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Clinical Trial Results:
A Randomized, Phase 1b/2 Trial of AMG 102 or AMG 479 in Combination with Panitumumab versus Panitumumab Alone in Subjects With Wild-Type KRAS Metastatic Colorectal Cancer

Summary
EudraCT number	2008-001751-21
Trial protocol	ES BE AT IT FR GB
Global end of trial date	31 Oct 2013

Results information
Results version number	v1(current)
This version publication date	20 Jun 2016
First version publication date	31 Jul 2015
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

20060447

ISRCTN number

US NCT number

NCT00788957

WHO universal trial number (UTN)

Sponsor organisation name

Amgen, Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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

08 Feb 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

31 Oct 2013

Was the trial ended prematurely?

Main objective of the trial

The primary objective of part 1 of this study was to identify a tolerable dose of rilotumumab in combination with panitumumab based on the incidence of dose-limiting toxicities (DLTs). The primary objective of part 2 of this study was to evaluate the efficacy, as assessed by the overall objective response rate (ORR), of rilotumumab (at the tolerable dose selected in Part 1) in combination with panitumumab and the efficacy of ganitumab in combination with panitumumab compared with that of panitumumab alone.

Protection of trial subjects

This study was conducted in accordance with US Food and Drug Administration (FDA) and International Conference on Harmonization (ICH) Good Clinical Practice (GCP) regulations/guidelines. The study protocol, amendments to the protocol, subject information, and informed consent forms were reviewed and approved by the independent ethics committee or institutional review board of each study center. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Oct 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 18

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Italy: 4

Country: Number of subjects enrolled

Poland: 43

Country: Number of subjects enrolled

Russian Federation: 26

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

United Kingdom: 6

Country: Number of subjects enrolled

United States: 23

Worldwide total number of subjects

153

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)

102

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

First subject enrolled 27 October 2008; last subject enrolled 05 February 2010. In Part 1, subjects with wild-type KRAS metastatic colorectal cancer received open-label rilotumumab and panitumumab to identify a tolerable dose of rilotumumab for Part 2 of the study. Participants enrolled in Part 1 were not eligible for randomization in Part 2.

Screening details

In Part 2 subjects were randomized in a 1:1:1 ratio to 1 of the 3 double-blinded treatment arms. In Part 3, subjects randomized to Panitumumab Alone in Part 2 and with disease progression or intolerability were re-randomized 1:1 into 2 double-blind groups. Participants completed a safety follow-up visit 30 days after the last dose of study drug.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

In Part 1 subjects received open-label rilotumumab in combination with panitumumab with the purpose of identifying a tolerable dose of rilotumumab for the Part 2 portion of the study. In Part 2, panitumumab was administered open-label and rilotumumab and ganitumab were double-blinded. Part 3 was double-blinded for both rilotumumab and ganitumab. Part 3 was double-blinded for both rilotumumab and ganitumab.

Are arms mutually exclusive

Part 1: Panitumumab + Rilotumumab

Arm description

Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

AMG 954

Other name

Vectibix®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

6 mg/kg by intravenous infusion once every 2 weeks

Investigational medicinal product name

Rilotumumab

Investigational medicinal product code

AMG 102

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

10 mg/kg by intravenous infusion once every 2 weeks

Part 2: Panitumumab Alone

Arm description

Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Arm type

Active comparator

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

AMG 954

Other name

Vectibix®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

6 mg/kg by intravenous infusion once every 2 weeks

Part 2: Panitumumab + Rilotumumab

Arm description

Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

AMG 954

Other name

Vectibix®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

6 mg/kg by intravenous infusion once every 2 weeks

Investigational medicinal product name

Rilotumumab

Investigational medicinal product code

AMG 102

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

10 mg/kg by intravenous infusion once every 2 weeks

Part 2: Panitumumab + Ganitumab

Arm description

Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

AMG 954

Other name

Vectibix®

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

6 mg/kg by intravenous infusion once every 2 weeks

Investigational medicinal product name

Ganitumab

Investigational medicinal product code

AMG 479

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

12 mg/kg by intravenous infusion once every 2 weeks

Part 3: Rilotumumab

Arm description

Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive rilotumumab 10 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision.

Arm type

Experimental

Investigational medicinal product name

Rilotumumab

Investigational medicinal product code

AMG 102

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

10 mg/kg by intravenous infusion once every 2 weeks

Part 3: Ganitumab

Arm description

Participants randomized to Panitumumab Alone in Part 2 who had disease progression (radiographic or clinical) or intolerability were re-randomized in Part 3 to receive ganitumab 12 mg/kg every 2 weeks until disease progression, intolerability, withdrawal, death, or sponsor decision.

Arm type

Experimental

Investigational medicinal product name

Ganitumab

Investigational medicinal product code

AMG 479

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

12 mg/kg by intravenous infusion once every 2 weeks

Number of subjects in period 1	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab	Part 3: Rilotumumab	Part 3: Ganitumab
Started	11	48	48	46	13	11
Completed	2	6	4	5	4	1
Not completed	9	42	44	41	9	10
Consent withdrawn by subject	-	9	5	3	-	2
Death	8	32	35	37	8	8
Lost to follow-up	1	-	3	-	-	-
On-study at time of data cut-off	-	1	1	1	1	-

Baseline characteristics

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Reporting group title

Part 1: Panitumumab + Rilotumumab

Reporting group description

Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 2: Panitumumab Alone

Reporting group description

Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 2: Panitumumab + Rilotumumab

Reporting group description

Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 2: Panitumumab + Ganitumab

Reporting group description

Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 3: Rilotumumab

Reporting group description

Reporting group title

Part 3: Ganitumab

Reporting group description

Reporting group values	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab	Part 3: Rilotumumab	Part 3: Ganitumab	Total
Number of subjects	11	48	48	46	13	11
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	56.5 ( 13.8 )	55 ( 12.5 )	62.1 ( 7.5 )	62 ( 9.7 )	54.8 ( 13.9 )	52 ( 11.3 )	-
Gender, Male/Female
Units: participants
Female	6	20	19	21	3	6	66
Male	5	28	29	25	10	5	87
Race/Ethnicity
Units: Subjects
White or Caucasian	11	45	47	45	13	10	148
Black or African American	0	0	1	1	0	0	2
Hispanic or Latino	0	1	0	0	0	0	1
Asian	0	1	0	0	0	0	1
Other	0	1	0	0	0	1	1
Primary Tumor Type
Units: Subjects
Colon cancer	6	31	33	28	8	8	98
Rectal cancer	5	17	15	18	5	3	55
Adenocarcinoma differential of primary tumor
Units: Subjects
Well differentiated	0	8	7	6	1	2	21
Moderately differentiated	6	27	27	25	8	6	85
Poorly differentiated	5	9	6	11	1	3	31
Undifferentiated	0	0	0	1	0	0	1
Unknown	0	4	8	3	3	0	15
Months since primary diagnosis
Data available for 9, 46, 46, 45, 13 and 10 subjects in each treatment group respectively
Units: months
arithmetic mean (standard deviation)	41.7 ( 29.7 )	30.3 ( 18.5 )	36.2 ( 31.8 )	34.7 ( 28.7 )	37.8 ( 24.8 )	34.7 ( 17.7 )	-
Months since metastatic disease diagnosis
Units: months
arithmetic mean (standard deviation)	29.7 ( 27.6 )	21.8 ( 12.6 )	25.8 ( 27 )	21.1 ( 16 )	27.3 ( 13.8 )	28.6 ( 15.8 )	-

