/kg dose of imalumab QW in combination with panitumumab 6 mg/kg Q2W IV infusion as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Imalumab

Investigational medicinal product code

BAX69

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received 6 mg/kg of panitumumab IV infusion Q2W as part of a 4-week /28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Part 1: Imalumab 10 mg/kg + 5-FU/LV

Arm description

Subjects with mutated tumors (KRAS mut, NRAS mut) received 10 mg/kg dose of imalumab QW in combination with 5-FU/LV (LV 400 mg/m^2 IV infusion over 2 hours, followed by 5 FU 2400 mg/m^2 IV infusion over 46 hours) Q2W IV infusion as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

5 Fluorouracil (FU)/Leucovorin (LV)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Imalumab

Investigational medicinal product code

BAX69

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Part 1: Imalumab 10 mg/kg + Panitumumab

Arm description

Subjects with wild-type tumors (KRAS wt, NRAS wt) received 10 mg/kg dose of imalumab QW in combination with panitumumab 6 mg/kg Q2W IV infusion as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Imalumab

Investigational medicinal product code

BAX69

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Part 2: Imalumab 10 mg/kg + 5-FU/LV

Arm description

Subjects with mutated tumors (KRAS mut, NRAS mut) received 10 mg/kg dose of imalumab as a recommended phase 2 dose (RP2D) QW in combination with 5-FU/LV (LV 400 mg/m^2 IV infusion over 2 hours, followed by 5 FU 2400 mg/m^2 IV infusion over 46 hours) Q2W IV infusion as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Imalumab

Investigational medicinal product code

BAX69

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

5 Fluorouracil (FU)/Leucovorin (LV)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Part 2: Standard of Care Mutant

Arm description

Subjects with mutated tumors (KRAS mut, NRAS mut) received standard of care (SoC) as chosen by the investigator and was administered in accordance to product label as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Part 2: Imalumab 10 mg/kg + Panitumumab

Arm description

Subjects with wild-type tumors (KRAS wt, NRAS wt) received 10 mg/kg dose of imalumab as a RP2D QW in combination with panitumumab 6 mg/kg Q2W IV infusion as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Imalumab

Investigational medicinal product code

BAX69

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Part 2: Standard of Care Wild Type

Arm description

Subjects with wild-type tumors (KRAS wt, NRAS wt) received SoC as chosen by the investigator and was administered in accordance to product label as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Started	3	3	3	3	31	16	18	8
Treated	3	3	3	3	29	13	18	7
Completed	0	0	0	0	0	0	0	0
Not completed	3	3	3	3	31	16	18	8
Adverse event, serious fatal	1	-	1	-	1	-	-	-
Consent withdrawn by subject	-	-	1	-	3	5	-	2
Adverse event, non-fatal	-	-	1	-	-	-	-	-
Other (study terminated by sponsor)	-	-	-	-	4	2	2	1
Other (Progressive disease)	2	2	-	3	23	9	14	5
Other (unspecified)	-	-	-	-	-	-	2	-
Lost to follow-up	-	1	-	-	-	-	-	-

Baseline characteristics

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Reporting group title

Part 1: Imalumab 7.5 mg/kg + 5 FU/LV

Reporting group description

Reporting group title

Part 1: Imalumab 7.5 mg/kg + Panitumumab

Reporting group description

Reporting group title

Part 1: Imalumab 10 mg/kg + 5-FU/LV

Reporting group description

Reporting group title

Part 1: Imalumab 10 mg/kg + Panitumumab

Reporting group description

Reporting group title

Part 2: Imalumab 10 mg/kg + 5-FU/LV

Reporting group description

Reporting group title

Part 2: Standard of Care Mutant

Reporting group description

Reporting group title

Part 2: Imalumab 10 mg/kg + Panitumumab

Reporting group description

Reporting group title

Part 2: Standard of Care Wild Type

Reporting group description

Reporting group values	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type	Total
Number of subjects	3	3	3	3	31	16	18	8	85
Age categorical
Units: Subjects
Adults (18-64 years)	1	0	3	2	19	12	12	4	53
From 65-84 years	2	3	0	1	11	4	6	4	31
85 years and over	0	0	0	0	1	0	0	0	1
Gender categorical
Units: Subjects
Female	1	0	0	1	13	5	7	6	33
Male	2	3	3	2	18	11	11	2	52
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	1	0	1	5	2	3	0	12
Not Hispanic or Latino	3	2	3	2	26	14	15	8	73
Unknown or Not Reported	0	0	0	0	0	0	0	0	0
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0
Asian	0	0	0	0	1	2	0	0	3
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0
Black or African American	1	0	0	0	4	0	0	2	7
White	2	3	3	2	26	14	18	6	74
More than one race	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	1	0	0	0	0	1

End points

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Reporting group title

Part 1: Imalumab 7.5 mg/kg + 5 FU/LV

Reporting group description

Reporting group title

Part 1: Imalumab 7.5 mg/kg + Panitumumab

Reporting group description

Reporting group title

Part 1: Imalumab 10 mg/kg + 5-FU/LV

Reporting group description

Reporting group title

Part 1: Imalumab 10 mg/kg + Panitumumab

Reporting group description

Reporting group title

Part 2: Imalumab 10 mg/kg + 5-FU/LV

Reporting group description

Reporting group title

Part 2: Standard of Care Mutant

Reporting group description

Reporting group title

Part 2: Imalumab 10 mg/kg + Panitumumab

Reporting group description

Reporting group title

Part 2: Standard of Care Wild Type

Reporting group description

Primary: Part 2: Progression-Free Survival (PFS)

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End point title

Part 2: Progression-Free Survival (PFS) ^[1]

End point description

PFS was defined as time between treatment initiation and tumor progression or death from any cause, with censoring of subjects who were lost to follow-up or withdrew consent. Full analysis set (FAS) included all subjects who received at least 1 administration of study drug, and who had 1 postbaseline tumor response assessment based on RECIST v1.1, or died within 18 weeks of the start of treatment. '99999' indicates data for upper limit was not available.

End point type

Primary

End point timeframe

From start of the study up to safety follow-up visit occurred (30 [-/+7]) days after the last dose of study treatment or until disease progression

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subjects included in Part 1 arms were excluded for this analysis since they did not contribute to the progression-free survival evaluation.

End point values	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Number of subjects analysed	29	12	18	7
Units: weeks
median (confidence interval 95%)
weeks	11.1 (8.4 to 16.1)	8.3 (7.4 to 23.3)	9.3 (8.1 to 24.9)	7.3 (3.7 to 99999)

Statistical analysis 1

Statistical analysis description

Hazard Ratio and 70% confidence interval (CI) are based on a Cox proportional hazards model with a covariate for treatment (imalumab vs SoC).

Comparison groups

Part 2: Imalumab 10 mg/kg + 5-FU/LV v Part 2: Standard of Care Mutant

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.246 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.8

Confidence interval

level

70%

sides

2-sided

lower limit

0.5

upper limit

1.1

Notes
[2] - P-value is based on a one-sided log-rank test.

Statistical analysis 2

Statistical analysis description

Hazard Ratio and 70% CI are based on a Cox proportional hazards model with a covariate for treatment (imalumab vs SoC).

Comparison groups

Part 2: Standard of Care Wild Type v Part 2: Imalumab 10 mg/kg + Panitumumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.354 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.8

Confidence interval

level

70%

sides

2-sided

lower limit

0.5

upper limit

1.4

Notes
[3] - P-value is based on a one-sided log-rank test.

Primary: Part 1: Number of Subjects With Occurrence of Dose Limiting Toxicity (DLT)

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End point title

Part 1: Number of Subjects With Occurrence of Dose Limiting Toxicity (DLT) ^[4] ^[5]

End point description

DLT was defined as any drug-related TEAE (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.03) that occurs during the first 28 days after treatment start and that meets any of the following criteria: i) >= Grade 3 non-hematologic toxicity (excluding: mucositis/stomatitis of Grade 3; diarrhea of <3 days duration; nausea and vomiting <3 days duration; fatigue of <7 days duration; alopecia; single laboratory value out of the normal range that has no clinical significance and that resolves to <= Grade 2 with adequate measures within 7 days ii) Any Grade 4 hematologic toxicity (excluding: grade 4 neutropenia lasting for <= 5 days; isolated grade 4 lymphocytopenia iii) Grade 3 febrile neutropenia iv) Grade 3 thrombocytopenia associated with bleeding v) Any life-threatening complication or abnormality not covered in NCI CTCAEv4.03. SAS included all subjects who received at least 1 administration of study drug.

End point type

Primary

End point timeframe

From start of study treatment up to 28 days

Notes
[4] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subjects from Part 2 arms were excluded from this analysis since they did not contribute to the dose-limiting toxicity evaluation.

End point values	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab
Number of subjects analysed	3	3	3	3
Units: subjects
Subjects	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Occurrence of Binding and/or Neutralizing Anti-imalumab Antibodies

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End point title

Number of Subjects With Occurrence of Binding and/or Neutralizing Anti-imalumab Antibodies

End point description

Number of subjects with occurrence of binding and/or neutralizing anti-imalumab antibodies were reported. Safety analysis set (SAS) included all subjects who received at least 1 administration of study drug. Here BA refers to binding antibody and NA refers to neutralizing antibody.

End point type

Secondary

End point timeframe

From start of study drug administration up to end of treatment (EOT) (approximately 21 Months)

End point values	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Number of subjects analysed	3	3	3	3	29	13	18	7
Units: subjects
Baseline (BA) (n=3, 3, 3, 1, 27, 12,18, 6)	0	0	0	0	0	0	1	0
End of Study (BA) (n=2, 1, 3, 1, 19, 2, 12, 2)	0	0	0	1	0	0	0	0
Baseline (NA) (n=3, 3, 3, 1, 27, 12,18, 6)	0	0	0	0	0	0	0	0
End of Study (NA) (n=2, 1, 3, 1, 19, 2, 12, 2)	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Incidence and Severity of Infusion Reactions After Imalumab Administration

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End point title

Number of Subjects With Incidence and Severity of Infusion Reactions After Imalumab Administration

End point description

Infusion reaction was defined as any relevant sign or symptom occurring during or after imalumab infusion and considered by the investigator as an infusion reaction. SAS included all subjects who received at least 1 administration of study drug.