End points

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Reporting group title

Part 1: Panitumumab + Rilotumumab

Reporting group description

Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 2: Panitumumab Alone

Reporting group description

Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 2: Panitumumab + Rilotumumab

Reporting group description

Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 2: Panitumumab + Ganitumab

Reporting group description

Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 3: Rilotumumab

Reporting group description

Reporting group title

Part 3: Ganitumab

Reporting group description

Subject analysis set title

Rilotumumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Rilotumumab pharmacokinetics in participants who received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Subject analysis set title

Panitumumab

Subject analysis set type

Sub-group analysis

Subject analysis set description

Panitumumab pharmacokinetics in participants who received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Primary: Part 1: Number of Subjects With Dose-limiting Toxicities (DLT)

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End point title

Part 1: Number of Subjects With Dose-limiting Toxicities (DLT) ^[1] ^[2]

End point description

A DLT is defined as any grade 3 or 4 rilotumumab-related or combination (panitumumab and rilotumumab)-related adverse event or laboratory abnormality that is deemed clinically significant by the investigator. This endpoint was analyzed in the first 6 DLT evaluable participants, which included subjects who received at least 2 doses of panitumumab and rilotumumab as scheduled (ie, Week 1 and Week 3) and had a minimum 28 days follow-up for safety, or received at least 1 dose of panitumumab and rilotumumab and had a DLT within the first 28 days on study.

End point type

Primary

End point timeframe

7 weeks

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: The primary objective of Part 1 was to identify a tolerable dose of rilotumumab in combination with panitumumab for use in Part 2, based n the number of dose-limiting toxicities. No statistical comparisons were performed in Part 1.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed for subjects in Part 1 only

End point values	Part 1: Panitumumab + Rilotumumab
Number of subjects analysed	6
Units: participants
number (not applicable)	0

No statistical analyses for this end point

Primary: Part 2: Percentage of Participants with an Objective Response

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End point title

Part 2: Percentage of Participants with an Objective Response ^[3]

End point description

Objective response is defined as a confirmed complete (CR) or partial response (PR) no less than 4 weeks after the criteria for response are first met, determined by the investigator considering the radiologic response of all existing target and non-target lesions, evidence of new lesions, and cytology evaluation (as appropriate) according to the Modified-Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 criteria: CR: Disappearance of all target and non-target and no new lesions. PR: At least a 30% decrease in the size of target lesions with no increase in non-target lesions, or, the disappearance of all target lesions and persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease. Participants without a post-baseline assessment were considered non-responders. Tumor assessments up to the initiation of another anti-tumor therapy including the Part 3 treatment, if applicable, were used.

End point type

Primary

End point timeframe

From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Notes
[3] - 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: This endpoint was analyzed for subjects in Part 2 only

End point values	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	48 ^[4]	48 ^[5]	46 ^[6]
Units: percentage of participants
number (not applicable)	21	31	22

Notes
[4] - Efficacy analysis set with Baseline measureable disease
[5] - Efficacy analysis set with Baseline measureable disease
[6] - Efficacy analysis set with Baseline measureable disease

Posterior Distribution of Objective Response Rate

Statistical analysis description

For the primary analysis of objective response rate (ORR) for Part 2, a Beta(6.3, 33.7) and Beta(1.1, 5.9) was used as priors for panitumumab alone and combination regimens in calculating the posterior distribution of the ORR for each respective treatment group. The posterior mean difference in ORR and the 95% credible region for the difference in the ORR between panitumumab + rilotumumab compared to panitumumab alone is reported.

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Rilotumumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[7]

Method

Parameter type

Posterior Mean Difference in ORR

Point estimate

10.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

26.2

Notes
[7] - The primary endpoint of ORR was analyzed by Bayesian approaches to determine if either of the combination treatments (panitumumab plus rilotumumab or panitumumab plus ganitumab) met the pre-specified criteria for promising or not promising.

Posterior Distribution of Objective Response Rate

Statistical analysis description

For the primary analysis of objective response rate (ORR) for Part 2, a Beta(6.3, 33.7) and Beta(1.1, 5.9) was used as priors for panitumumab alone and combination regimens in calculating the posterior distribution of the ORR for each respective treatment group. The posterior mean difference in ORR and the 95% credible region for the difference in the ORR between panitumumab + ganitumab compared to panitumumab alone is reported.

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Ganitumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[8]

Method

Parameter type

Posterior Mean Difference in ORR

Point estimate

2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-10.6

upper limit

16.4

Notes
[8] - The primary endpoint of ORR was analyzed by Bayesian approaches to determine if either of the combination treatments (panitumumab plus rilotumumab or panitumumab plus ganitumab) met the pre-specified criteria for promising or not promising.

Posterior Distribution of ORR - Odds Ratio

Statistical analysis description

The posterior distribution of the odds ratio for an ORR was used to assess whether rilotumumab and/or ganitumab in combination with panitumumab has a higher ORR compared to panitumumab alone. A 95% credible region was calculated for the odds ratio. An odds ratio value greater than 1 implies a higher ORR for the respective combination therapy relative to panitumumab alone.

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Rilotumumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[9]

P-value

= 0.9318 ^[10]

Method

Posterior probability of OR > 1

Parameter type

Posterior Mean odds ratio (OR)

Point estimate

2.003

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

4.243

Notes
[9] - The primary endpoint of ORR was analyzed by Bayesian approaches to determine if either of the combination treatments (panitumumab plus rilotumumab or panitumumab plus ganitumab) met the pre-specified criteria for promising or not promising.
[10] - The posterior probability of the odds ratio being > 1 is reported as the P-value.

Posterior Distribution of ORR - Odds Ratio

Statistical analysis description

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Ganitumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

= 0.6336 ^[12]

Method

Posterior probability of OR > 1

Parameter type

Posterior Mean odds ratio (OR)

Point estimate

1.281

Confidence interval

level

95%

sides

2-sided

lower limit

0.478

upper limit

2.726

Notes
[11] - The primary endpoint of ORR was analyzed by Bayesian approaches to determine if either of the combination treatments (panitumumab plus rilotumumab or panitumumab plus ganitumab) met the pre-specified criteria for promising or not promising.
[12] - The posterior probability of the odds ratio being > 1 is reported as the P-value.

Secondary: Part 2: Duration of Response

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End point title

Part 2: Duration of Response ^[13]

End point description

The interval from the first visit of a confirmed objective response to disease progression as defined by the modified RECIST v1.0 criteria. Participants who did not progress by the earlier of the analysis data cutoff date, initiating a new line of anti-tumor therapy, and the start of Part 3 dosing where applicable were censored at their last evaluable disease assessment date prior to the end of reporting period. Progressive disease is defined as at least a 20% increase in the size of target lesions, or unequivocal progression of existing non-target lesions, or any new lesions. "99999" indicates values that could not be estimated due to the low number of events.