End point type

Secondary

End point timeframe

From start of study drug administration up to EOT (approximately 21 Months)

End point values	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Number of subjects analysed	3	3	3	3	29	13	18	7
Units: subjects
Subjects	0	0	0	0	0	0	1	0

No statistical analyses for this end point

Secondary: Number of Subjects With Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events (TEAEs)

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End point title

Number of Subjects With Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events (TEAEs)

End point description

An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was any AE that results in any of the following outcomes: death, a life-threatening event, inpatient hospitalization or prolongation of an existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect, other medically important events based upon appropriate medical judgement. TEAEs were defined as any event not present prior to the initiation of the treatments or any event already present that worsens in either intensity or frequency following exposure to the treatments. SAS included all subjects who received at least 1 administration of study drug.

End point type

Secondary

End point timeframe

From start of study drug administration up to EOT (approximately 21 Months)

End point values	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Number of subjects analysed	3	3	3	3	29	13	18	7
Units: number of subjects
SAEs	1	1	1	2	15	8	7	2
TEAEs	3	3	3	3	28	13	17	7

No statistical analyses for this end point

Secondary: Number of Subjects With Response Evaluation According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

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End point title

Number of Subjects With Response Evaluation According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

End point description

Number of subjects with response evaluation according to RECIST v1.1 was evaluated according to complete response (CR): disappearance of all target and non-target lesions and no new lesions; partial response (PR): >= 30 percent (%) decrease in the sum of diameters of target lesions (compared to baseline) and no new lesions; stable disease (SD): neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; progressive disease (PD): >= 20% increase in the sum of diameters of target lesions and an absolute increase in sum of diameters of >=5 millimeter (mm) (compared to the previous minimum sum) or progression of a new lesion. FAS included all subjects who received at least 1 administration of study drug, and who had 1 postbaseline tumor response.

End point type

Secondary

End point timeframe

Day 28 of Cycle 2 followed by every 2 Cycles of 28 day Cycles: Day 56, Day 112, Day 168 and Day 224

End point values	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Number of subjects analysed	3	3	3	3	29	12	18	7
Units: subjects
Best Overall Response: Complete Response (CR)	0	0	0	0	0	0	0	0
Best Overall Response: Partial Response (PR)	0	2	0	0	0	0	3	1
Best Overall Response: Stable Disease (SD)	1	1	2	1	14	4	6	2
Best Overall Response: Progressive Disease (PD)	2	0	1	2	15	7	8	4
Best Overall Response: Not Evaluable (NE)	0	0	0	0	0	1	1	0

No statistical analyses for this end point

Secondary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival was defined as the time from randomization until death due to any cause. FAS included all subjects who received at least 1 administration of study drug, and who had 1 postbaseline tumor response. Here '99999' indicates upper limit of 95% CI was not available and '88888' indicates median and 95% CI were not available due to insufficient number of events at the end of the study.

End point type

Secondary

End point timeframe

From start of study drug administration up to EOT (approximately 21 Months)

End point values	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Number of subjects analysed	3	3	3	2	16	10	8	3
Units: weeks
median (confidence interval 95%)
weeks	24.9 (7.4 to 40.4)	42.7 (15.4 to 77.4)	42.7 (16.9 to 42.7)	24.9 (9.4 to 42.1)	31.9 (26.3 to 58.0)	27.2 (9.3 to 46.7)	31.4 (19.9 to 99999)	88888 (88888 to 88888)

No statistical analyses for this end point

Secondary: Number of Subjects With Plasma Imalumab Concentrations in Combination With 5-Fluourouracil/Leucovorin (FU/LV) or Panitumumab

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End point title

Number of Subjects With Plasma Imalumab Concentrations in Combination With 5-Fluourouracil/Leucovorin (FU/LV) or Panitumumab

End point description

Imalumab plasma pharmacokinetic (PK) was characterized using a population PK modeling approach. Due to early termination and discontinuation of the imalumab clinical development program, no population PK analysis was performed, as the results of this analysis will not be needed for further studies.

End point type

Secondary

End point timeframe

Day 1 predose and postdose; Day 2 post first dose; Day 4 post first dose; Days 8, 15 and 22 predose and postdose

End point values	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Number of subjects analysed	0 ^[6]	0 ^[7]	0 ^[8]	0 ^[9]	0 ^[10]	0 ^[11]	0 ^[12]	0 ^[13]
Units: Subjects

Notes
[6] - No PK analysis was performed.
[7] - No PK analysis was performed.
[8] - No PK analysis was performed.
[9] - No PK analysis was performed.
[10] - No PK analysis was performed.
[11] - No PK analysis was performed.
[12] - No PK analysis was performed.
[13] - No PK analysis was performed.

No statistical analyses for this end point

Secondary: Change From Baseline for Quality of Life (QoL) Measure - European Organization for Research and Treatment of Cancer Quality of life Questionnaire Core 30 (EORTC QLQ-C30)

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End point title

Change From Baseline for Quality of Life (QoL) Measure - European Organization for Research and Treatment of Cancer Quality of life Questionnaire Core 30 (EORTC QLQ-C30)

End point description

EORTC QLQ-C30 was used to measure QOL and assess symptoms and side effects of treatment and the impact on everyday life. The QLQ-C30 was composed of 5 multi-item functional scales (FS) (physical [PFS], role [RFS], social [SFS], emotional [EFS] and cognitive functioning [CFS]), a global health status (GHS)/QoL scale, and 9 symptom scales (SS) (fatigue [FSS], nausea/vomiting [NVSS], pain [PSS], financial impact/difficulties [FDSS], appetite loss [ALSS], diarrhea [Dia SS], constipation [CSS], sleep disturbance/insomnia [ISS] and dyspnea [Dys SS]). Most items were answered on a 4-point scale (i.e., 1=Not at all,2=A Little,3=Quite a bit,4=Very Much) except items contributing to GHS/QOL which have a 7-point scale:1=very poor to 7=excellent. For GHS/FS scores-higher score:better QOL; SS scores-lower score:better QoL. SAS included all subjects who received at least 1 administration of study drug. ‘99999’ and ‘88888’: Mean/SD not calculated as number of subjects analyzed were less or 0.