End point type

Secondary

End point timeframe

From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Notes
[13] - 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: This endpoint was analyzed for subjects in Part 2 only

End point values	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	10 ^[14]	15 ^[15]	10 ^[16]
Units: months
median (confidence interval 95%)	3.7 (3.6 to 99999)	5.1 (3.7 to 5.6)	3.7 (3.6 to 5.8)

Notes
[14] - Efficacy analysis set; participants with an objective response of CR or PR.
[15] - Efficacy analysis set; participants with an objective response of CR or PR.
[16] - Efficacy analysis set; participants with an objective response of CR or PR.

No statistical analyses for this end point

Secondary: Part 2: Time to Response

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End point title

Part 2: Time to Response ^[17]

End point description

The interval from the first dose of study therapy to the date of the first confirmed objective response, calculated only for participants with an objective response.

End point type

Secondary

End point timeframe

From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Notes
[17] - 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: This endpoint was analyzed for subjects in Part 2 only

End point values	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	10 ^[18]	15 ^[19]	10 ^[20]
Units: months
median (confidence interval 95%)	1.8 (1.6 to 2.5)	1.6 (1.6 to 1.7)	1.7 (1.6 to 1.7)

Notes
[18] - Efficacy analysis set; participants with an objective response of CR or PR.
[19] - Efficacy analysis set; participants with an objective response of CR or PR.
[20] - Efficacy analysis set; participants with an objective response of CR or PR.

No statistical analyses for this end point

Secondary: Part 2: Percentage of Participants with Disease Control

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End point title

Part 2: Percentage of Participants with Disease Control ^[21]

End point description

The percentage of participants with an overall objective response of CR, PR, or stable disease (SD). CR: Disappearance of all target and non-target and no new lesions. PR: At least a 30% decrease in the size of target lesions with no increase in non-target lesions, or, the disappearance of all target lesions and persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease (PD). SD: Neither sufficient shrinkage of target lesions to qualify for PR nor sufficient increase to qualify for PD and no progression of non-target lesions, or the persistence of one or more non-target lesion(s) not qualifying for either CR or PD.

End point type

Secondary

End point timeframe

From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Notes
[21] - 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: This endpoint was analyzed for subjects in Part 2 only

End point values	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	48 ^[22]	48 ^[23]	46 ^[24]
Units: percentage of participants
number (confidence interval 95%)	56 (41 to 71)	71 (56 to 83)	61 (45 to 75)

Notes
[22] - Efficacy analysis set with baseline measurable disease.
[23] - Efficacy analysis set with baseline measurable disease.
[24] - Efficacy analysis set with baseline measurable disease.

Difference in disease control rate

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Rilotumumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

Difference in disease control rate

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Ganitumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-16

upper limit

Secondary: Part 2: Progression-free Survival (PFS)

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End point title

Part 2: Progression-free Survival (PFS) ^[25]

End point description

The interval from the first dose of study therapy to the earlier date of disease progression (per modified-RECIST v1.0) or death. Participants who did not progress or die by the analysis data cutoff date were censored at their last evaluable disease assessment date prior to the earlier of the analysis data cutoff date, initiating a new line of anti-tumor therapy, and receiving study treatment in part 3 where applicable. Participants enrolled into Part 3 or who started a new line of anti-tumor therapy before radiographic progression but subsequently died were considered as having an event with the event date same as the death date.

End point type

Secondary

End point timeframe

From the date of first dose until the data cut-off date of 23 July 2010. Median follow-up time was 30 weeks.

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed for subjects in Part 2 only

End point values	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	48 ^[26]	48 ^[27]	46 ^[28]
Units: months
median (confidence interval 95%)	3.7 (2.5 to 5.3)	5.2 (3.6 to 5.4)	5.3 (2.7 to 5.7)

Notes
[26] - Efficacy analysis set
[27] - Efficacy analysis set
[28] - Efficacy analysis set

Difference in progression-free survival

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Rilotumumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in median time

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

2.8

Difference in progression-free survival

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Ganitumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in median time

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

2.9

Secondary: Part 2: On-treatment Progression-free Survival

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End point title

Part 2: On-treatment Progression-free Survival ^[29]

End point description

An event is defined as a radiographic progression or death that occurred from the first dose to 28 days since the last dose of study therapy. Participants who did not progress or die during this period were censored at their last evaluable disease assessment before the end of the 28-day period. Participants who received Part 3 treatment before 28 days since their last dose of study drug in Part 2 and did not have radiographic progression or die were censored at their last evaluable disease assessment prior to receiving therapy in Part 3. Radiographic progressions after start of a new anti-tumor therapy, including Part 3 treatment, or after 28 days since the last dose in Part 2 were excluded from the analysis. Participants who died with no prior radiographic disease progression during Part 3 treatment, but within the 28-day period since the last dose in Part 2 were considered as having an event.

End point type

Secondary

End point timeframe

From the date of first dose until 28 days after the last dose until the data cut-off date of 23 July 2010. Median time on treatment was 3.7, 4.9 and 5.1 months in each treatment arm respectively.

Notes
[29] - 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: This endpoint was analyzed for subjects in Part 2 only

End point values	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	48 ^[30]	48 ^[31]	46 ^[32]
Units: months
median (confidence interval 95%)	3.8 (2.5 to 5.3)	5.3 (3.6 to 5.4)	5.3 (2.7 to 5.7)

Notes
[30] - Efficacy analysis set
[31] - Efficacy analysis set
[32] - Efficacy analysis set

Difference in on-treatment PFS

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Rilotumumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in median time

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

2.8

Difference in on-treatment PFS

Comparison groups

Part 2: Panitumumab Alone v Part 2: Panitumumab + Ganitumab

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in median time

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

2.9

Secondary: Part 2: Overall Survival

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End point title

Part 2: Overall Survival ^[33]

End point description

The interval from the first dose of study therapy to the date of death. Participants still alive at the analysis data cutoff date were censored at their last contact date.

End point type

Secondary

End point timeframe

From the date of first dose until the data cut-off date of 08 February 2012. Median follow-up time was 45.5 weeks.

Notes
[33] - 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: This endpoint was analyzed for subjects in Part 2 only

End point values	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	48 ^[34]	48 ^[35]	46 ^[36]
Units: months
median (confidence interval 95%)	11.6 (9.8 to 18)	13.8 (11 to 17.9)	10.6 (7.3 to 14.3)

Notes
[34] - Efficacy analysis set
[35] - Efficacy analysis set
[36] - Efficacy analysis set

No statistical analyses for this end point

Secondary: Number of Subjects with Adverse Events (AEs)

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End point title

Number of Subjects with Adverse Events (AEs) ^[37]

End point description

A serious adverse event (SAE) is defined as an AE that is fatal, life threatening (places the participant at immediate risk of death), requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or other significant medical hazard. AEs were graded for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) version 3: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. AEs were assessed by the investigator for the relationship of the AE to each one or more of the investigational products by the question: “Is there a reasonable possibility that the event may have been caused by the investigational product?”