End point type

Secondary

End point timeframe

Baseline, 21 Months (EOT) up to follow-up

End point values	Part 1: Imalumab 7.5 mg/kg + 5 FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Number of subjects analysed	3	3	3	3	29	13	18	7
Units: score on a scale
arithmetic mean (standard deviation)
GHS (Baseline) (n=3, 3, 3, 3, 29, 13, 17, 7)	33.33 ( 16.665 )	66.7 ( 8.335 )	75 ( 8.330 )	66.67 ( 16.665 )	68.10 ( 18.510 )	62.18 ( 25.371 )	66.18 ( 22.529 )	59.52 ( 19.501 )
GHS (CFB) (n=2, 0, 3, 1, 19, 8, 12, 5)	8.33 ( 35.355 )	99999 ( 99999 )	-5.56 ( 4.812 )	-16.67 ( 88888 )	-13.16 ( 23.293 )	-13.54 ( 21.333 )	-10.42 ( 17.810 )	-11.67 ( 9.502 )
PFS (Baseline) (n=3, 3, 3, 3, 28, 13, 18, 7)	63.33 ( 26.031 )	75.56 ( 19.249 )	88.89 ( 7.696 )	80 ( 6.670 )	78.45 ( 18.670 )	81.15 ( 15.537 )	78.89 ( 20.612 )	70 ( 17.950 )
PFS (CFB) (n=2, 0, 3, 1, 18, 8, 13, 5)	0 ( 0 )	99999 ( 99999 )	-2.22 ( 7.699 )	-20 ( 88888 )	-5 ( 17.198 )	-21.04 ( 23.489 )	-4.10 ( 10.379 )	-14.67 ( 15.918 )
RFS (Baseline) (n=3, 3, 3, 3, 28, 13, 18, 7)	50 ( 50 )	88.89 ( 19.243 )	72.22 ( 9.619 )	77.78 ( 19.243 )	74.41 ( 24.630 )	73.08 ( 30.076 )	76.85 ( 19.078 )	66.67 ( 25.459 )
RFS (CFB) (n=2, 0, 3, 1, 18, 8, 13, 5)	-25 ( 35.355 )	99999 ( 99999 )	-16.67 ( 16.670 )	0 ( 88888 )	-12.04 ( 24.122 )	-16.67 ( 43.642 )	-11.54 ( 29.957 )	-10 ( 14.910 )
EFS (Baseline) (n=3, 3, 3, 3, 28, 13, 17, 7)	79.67 ( 26.274 )	97.22 ( 4.809 )	91.67 ( 8.335 )	83.33 ( 16.665 )	78.87 ( 18.494 )	73.08 ( 25.720 )	77.45 ( 19.490 )	66.66 ( 18.003 )
EFS (CFB) (n=2, 0, 3, 1, 18, 8, 12, 5)	-7 ( 13.675 )	99999 ( 99999 )	-5.56 ( 17.346 )	-41.66 ( 88888 )	-3.24 ( 15.163 )	-1.04 ( 16.925 )	-2.78 ( 16.792 )	-11.66 ( 20.916 )
CFS (Baseline) (n=3, 3, 3, 3, 28, 13, 17, 7)	83.33 ( 16.665 )	88.89 ( 19.243 )	100 ( 0 )	83.33 ( 16.665 )	88.10 ( 18.063 )	89.74 ( 14.496 )	93.14 ( 10.306 )	83.33 ( 23.571 )
CFS (CFB) (n=2, 0, 3, 1, 18, 8, 12, 5)	0 ( 0 )	99999 ( 99999 )	0 ( 0 )	-33.33 ( 88888 )	-1.85 ( 15.003 )	-27.08 ( 30.779 )	-8.33 ( 15.075 )	-6.67 ( 9.128 )
SFS (Baseline) (n=3, 3, 3, 3, 28, 13, 17, 7)	77.78 ( 25.458 )	66.67 ( 0 )	77.78 ( 9.619 )	77.78 ( 9.619 )	88.69 ( 15.080 )	80.77 ( 24.387 )	73.53 ( 29.498 )	66.67 ( 27.215 )
SFS (CFB) (n=2, 0, 3, 1, 18, 8, 12, 5)	-8.34 ( 11.787 )	99999 ( 99999 )	-22.22 ( 9.630 )	-33.34 ( 88888 )	-13.89 ( 25.726 )	-25 ( 15.430 )	0 ( 38.924 )	-10 ( 19.004 )
FSS (Baseline) (n=3, 3, 3, 3, 28, 13, 18, 7)	29.67 ( 28.015 )	29.66 ( 6.351 )	22.33 ( 0 )	26 ( 6.351 )	33.74 ( 20.645 )	38.46 ( 28.580 )	29.63 ( 19.041 )	41.24 ( 21.943 )
FSS (CFB) (n=2, 0, 3, 1, 18, 8, 13, 5)	44.50 ( 15.797 )	99999 ( 99999 )	29.45 ( 23.089 )	44.34 ( 88888 )	9.28 ( 19.828 )	23.63 ( 19.197 )	3.44 ( 21.919 )	13.33 ( 18.209 )
NVSS (Baseline) (n=3, 3, 3, 3, 28, 13, 18, 7)	11.11 ( 19.243 )	0 ( 0 )	5.56 ( 9.624 )	16.67 ( 16.665 )	13.10 ( 22.843 )	6.41 ( 10.841 )	7.41 ( 11.746 )	4.76 ( 8.134 )
NVSS (CFB) (n=2, 0, 3, 1, 18, 8, 13, 5)	25 ( 11.780 )	99999 ( 99999 )	5.55 ( 9.619 )	-16.66 ( 88888 )	2.78 ( 24.421 )	14.58 ( 20.773 )	5.13 ( 30.720 )	10 ( 14.906 )
PSS (Baseline) (n=3, 3, 3, 3, 28, 13, 18, 7)	38.89 ( 38.486 )	27.78 ( 9.619 )	16.67 ( 16.665 )	38.89 ( 19.243 )	31.55 ( 27.719 )	23.08 ( 30.074 )	22.22 ( 17.149 )	35.71 ( 29.546 )
PSS (CFB) (n=2, 0, 3, 1, 18, 8, 13, 5)	41.66 ( 35.355 )	99999 ( 99999 )	11.11 ( 19.243 )	0 ( 88888 )	5.55 ( 21.390 )	12.50 ( 21.362 )	6.41 ( 19.882 )	13.33 ( 18.258 )
Dys SS (Baseline) (n=3, 3, 3, 3, 28, 13, 18, 7)	11.11 ( 19.243 )	11.11 ( 19.243 )	0 ( 0 )	22.22 ( 19.243 )	11.90 ( 20.716 )	20.51 ( 25.599 )	14.81 ( 26.127 )	9.52 ( 16.263 )
Dys SS (CFB) (n=2, 0, 3, 1, 18, 8, 13, 5)	33.34 ( 47.143 )	99999 ( 99999 )	11.11 ( 19.243 )	33.33 ( 88888 )	5.56 ( 20.612 )	16.67 ( 30.861 )	17.95 ( 17.296 )	6.67 ( 27.886 )
ISS (Baseline) (n=3, 3, 3, 3, 27, 13, 18, 7)	44.45 ( 38.492 )	0 ( 0 )	33.33 ( 0 )	22.22 ( 19.243 )	23.46 ( 28.964 )	20.51 ( 25.599 )	22.22 ( 25.566 )	47.62 ( 42.415 )
ISS (CFB) (n=2, 0, 3, 1, 17, 8, 13, 5)	-0.01 ( 47.143 )	99999 ( 99999 )	33.34 ( 33.335 )	0 ( 88888 )	7.84 ( 34.421 )	12.50 ( 30.537 )	7.69 ( 14.616 )	-6.67 ( 27.886 )
ALSS (Baseline) (n=3, 3, 3, 3, 28, 13, 18, 7)	11.11 ( 19.243 )	22.22 ( 38.492 )	11.11 ( 19.243 )	22.22 ( 19.243 )	25 ( 33.488 )	33.33 ( 38.490 )	12.96 ( 20.256 )	14.28 ( 17.816 )
ALSS (CFB) (n=2, 0, 3, 1, 18, 8, 13, 5)	66.67 ( 0 )	99999 ( 99999 )	33.33 ( 33.335 )	66.67 ( 88888 )	9.26 ( 29.826 )	4.17 ( 27.820 )	7.69 ( 24.165 )	20 ( 29.816 )
CSS (Baseline) (n=3, 3, 3, 3, 29, 13, 18, 7)	11.11 ( 19.243 )	22.22 ( 19.243 )	0 ( 0 )	22.22 ( 19.243 )	17.24 ( 26.157 )	25.64 ( 30.895 )	22.22 ( 28.005 )	19.05 ( 26.227 )
CSS (CFB) (n=2, 0, 3, 1, 18, 8, 13, 5)	0 ( 0 )	99999 ( 99999 )	22.22 ( 38.492 )	0 ( 88888 )	7.41 ( 33.442 )	16.67 ( 43.645 )	2.56 ( 34.591 )	6.67 ( 27.886 )
Dia SS (Baseline) (n=3, 3, 3, 3, 29, 13, 17, 7)	0 ( 0 )	0 ( 0 )	22.22 ( 19.243 )	11.11 ( 19.243 )	10.34 ( 18.046 )	20.51 ( 34.798 )	17.65 ( 26.660 )	23.81 ( 25.198 )
Dia SS (CFB) (n=2, 0, 3, 1, 19, 8, 12, 5)	33.33 ( 0 )	99999 ( 99999 )	11.11 ( 19.243 )	-33.33 ( 88888 )	8.77 ( 33.040 )	8.33 ( 38.834 )	-11.11 ( 16.411 )	0 ( 23.568 )
FDS (Baseline) (n=3, 3, 3, 3, 29, 13, 17, 7)	11.11 ( 19.243 )	11.11 ( 19.243 )	44.44 ( 50.918 )	44.44 ( 19.249 )	18.39 ( 30.324 )	25.64 ( 33.758 )	19.61 ( 23.743 )	28.57 ( 23.003 )
FDS (CFB) (n=2, 0, 3, 1, 19, 8, 12, 5)	16.67 ( 23.568 )	99999 ( 99999 )	-11.11 ( 19.243 )	0 ( 88888 )	-1.75 ( 25.996 )	-12.50 ( 24.801 )	-5.56 ( 12.976 )	20 ( 18.259 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From start of study drug administration up to 30 (+/-7) days after the last dose of study treatment (approximately 21 months)

Adverse event reporting additional description

The MHRA identified data integrity issues and deficiencies for AEs/SAEs for non-Shire IMPs. As per Sponsor assessment, there was no impact of initial non-assessment of absence of causality for SAEs associated with non-Shire IMPs (i.e.,apart from BAX069) on patient safety, integrity of safety conclusion or on post-marketing safety profile.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Part 1: Imalumab 7.5 mg/kg + 5-FU/LV

Reporting group description

Subjects with mutated tumors (KRAS mut, NRAS mut) received 7.5 mg/kg dose of imalumab QW in combination with 5- FU/LV (LV 400 mg/m^2 IV infusion over 2 hours, followed by 5 FU 2400 mg/m^2 IV infusion over 46 hours) for Q2W IV infusion as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Reporting group title

Part 1: Imalumab 10 mg/kg + 5-FU/LV

Reporting group description

Reporting group title

Part 1: Imalumab 7.5 mg/kg + Panitumumab

Reporting group description

Subjects with wild-type tumors (KRAS wt, NRAS wt) received 7.5 mg/kg dose of imalumab QW in combination with panitumumab 6 mg/kg Q2W IV infusion as a part of 4-week/28-day treatment cycle and continued until disease progression, unacceptable toxicity, death, or subject withdrawal of consent, whichever occurred first.