End point type

Secondary

End point timeframe

From the first dose date to 30 days after the last dose of study drug, up to the data cutoff date of 08 February 2012. Median time on treatment was 5.2 months for Part 1, 2.8, 3.9 and 4.2 months for each Part 2 treatment arm respectively.

Notes
[37] - 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: This endpoint was analyzed for subjects in Part 1 and Part 2 only

End point values	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	11 ^[38]	48 ^[39]	48 ^[40]	46 ^[41]
Units: participants
number (not applicable)
Any adverse event	11	45	48	46
Worst grade of 3	8	19	28	25
Worst grade of 4	1	3	6	4
Worst grade of 5	1	1	4	4
Serious adverse event	5	10	9	10
AE leading to study drug / study discontinuation	4	4	9	7
Treatment-related adverse event (TRAE)	10	43	47	45
TRAE worst grade of 3	7	11	26	20
TRAE worst grade of 4	0	3	6	4
TRAE worst grade of 5	0	0	0	0
Serious treatment-related adverse event	2	1	2	2
TRAE leading to study drug/study discontinuation	3	2	4	2

Notes
[38] - Safety analysis set
[39] - Safety analysis set
[40] - Safety analysis set
[41] - Safety analysis set

No statistical analyses for this end point

Secondary: Number of Subjects with Grade 3 or Higher Laboratory Toxicities

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End point title

Number of Subjects with Grade 3 or Higher Laboratory Toxicities ^[42]

End point description

The severity of laboratory toxicities was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) version 3: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal.

End point type

Secondary

End point timeframe

Notes
[42] - 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: This endpoint was analyzed for subjects in Part 1 and Part 2 only

End point values	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	11 ^[43]	48 ^[44]	48 ^[45]	46 ^[46]
Units: participants
number (not applicable)
Increased Alanine Amino Transferase	0	1	0	2
Decreased albumin	0	1	3	0
Increased Alkaline Phosphatase	1	2	3	5
Increased Aspartate Amino Transferase	0	0	0	4
Decreased calcium	0	3	1	2
Increased calcium	1	0	1	2
Increased Creatinine	0	0	0	1
Decreased Glucose	0	0	0	0
Increased Glucose	1	0	2	0
Decreased Magnesium	0	1	2	8
Increased Magnesium	0	4	2	2
Decreased Phosphorus	0	1	4	1
Decreased Potassium	1	1	1	0
Increased Potassium	0	0	1	0
Decreased Sodium	0	3	2	3
Increased Sodium	0	0	1	0
Increased Total Bilirubin	0	3	0	5
Increased Uric Acid	1	1	2	1
Decreased Absolute Neutrophil Count	0	1	1	2
Decreased Hemoglobin	1	2	1	0
Decreased Lymphocytes	1	3	2	1
Decreased Platelets	0	0	0	1
Decreased Total Neutrophils	0	1	1	2
Decreased White Blood Cells	0	0	0	0

Notes
[43] - Safety analysis set
[44] - Safety analysis set
[45] - Safety analysis set
[46] - Safety analysis set

No statistical analyses for this end point

Secondary: Number of Subjects With Antibody Formation to Panitumumab, Rilotumumab or Ganitumab

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End point title

Number of Subjects With Antibody Formation to Panitumumab, Rilotumumab or Ganitumab ^[47]

End point description

Validated immunoassays were used to detect anti-panitumumab, anti-rilotumumab and anti-ganitumab binding antibodies.

End point type

Secondary

End point timeframe

Notes
[47] - 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: This endpoint was analyzed for subjects in Part 1 and Part 2 only

End point values	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	8 ^[48]	40 ^[49]	44 ^[50]	43 ^[51]
Units: participants
number (not applicable)
Anti-panitumumab antibodies	0	3	3	4
Anti-rilotumumab antibodies	0	0	3	0
Anti-ganitumab antibodies	0	0	0	2

Notes
[48] - Safety analysis set participants with at least one post-baseline immunoassay result.
[49] - Safety analysis set participants with at least one post-baseline immunoassay result.
[50] - Safety analysis set participants with at least one post-baseline immunoassay result.
[51] - Safety analysis set participants with at least one post-baseline immunoassay result.

No statistical analyses for this end point

Secondary: Part 1: Maximum Observed Drug Concentration (Cmax) and Minimum drug concentration (Cmin) for Panitumumab and Rilotumumab

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End point title

Part 1: Maximum Observed Drug Concentration (Cmax) and Minimum drug concentration (Cmin) for Panitumumab and Rilotumumab

End point description

End point type

Secondary

End point timeframe

Week 5 (third dose) at pre-dose, 5 minutes after infusion and at 24, 48 and 96, and 168 hours post infusion.

End point values	Panitumumab	Rilotumumab
Number of subjects analysed	6	6
Units: μg/ml
arithmetic mean (standard deviation)
Cmax (n=6, 6)	227 ( 37.23 )	346 ( 88.58 )
Cmin (n=5, 4)	61.1 ( 32.93 )	124 ( 35.22 )

No statistical analyses for this end point

Secondary: Part 1: Area Under the Drug Concentration-time Curve During a Dosing Interval (AUCtau) for Panitumumab and Rilotumumab

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End point title

Part 1: Area Under the Drug Concentration-time Curve During a Dosing Interval (AUCtau) for Panitumumab and Rilotumumab

End point description

End point type

Secondary

End point timeframe

Week 5 (third dose) at pre-dose, 5 minutes after infusion and at 24, 48 and 96, and 168 hours post infusion.

End point values	Panitumumab	Rilotumumab
Number of subjects analysed	5 ^[52]	4 ^[53]
Units: day*μg/ml
arithmetic mean (standard deviation)	1420 ( 386.24 )	2560 ( 675.84 )

Notes
[52] - Part 1 subjects with available intensive pharmacokinetic samples after the third dose (Week 5)
[53] - Part 1 subjects with available intensive pharmacokinetic samples after the third dose (Week 5)

No statistical analyses for this end point

Secondary: Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Panitumumab

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End point title

Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Panitumumab ^[54]

End point description

End point type

Secondary

End point timeframe

Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23.

Notes
[54] - 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: This endpoint was analyzed for subjects in Part 2 only

End point values	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	48 ^[55]	48 ^[56]	46 ^[57]
Units: μg/mL
arithmetic mean (standard deviation)
Week 1 (n=43, 42, 44)	114 ( 31.58 )	124 ( 32.74 )	118 ( 40.95 )
Week 3 (n=38, 37, 38)	149 ( 46.79 )	154 ( 44.66 )	139 ( 33.92 )
Week 5 (n=35, 35, 35)	165 ( 49.67 )	172 ( 55.56 )	150 ( 39.75 )
Week 7 (n=30, 35, 29)	166 ( 51.13 )	180 ( 53.28 )	167 ( 39.91 )
Week 13 (n=16, 17, 21)	201 ( 53.67 )	199 ( 51.14 )	192 ( 59.9 )
Week 23 (n=10, 10, 9)	196 ( 48.02 )	207 ( 51.54 )	187 ( 41.7 )

Notes
[55] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).
[56] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).
[57] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).