Reporting group title

Part 1: Imalumab 10 mg/kg + Panitumumab

Reporting group description

Reporting group title

Part 2: Imalumab 10 mg/kg + 5-FU/LV

Reporting group description

Reporting group title

Part 2: Standard of Care Mutant

Reporting group description

Reporting group title

Part 2: Imalumab 10 mg/kg + Panitumumab

Reporting group description

Reporting group title

Part 2: Standard of Care Wild Type

Reporting group description

Serious adverse events	Part 1: Imalumab 7.5 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 3 (66.67%)	15 / 29 (51.72%)	8 / 13 (61.54%)	7 / 18 (38.89%)	2 / 7 (28.57%)
number of deaths (all causes)	1	0	0	0	10	7	4	2
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 29 (6.90%)	2 / 13 (15.38%)	2 / 18 (11.11%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 3	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2	0 / 2	0 / 1
Rectal cancer metastatic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	2 / 13 (15.38%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 2	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Hepatic encephalopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Disease progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 29 (27.59%)	3 / 13 (23.08%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 8	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 8	0 / 3	0 / 1	0 / 1
General physical health deterioration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Gallbladder pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	2 / 13 (15.38%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 2	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Infections and infestations
Perineal abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part 1: Imalumab 7.5 mg/kg + 5-FU/LV	Part 1: Imalumab 10 mg/kg + 5-FU/LV	Part 1: Imalumab 7.5 mg/kg + Panitumumab	Part 1: Imalumab 10 mg/kg + Panitumumab	Part 2: Imalumab 10 mg/kg + 5-FU/LV	Part 2: Standard of Care Mutant	Part 2: Imalumab 10 mg/kg + Panitumumab	Part 2: Standard of Care Wild Type
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 3 (66.67%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	28 / 29 (96.55%)	12 / 13 (92.31%)	17 / 18 (94.44%)	7 / 7 (100.00%)
Vascular disorders
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	2 / 13 (15.38%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	0	6	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 29 (20.69%)	3 / 13 (23.08%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	13	5	1	1
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 29 (6.90%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 29 (6.90%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0
Early satiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	16 / 29 (55.17%)	4 / 13 (30.77%)	5 / 18 (27.78%)	5 / 7 (71.43%)
occurrences all number	0	1	1	0	28	11	6	8
Hypothermia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Localised oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	1	0	1
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 29 (31.03%)	1 / 13 (7.69%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	18	2	2	1
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 29 (10.34%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	3	1	0	0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 29 (6.90%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0
Temperature intolerance
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Reproductive system and breast disorders
Menorrhagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	2
Pelvic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	2	0
Prostatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Scrotal disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Sexual dysfunction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Vaginal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 29 (6.90%)	1 / 13 (7.69%)	3 / 18 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	0	0	2	2	1	3	1
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 29 (13.79%)	1 / 13 (7.69%)	3 / 18 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	5	1	4	0
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1	1
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 29 (6.90%)	0 / 13 (0.00%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	2	0	3	0
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0
Rhinorrhoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Throat irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Upper-Airway cough syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	2	2	0
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 29 (6.90%)	0 / 13 (0.00%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	2	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 29 (6.90%)	1 / 13 (7.69%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	3	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	2 / 13 (15.38%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	2	8	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 29 (6.90%)	2 / 13 (15.38%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	2	6	0	1
Blood albumin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 29 (6.90%)	2 / 13 (15.38%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	4	2	1	0
Blood creatinine increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	4	0	1	0	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	2 / 13 (15.38%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	3 / 13 (23.08%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	16	0	1
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1	0	1
Weight decreased
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 29 (0.00%)	2 / 13 (15.38%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	1	2	0	1	0	2	1	0
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	13	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Laceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Scratch
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Venomous sting
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Congenital, familial and genetic disorders
Dermoid cyst
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	1	2	0
Migraine
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0
Neuralgia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1	1
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	6	0	0
Parosmia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Restless legs syndrome
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Somnolence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 29 (17.24%)	3 / 13 (23.08%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	11	3	1	0
Coagulopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	4	0	0
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Eye disorders
Blepharitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	2	0
Episcleritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Lacrimation increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	2	0
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1	1	1
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 29 (24.14%)	4 / 13 (30.77%)	1 / 18 (5.56%)	3 / 7 (42.86%)
occurrences all number	1	1	0	0	8	4	1	4
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	2 / 13 (15.38%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	2	4	0
Abdominal rigidity
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Constipation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	9 / 29 (31.03%)	4 / 13 (30.77%)	3 / 18 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	1	2	0	9	4	7	1
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 29 (27.59%)	5 / 13 (38.46%)	5 / 18 (27.78%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	10	11	6	2
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 29 (10.34%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0
Flatulence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Haematochezia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Haemorrhoids
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 29 (31.03%)	5 / 13 (38.46%)	4 / 18 (22.22%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	13	7	9	2
Oral dysaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Proctalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	2	0
Rectal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 29 (13.79%)	1 / 13 (7.69%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	8	1	1	1
Tongue ulceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 29 (27.59%)	2 / 13 (15.38%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	9	3	3	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	1
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	1
Blister
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	8 / 18 (44.44%)	2 / 7 (28.57%)
occurrences all number	0	0	3	0	0	0	22	4
Dermatitis contact
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 29 (0.00%)	1 / 13 (7.69%)	6 / 18 (33.33%)	1 / 7 (14.29%)
occurrences all number	0	0	1	1	0	2	6	1
Nail discolouration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	2
Nail discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	2
Nail disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Palmar-Plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	4	0	1
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	4 / 18 (22.22%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	5	3
Rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	9 / 18 (50.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	1	0	18	0
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Rash generalised
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1	1
Rash papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Skin fissures
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	3 / 18 (16.67%)	1 / 7 (14.29%)
occurrences all number	0	0	1	0	0	0	9	1
Skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Trichorrhexis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Renal and urinary disorders
Chromaturia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	1
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	0	1
Haematuria
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Micturition urgency
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Urinary retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	3	2
Back pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 29 (13.79%)	3 / 13 (23.08%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	1	0	1	6	3	0	2
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	0 / 13 (0.00%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	0	2	2
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	2 / 13 (15.38%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 29 (10.34%)	0 / 13 (0.00%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	4	0	1	1
Musculoskeletal stiffness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 29 (6.90%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	3	1	0	0
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Genital herpes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Localised infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Lymph gland infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Paronychia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	4 / 18 (22.22%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	6	0
Rash pustular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 29 (3.45%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	2	1	1	0	1	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 29 (3.45%)	1 / 13 (7.69%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	2	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 29 (20.69%)	5 / 13 (38.46%)	2 / 18 (11.11%)	2 / 7 (28.57%)
occurrences all number	1	1	0	0	10	6	2	3
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 29 (3.45%)	2 / 13 (15.38%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	1	0	1	3	0	0
Hyperkalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 29 (0.00%)	2 / 13 (15.38%)	2 / 18 (11.11%)	1 / 7 (14.29%)
occurrences all number	0	0	0	1	0	2	2	1
Hypomagnesaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 29 (0.00%)	0 / 13 (0.00%)	3 / 18 (16.67%)	0 / 7 (0.00%)
occurrences all number	1	0	2	0	0	0	3	0
Iron deficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 29 (0.00%)	1 / 13 (7.69%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0

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Were there any global substantial amendments to the protocol? Yes

06 Mar 2015

Phase 1 safety data was updated; DLT definition was corrected specifically for the out of range laboratory values, to read as an exclusion to the DLT definition; Administration Description of Change was corrected in SoC Drugs for 5 FU, LV, Panitumumab, and SoC; Exclusion criteria were updated.