No statistical analyses for this end point

Secondary: Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Panitumumab

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End point title

Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Panitumumab ^[58]

End point description

Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).

End point type

Secondary

End point timeframe

Pre-dose at Weeks 3, 5, 7, 13 and 23.

Notes
[58] - 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: This endpoint was analyzed for subjects in Part 2 only

End point values	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	48 ^[59]	48 ^[60]	46 ^[61]
Units: μg/mL
arithmetic mean (standard deviation)
Week 3 (n=39, 36, 36)	19.8 ( 15.9 )	22.8 ( 16.76 )	17.2 ( 9.72 )
Week 5 (n=35, 34, 35)	34.8 ( 20.5 )	37.9 ( 19.9 )	29.8 ( 16.6 )
Week 7 (n=29, 32, 31)	39.9 ( 24.82 )	45.2 ( 22.78 )	37.4 ( 20.38 )
Week 13 (n=16, 17, 20)	63.5 ( 27.31 )	63.4 ( 28.66 )	51.4 ( 32.43 )
Week 23 (n=8, 9, 9)	82.1 ( 23.15 )	62.1 ( 27.51 )	54.8 ( 29.48 )

Notes
[59] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).
[60] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).
[61] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).

No statistical analyses for this end point

Secondary: Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Rilotumumab

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End point title

Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Rilotumumab ^[62]

End point description

End point type

Secondary

End point timeframe

Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23.

Notes
[62] - 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: This endpoint was analyzed for subjects in Part 2 who received rilotumumab

End point values	Part 2: Panitumumab + Rilotumumab
Number of subjects analysed	48 ^[63]
Units: μg/mL
arithmetic mean (standard deviation)
Week 1 (n=43)	239 ( 70.03 )
Week 3 (n=37)	316 ( 89.74 )
Week 5 (n=38)	357 ( 89.25 )
Week 7 (n=37)	397 ( 98.46 )
Week 13 (n=18)	453 ( 107.36 )
Week 23 (n=17)	421 ( 109.46 )

Notes
[63] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).

No statistical analyses for this end point

Secondary: Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Rilotumumab

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End point title

Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Rilotumumab ^[64]

End point description

Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).

End point type

Secondary

End point timeframe

Pre-dose at Weeks 3, 5, 7, 13 and 23.

Notes
[64] - 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: This endpoint was analyzed for subjects in Part 2 who received rilotumumab

End point values	Part 2: Panitumumab + Rilotumumab
Number of subjects analysed	48 ^[65]
Units: μg/mL
arithmetic mean (standard deviation)
Week 3 (n=38)	70.1 ( 28.88 )
Week 5 (n=34)	119 ( 37.84 )
Week 7 (n=33)	143 ( 39.33 )
Week 13 (n=19)	186 ( 75.7 )
Week 23 (n=17)	181 ( 65.7 )

Notes
[65] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).

No statistical analyses for this end point

Secondary: Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Ganitumab

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End point title

Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Ganitumab ^[66]

End point description

End point type

Secondary

End point timeframe

Pre-dose and 5 minutes after the completion of infusion at Weeks 1, 3, 5, 7, 13 and 23.

Notes
[66] - 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: This endpoint was analyzed for subjects in Part 2 who received ganitumab

End point values	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	46 ^[67]
Units: μg/mL
arithmetic mean (standard deviation)
Week 1 (n=40)	218 ( 65.4 )
Week 3 (n=42)	240 ( 60.72 )
Week 5 (n=38)	244 ( 71.49 )
Week 7 (n=35)	279 ( 99.05 )
Week 13 (n=22)	274 ( 76.99 )
Week 23 (n=16)	276 ( 62.93 )

Notes
[67] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).

No statistical analyses for this end point

Secondary: Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Ganitumab

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End point title

Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Ganitumab ^[68]

End point description

Concentration represents the Cmin from the previous dose (eg, Week 3 Cmin is the Cmin after the 1st dose).

End point type

Secondary

End point timeframe

Pre-dose at Weeks 3, 5, 7, 13 and 23.

Notes
[68] - 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: This endpoint was analyzed for subjects in Part 2 who received ganitumab

End point values	Part 2: Panitumumab + Ganitumab
Number of subjects analysed	46 ^[69]
Units: μg/mL
arithmetic mean (standard deviation)
Week 3 (n=39)	19.8 ( 10.22 )
Week 5 (n=39)	24.4 ( 13.47 )
Week 7 (n=37)	28.9 ( 15.66 )
Week 13 (n=22)	38.8 ( 23.9 )
Week 23 (n=16)	39.7 ( 23.34 )

Notes
[69] - Part 2 subjects with available pharmacokinetic data at each time point (indicated by n).

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

The time frame for adverse event reporting is from the first dose date to 30 days since the last dose date in each part of the study. The median time frame is 6.1, 3.7, 4.9., 5.1, 2.4 and 2.3 months by treatment arm respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Part 1: Panitumumab + Rilotumumab

Reporting group description

Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 2: Panitumumab Alone

Reporting group description

Participants received panitumumab 6 mg/kg and placebo by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 2: Panitumumab + Rilotumumab

Reporting group description

Participants received panitumumab 6 mg/kg and rilotumumab 10 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 2: Panitumumab + Ganitumab

Reporting group description

Participants received panitumumab 6 mg/kg and ganitumab 12 mg/kg by intravenous infusion once every 2 weeks until progressive disease, intolerability, withdrawal, death or sponsor decision.

Reporting group title

Part 3: Rilotumumab

Reporting group description

Reporting group title

Part 3: Ganitumab

Reporting group description

Serious adverse events	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab	Part 3: Rilotumumab	Part 3: Ganitumab
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 11 (45.45%)	10 / 48 (20.83%)	9 / 48 (18.75%)	10 / 46 (21.74%)	6 / 13 (46.15%)	2 / 11 (18.18%)
number of deaths (all causes)	1	1	4	4	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
CANCER PAIN
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
COLORECTAL CANCER
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	3 / 48 (6.25%)	2 / 46 (4.35%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 2	0 / 0	0 / 0
COLORECTAL CANCER METASTATIC
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
METASTASES TO CENTRAL NERVOUS SYSTEM
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Vascular disorders
CAPILLARY LEAK SYNDROME
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEEP VEIN THROMBOSIS
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
General disorders and administration site conditions
DISEASE PROGRESSION
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FATIGUE
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
DYSPNOEA
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
RESPIRATORY FAILURE
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Investigations
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS WORSENED
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
HIP FRACTURE
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Cardiac disorders
ARRHYTHMIA SUPRAVENTRICULAR
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
LOSS OF CONSCIOUSNESS
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	0 / 11 (0.00%)	2 / 48 (4.17%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ASCITES
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	1 / 48 (2.08%)	2 / 46 (4.35%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INTESTINAL OBSTRUCTION
subjects affected / exposed	1 / 11 (9.09%)	2 / 48 (4.17%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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 / 0
Hepatobiliary disorders
HYPERBILIRUBINAEMIA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Skin and subcutaneous tissue disorders
DERMATITIS ACNEIFORM
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RASH
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
HYDRONEPHROSIS
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL FAILURE ACUTE
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
URINARY RETENTION
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
BACK PAIN
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
CATHETER SITE INFECTION
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENTEROCOCCAL INFECTION
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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
STAPHYLOCOCCAL SEPSIS
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0	0 / 0
Metabolism and nutrition disorders
HYPERCREATININAEMIA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOALBUMINAEMIA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOGLYCAEMIA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOMAGNESAEMIA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	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

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

Non-serious adverse events	Part 1: Panitumumab + Rilotumumab	Part 2: Panitumumab Alone	Part 2: Panitumumab + Rilotumumab	Part 2: Panitumumab + Ganitumab	Part 3: Rilotumumab	Part 3: Ganitumab
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 11 (100.00%)	43 / 48 (89.58%)	48 / 48 (100.00%)	44 / 46 (95.65%)	9 / 13 (69.23%)	9 / 11 (81.82%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ANOGENITAL WARTS
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
PYOGENIC GRANULOMA
subjects affected / exposed	2 / 11 (18.18%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	6	0	0	1	0	0
Vascular disorders
CAPILLARY LEAK SYNDROME
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	5	0	0	0	0	0
FLUSHING
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	0	0	1
HYPERTENSION
subjects affected / exposed	3 / 11 (27.27%)	1 / 48 (2.08%)	2 / 48 (4.17%)	2 / 46 (4.35%)	1 / 13 (7.69%)	1 / 11 (9.09%)
occurrences all number	3	1	3	3	1	1
HYPERTENSIVE CRISIS
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	3 / 11 (27.27%)	7 / 48 (14.58%)	4 / 48 (8.33%)	6 / 46 (13.04%)	0 / 13 (0.00%)	5 / 11 (45.45%)
occurrences all number	3	11	5	14	0	9
CHILLS
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	4 / 46 (8.70%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	4	0	0
FACE OEDEMA
subjects affected / exposed	1 / 11 (9.09%)	2 / 48 (4.17%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	5	1	0	0	0
FACIAL PAIN
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
FATIGUE
subjects affected / exposed	4 / 11 (36.36%)	10 / 48 (20.83%)	4 / 48 (8.33%)	9 / 46 (19.57%)	1 / 13 (7.69%)	3 / 11 (27.27%)
occurrences all number	14	21	12	13	1	4
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	0	0
INFLAMMATION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	0	1
INFUSION SITE INFLAMMATION
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
MUCOSAL INFLAMMATION
subjects affected / exposed	3 / 11 (27.27%)	3 / 48 (6.25%)	6 / 48 (12.50%)	5 / 46 (10.87%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	3	10	7	0	0
LOCALISED OEDEMA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
OEDEMA PERIPHERAL
subjects affected / exposed	2 / 11 (18.18%)	6 / 48 (12.50%)	9 / 48 (18.75%)	2 / 46 (4.35%)	2 / 13 (15.38%)	0 / 11 (0.00%)
occurrences all number	2	6	11	2	2	0
OEDEMA
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	2	0	0	0
PYREXIA
subjects affected / exposed	1 / 11 (9.09%)	4 / 48 (8.33%)	2 / 48 (4.17%)	2 / 46 (4.35%)	1 / 13 (7.69%)	2 / 11 (18.18%)
occurrences all number	1	8	4	2	1	2
Immune system disorders
DRUG HYPERSENSITIVITY
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
HYPERSENSITIVITY
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	1 / 48 (2.08%)	1 / 46 (2.17%)	1 / 13 (7.69%)	1 / 11 (9.09%)
occurrences all number	0	1	1	1	1	1
Reproductive system and breast disorders
GENITAL TRACT INFLAMMATION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	1 / 11 (9.09%)	2 / 48 (4.17%)	2 / 48 (4.17%)	2 / 46 (4.35%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	2	2	2	0	1
DYSPNOEA
subjects affected / exposed	2 / 11 (18.18%)	1 / 48 (2.08%)	3 / 48 (6.25%)	3 / 46 (6.52%)	1 / 13 (7.69%)	1 / 11 (9.09%)
occurrences all number	5	1	3	4	1	1
EPISTAXIS
subjects affected / exposed	2 / 11 (18.18%)	1 / 48 (2.08%)	7 / 48 (14.58%)	2 / 46 (4.35%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	2	1	7	2	0	1
HICCUPS
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	0	0
NASAL CONGESTION
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	0	0	0
NASAL OEDEMA
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	0	0
OROPHARYNGEAL PAIN
subjects affected / exposed	2 / 11 (18.18%)	1 / 48 (2.08%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	2	2	1	0	0
PHARYNGEAL INFLAMMATION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
Psychiatric disorders
ANXIETY
subjects affected / exposed	0 / 11 (0.00%)	4 / 48 (8.33%)	0 / 48 (0.00%)	2 / 46 (4.35%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	4	0	3	4	0
CONFUSIONAL STATE
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
DEPRESSION
subjects affected / exposed	0 / 11 (0.00%)	4 / 48 (8.33%)	0 / 48 (0.00%)	0 / 46 (0.00%)	2 / 13 (15.38%)	0 / 11 (0.00%)
occurrences all number	0	4	0	0	4	0
INSOMNIA
subjects affected / exposed	3 / 11 (27.27%)	6 / 48 (12.50%)	5 / 48 (10.42%)	4 / 46 (8.70%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	4	6	5	4	1	0
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 11 (0.00%)	2 / 48 (4.17%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 13 (7.69%)	1 / 11 (9.09%)
occurrences all number	0	3	2	0	1	1
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 11 (0.00%)	3 / 48 (6.25%)	1 / 48 (2.08%)	2 / 46 (4.35%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	3	2	2	0	0
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed	0 / 11 (0.00%)	2 / 48 (4.17%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 13 (7.69%)	1 / 11 (9.09%)
occurrences all number	0	4	1	0	1	1
BREATH SOUNDS ABNORMAL
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
GLYCOSYLATED HAEMOGLOBIN INCREASED
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
WEIGHT DECREASED
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	1 / 48 (2.08%)	5 / 46 (10.87%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	1	1	6	1	0
WEIGHT INCREASED
subjects affected / exposed	0 / 11 (0.00%)	3 / 48 (6.25%)	1 / 48 (2.08%)	2 / 46 (4.35%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	4	1	3	1	0
Injury, poisoning and procedural complications
CONTRAST MEDIA REACTION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
EYE INJURY
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
INFUSION RELATED REACTION
subjects affected / exposed	2 / 11 (18.18%)	0 / 48 (0.00%)	0 / 48 (0.00%)	4 / 46 (8.70%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	5	0	0
PROCEDURAL PAIN
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	0	0	2
LACERATION
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	3 / 46 (6.52%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	4	0	0
PROCEDURAL VOMITING
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
Cardiac disorders
TACHYCARDIA
subjects affected / exposed	2 / 11 (18.18%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	1	0	0	0	0
Nervous system disorders
DIZZINESS
subjects affected / exposed	1 / 11 (9.09%)	2 / 48 (4.17%)	1 / 48 (2.08%)	1 / 46 (2.17%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	1	2	2	1	1	0
DYSARTHRIA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
HEADACHE
subjects affected / exposed	1 / 11 (9.09%)	6 / 48 (12.50%)	0 / 48 (0.00%)	1 / 46 (2.17%)	1 / 13 (7.69%)	1 / 11 (9.09%)
occurrences all number	1	6	0	1	1	1
LETHARGY
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	3 / 48 (6.25%)	2 / 46 (4.35%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	4	6	2	0	0
NEUROPATHY PERIPHERAL
subjects affected / exposed	1 / 11 (9.09%)	2 / 48 (4.17%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	2	1	0	0	2
POLYNEUROPATHY
subjects affected / exposed	2 / 11 (18.18%)	2 / 48 (4.17%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	2	0	1	0	0
PARAESTHESIA
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	1	0	0
SOMNOLENCE
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0
TREMOR
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	1
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	1 / 11 (9.09%)	7 / 48 (14.58%)	2 / 48 (4.17%)	2 / 46 (4.35%)	3 / 13 (23.08%)	3 / 11 (27.27%)
occurrences all number	1	10	2	8	5	9
LEUKOPENIA
subjects affected / exposed	0 / 11 (0.00%)	2 / 48 (4.17%)	1 / 48 (2.08%)	2 / 46 (4.35%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	2	2	2	0	1
THROMBOCYTOPENIA
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	3 / 48 (6.25%)	3 / 46 (6.52%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	3	14	0	0
Ear and labyrinth disorders
EAR PAIN
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
HYPOACUSIS
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	1	0	0
OTORRHOEA
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
TINNITUS
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
Eye disorders
CONJUNCTIVITIS
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	7 / 48 (14.58%)	4 / 46 (8.70%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	8	4	0	0
DRY EYE
subjects affected / exposed	2 / 11 (18.18%)	1 / 48 (2.08%)	2 / 48 (4.17%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	1	2	1	0	0
EYE IRRITATION
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	1 / 48 (2.08%)	2 / 46 (4.35%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	1	2	0	0
KERATITIS
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastrointestinal disorders
ABDOMINAL DISCOMFORT
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
ABDOMINAL PAIN
subjects affected / exposed	2 / 11 (18.18%)	7 / 48 (14.58%)	5 / 48 (10.42%)	5 / 46 (10.87%)	1 / 13 (7.69%)	2 / 11 (18.18%)
occurrences all number	6	10	10	13	4	5
ABDOMINAL PAIN UPPER
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	5 / 48 (10.42%)	2 / 46 (4.35%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	2	3	5	4	0	1
ANAL INFLAMMATION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