13 Jul 2015

Treatment descriptions involving BAX69 were clarified to indicate that BAX69 should be administered 1 hour before either 5 FU/LV or panitumumab; Updated screening and baseline assessments.

09 May 2016

"BAX69” was changed to “imalumab”, where appropriate; "Patients” was changed to “subjects” where appropriate; Exploratory objectives were added to clinical study protocol, to be consistent with the exploratory outcome measures; Duration of Screening was extended from 3 weeks (21 days) to 4 weeks (28 days); Exclusion criteria was added; Included rationale for the inclusion of subjects in this study with ECOG PS 0 to 2 and potential treatment with panitumumab; Provided reference for dose modifications that were implemented in response to a dermatologic reaction (NCI CTCAE Grade 3 or higher, or considered intolerable) in subjects treated with panitumumab; Changed definition of FAS.

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.

On 2016 DEC 16, the Data Safety Monitoring Board (DSMB) reviewed the periodic safety data, and in addition also reviewed available efficacy data from the first 33 PFS events and non-clinical information and recommended to terminate Study 391401.

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Clinical trials

Clinical Trial Results:
A Phase 2a Randomized, Open-Label Study to Assess the Safety, Tolerability, and Efficacy of BAX69 in Combination with 5 FU/Leucovorin or Panitumumab versus Standard of Care in Subjects with Metastatic Colorectal Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 2: Progression-Free Survival (PFS)

Primary: Part 2: Progression-Free Survival (PFS)

Primary: Part 1: Number of Subjects With Occurrence of Dose Limiting Toxicity (DLT)

Primary: Part 1: Number of Subjects With Occurrence of Dose Limiting Toxicity (DLT)

Secondary: Number of Subjects With Occurrence of Binding and/or Neutralizing Anti-imalumab Antibodies

Secondary: Number of Subjects With Occurrence of Binding and/or Neutralizing Anti-imalumab Antibodies

Secondary: Number of Subjects With Incidence and Severity of Infusion Reactions After Imalumab Administration

Secondary: Number of Subjects With Incidence and Severity of Infusion Reactions After Imalumab Administration

Secondary: Number of Subjects With Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events (TEAEs)

Secondary: Number of Subjects With Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events (TEAEs)

Secondary: Number of Subjects With Response Evaluation According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Secondary: Number of Subjects With Response Evaluation According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Number of Subjects With Plasma Imalumab Concentrations in Combination With 5-Fluourouracil/Leucovorin (FU/LV) or Panitumumab

Secondary: Number of Subjects With Plasma Imalumab Concentrations in Combination With 5-Fluourouracil/Leucovorin (FU/LV) or Panitumumab

Secondary: Change From Baseline for Quality of Life (QoL) Measure - European Organization for Research and Treatment of Cancer Quality of life Questionnaire Core 30 (EORTC QLQ-C30)

Secondary: Change From Baseline for Quality of Life (QoL) Measure - European Organization for Research and Treatment of Cancer Quality of life Questionnaire Core 30 (EORTC QLQ-C30)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase 2a Randomized, Open-Label Study to Assess the Safety, Tolerability, and Efficacy of BAX69 in Combination with 5 FU/Leucovorin or Panitumumab versus Standard of Care in Subjects with Metastatic Colorectal Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 2: Progression-Free Survival (PFS)

Primary: Part 2: Progression-Free Survival (PFS)

Primary: Part 1: Number of Subjects With Occurrence of Dose Limiting Toxicity (DLT)

Primary: Part 1: Number of Subjects With Occurrence of Dose Limiting Toxicity (DLT)

Secondary: Number of Subjects With Occurrence of Binding and/or Neutralizing Anti-imalumab Antibodies

Secondary: Number of Subjects With Occurrence of Binding and/or Neutralizing Anti-imalumab Antibodies

Secondary: Number of Subjects With Incidence and Severity of Infusion Reactions After Imalumab Administration

Secondary: Number of Subjects With Incidence and Severity of Infusion Reactions After Imalumab Administration

Secondary: Number of Subjects With Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events (TEAEs)

Secondary: Number of Subjects With Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events (TEAEs)

Secondary: Number of Subjects With Response Evaluation According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Secondary: Number of Subjects With Response Evaluation According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Number of Subjects With Plasma Imalumab Concentrations in Combination With 5-Fluourouracil/Leucovorin (FU/LV) or Panitumumab

Secondary: Number of Subjects With Plasma Imalumab Concentrations in Combination With 5-Fluourouracil/Leucovorin (FU/LV) or Panitumumab

Secondary: Change From Baseline for Quality of Life (QoL) Measure - European Organization for Research and Treatment of Cancer Quality of life Questionnaire Core 30 (EORTC QLQ-C30)

Secondary: Change From Baseline for Quality of Life (QoL) Measure - European Organization for Research and Treatment of Cancer Quality of life Questionnaire Core 30 (EORTC QLQ-C30)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2a Randomized, Open-Label Study to Assess the Safety, Tolerability, and Efficacy of BAX69 in Combination with 5 FU/Leucovorin or Panitumumab versus Standard of Care in Subjects with Metastatic Colorectal Cancer