CHEILITIS
subjects affected / exposed	2 / 11 (18.18%)	1 / 48 (2.08%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	1	0	1	0	0
CONSTIPATION
subjects affected / exposed	6 / 11 (54.55%)	12 / 48 (25.00%)	5 / 48 (10.42%)	7 / 46 (15.22%)	3 / 13 (23.08%)	1 / 11 (9.09%)
occurrences all number	8	15	7	13	6	1
DIARRHOEA
subjects affected / exposed	4 / 11 (36.36%)	5 / 48 (10.42%)	8 / 48 (16.67%)	12 / 46 (26.09%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	7	5	10	19	1	0
DRY MOUTH
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	3 / 46 (6.52%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	0	3	0	0
DYSPHAGIA
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	2	0	0
DYSPEPSIA
subjects affected / exposed	1 / 11 (9.09%)	2 / 48 (4.17%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	2	1	1	0	0
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	1	0
GINGIVAL PAIN
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	1	0	0
GINGIVAL BLEEDING
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	3	0	0	0
NAUSEA
subjects affected / exposed	4 / 11 (36.36%)	8 / 48 (16.67%)	6 / 48 (12.50%)	4 / 46 (8.70%)	2 / 13 (15.38%)	2 / 11 (18.18%)
occurrences all number	5	16	7	5	2	3
STOMATITIS
subjects affected / exposed	2 / 11 (18.18%)	1 / 48 (2.08%)	4 / 48 (8.33%)	6 / 46 (13.04%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	5	1	7	9	0	0
PERITONEAL HAEMORRHAGE
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
VOMITING
subjects affected / exposed	2 / 11 (18.18%)	8 / 48 (16.67%)	3 / 48 (6.25%)	5 / 46 (10.87%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	2	13	3	9	1	0
Hepatobiliary disorders
HEPATIC PAIN
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	1	0	0
JAUNDICE
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	3	0	1
Skin and subcutaneous tissue disorders
ACNE
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	3 / 48 (6.25%)	5 / 46 (10.87%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	6	8	0	0
DERMATITIS
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	1	7	0	0	0
DERMATITIS ACNEIFORM
subjects affected / exposed	6 / 11 (54.55%)	16 / 48 (33.33%)	17 / 48 (35.42%)	13 / 46 (28.26%)	0 / 13 (0.00%)	2 / 11 (18.18%)
occurrences all number	34	47	47	48	0	2
DRY SKIN
subjects affected / exposed	4 / 11 (36.36%)	7 / 48 (14.58%)	11 / 48 (22.92%)	10 / 46 (21.74%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	16	11	16	14	0	1
ECZEMA
subjects affected / exposed	2 / 11 (18.18%)	0 / 48 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	5	0	0
ERYTHEMA
subjects affected / exposed	3 / 11 (27.27%)	2 / 48 (4.17%)	4 / 48 (8.33%)	7 / 46 (15.22%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	8	2	4	13	0	2
HIRSUTISM
subjects affected / exposed	1 / 11 (9.09%)	2 / 48 (4.17%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	2	1	1	0	0
HYPERHIDROSIS
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	2	0	0	1
INGROWING NAIL
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	0	0	0
HYPERTRICHOSIS
subjects affected / exposed	3 / 11 (27.27%)	2 / 48 (4.17%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	6	4	0	2	0	0
KOILONYCHIA
subjects affected / exposed	2 / 11 (18.18%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	4	0	0	0	0	0
NAIL DISORDER
subjects affected / exposed	2 / 11 (18.18%)	0 / 48 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	6	0	3	0	0	0
PAIN OF SKIN
subjects affected / exposed	3 / 11 (27.27%)	2 / 48 (4.17%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	6	2	0	1	0	0
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	1 / 48 (2.08%)	2 / 46 (4.35%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	5	3	2	0	0
PRURITUS
subjects affected / exposed	5 / 11 (45.45%)	12 / 48 (25.00%)	10 / 48 (20.83%)	14 / 46 (30.43%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	20	18	15	27	0	0
RASH
subjects affected / exposed	4 / 11 (36.36%)	24 / 48 (50.00%)	28 / 48 (58.33%)	23 / 46 (50.00%)	3 / 13 (23.08%)	1 / 11 (9.09%)
occurrences all number	9	47	106	57	3	1
SKIN FISSURES
subjects affected / exposed	3 / 11 (27.27%)	8 / 48 (16.67%)	7 / 48 (14.58%)	12 / 46 (26.09%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	9	9	12	31	0	0
SKIN OEDEMA
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
SKIN HYPERPIGMENTATION
subjects affected / exposed	1 / 11 (9.09%)	1 / 48 (2.08%)	1 / 48 (2.08%)	2 / 46 (4.35%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	4	1	2	0	0
Renal and urinary disorders
OLIGURIA
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
RENAL FAILURE CHRONIC
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
RENAL IMPAIRMENT
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
Endocrine disorders
HYPERTHYROIDISM
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	0 / 11 (0.00%)	3 / 48 (6.25%)	4 / 48 (8.33%)	1 / 46 (2.17%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	4	6	1	0	1
BACK PAIN
subjects affected / exposed	2 / 11 (18.18%)	3 / 48 (6.25%)	4 / 48 (8.33%)	0 / 46 (0.00%)	0 / 13 (0.00%)	3 / 11 (27.27%)
occurrences all number	2	4	4	0	0	5
INTERVERTEBRAL DISC PROTRUSION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
MUSCLE SPASMS
subjects affected / exposed	2 / 11 (18.18%)	2 / 48 (4.17%)	3 / 48 (6.25%)	4 / 46 (8.70%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	4	2	3	4	0	1
MUSCULAR WEAKNESS
subjects affected / exposed	0 / 11 (0.00%)	3 / 48 (6.25%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	3	0	0	0	0
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	0 / 11 (0.00%)	2 / 48 (4.17%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 13 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	2	4	0	0	2
MUSCULOSKELETAL PAIN
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	0	0	0
MYOPATHY
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
PAIN IN EXTREMITY
subjects affected / exposed	1 / 11 (9.09%)	2 / 48 (4.17%)	3 / 48 (6.25%)	1 / 46 (2.17%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	2	2	4	1	1	0
Infections and infestations
CANDIDIASIS
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	2	1	0	0
INFECTION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	3	0	0	0
PARONYCHIA
subjects affected / exposed	4 / 11 (36.36%)	7 / 48 (14.58%)	16 / 48 (33.33%)	10 / 46 (21.74%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	16	12	56	25	0	1
NASOPHARYNGITIS
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	1 / 48 (2.08%)	3 / 46 (6.52%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	1	1	3	0	0
PNEUMONIA
subjects affected / exposed	2 / 11 (18.18%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	1	0	0
SKIN BACTERIAL INFECTION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
RASH PUSTULAR
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	2 / 48 (4.17%)	3 / 46 (6.52%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	2	3	6	0	0
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	2 / 11 (18.18%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0	0	0
VULVOVAGINAL CANDIDIASIS
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	2
URINARY TRACT INFECTION
subjects affected / exposed	1 / 11 (9.09%)	2 / 48 (4.17%)	2 / 48 (4.17%)	1 / 46 (2.17%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	1	2	2	1	1	0
VULVOVAGINAL MYCOTIC INFECTION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	1	0	0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	2 / 11 (18.18%)	8 / 48 (16.67%)	11 / 48 (22.92%)	9 / 46 (19.57%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	2	11	12	14	0	1
DEHYDRATION
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	0	0	0	0	0
HYPERCALCAEMIA
subjects affected / exposed	1 / 11 (9.09%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	0	0	1
GLUCOSE TOLERANCE IMPAIRED
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 13 (7.69%)	2 / 11 (18.18%)
occurrences all number	0	0	1	0	1	2
HYPERCREATININAEMIA
subjects affected / exposed	0 / 11 (0.00%)	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
HYPERGLYCAEMIA
subjects affected / exposed	0 / 11 (0.00%)	3 / 48 (6.25%)	1 / 48 (2.08%)	6 / 46 (13.04%)	1 / 13 (7.69%)	2 / 11 (18.18%)
occurrences all number	0	4	2	8	3	3
HYPERKALAEMIA
subjects affected / exposed	0 / 11 (0.00%)	2 / 48 (4.17%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	3	0	1	0	1
HYPERURICAEMIA
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	1	0
HYPOCALCAEMIA
subjects affected / exposed	3 / 11 (27.27%)	0 / 48 (0.00%)	3 / 48 (6.25%)	2 / 46 (4.35%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	7	0	4	3	0	0
HYPOALBUMINAEMIA
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	4 / 48 (8.33%)	1 / 46 (2.17%)	2 / 13 (15.38%)	1 / 11 (9.09%)
occurrences all number	0	1	5	1	4	1
HYPOKALAEMIA
subjects affected / exposed	2 / 11 (18.18%)	5 / 48 (10.42%)	7 / 48 (14.58%)	5 / 46 (10.87%)	0 / 13 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	12	8	5	0	0
HYPOMAGNESAEMIA
subjects affected / exposed	2 / 11 (18.18%)	10 / 48 (20.83%)	14 / 48 (29.17%)	19 / 46 (41.30%)	0 / 13 (0.00%)	1 / 11 (9.09%)
occurrences all number	3	17	34	47	0	2
HYPONATRAEMIA
subjects affected / exposed	0 / 11 (0.00%)	1 / 48 (2.08%)	1 / 48 (2.08%)	2 / 46 (4.35%)	1 / 13 (7.69%)	0 / 11 (0.00%)
occurrences all number	0	1	1	2	1	0

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Were there any global substantial amendments to the protocol? Yes

09 Feb 2010

• Added the secondary endpoint of on-treatment progression-free survival. • Clarified the inclusion criteria for wild-type KRAS tumor status. • Changed inclusion criteria for measureable lesion to also include ≥ 10 mm for spiral CT. • Added results of Part 1, specifying the determined dose of rilotumumab to be used in Parts 2 and 3. • Defined end of study as when all subjects have completed or have had the opportunity to complete the 30-day safety follow-up and 60-day follow-up visits or 2 years after the last subject is enrolled in Part 2, whichever is later. • Revised inclusion criteria for Part 3 to include hemoglobin ≥ 8 g/dL, bilirubin < 1.5 x ULN, and hypomagnesemia ≤ grade 2. • Revised inclusion criteria for Part 3 to include no history or evidence of thrombosis or vascular ischemic events with 12 months of enrollment into Part 3. • Clarified dose withholding or discontinuation procedures related to changes in ALT, AST, or thrombocytopenia. • Further explained procedures related to proscribed therapy during the study and added information on pre-emptive management of panitumumab-related skin toxicities.

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.

None reported

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Clinical trials

Clinical Trial Results: A Randomized, Phase 1b/2 Trial of AMG 102 or AMG 479 in Combination with Panitumumab versus Panitumumab Alone in Subjects With Wild-Type KRAS Metastatic Colorectal Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Number of Subjects With Dose-limiting Toxicities (DLT)

Primary: Part 1: Number of Subjects With Dose-limiting Toxicities (DLT)

Primary: Part 2: Percentage of Participants with an Objective Response

Primary: Part 2: Percentage of Participants with an Objective Response

Secondary: Part 2: Duration of Response

Secondary: Part 2: Duration of Response

Secondary: Part 2: Time to Response

Secondary: Part 2: Time to Response

Secondary: Part 2: Percentage of Participants with Disease Control

Secondary: Part 2: Percentage of Participants with Disease Control

Secondary: Part 2: Progression-free Survival (PFS)

Secondary: Part 2: Progression-free Survival (PFS)

Secondary: Part 2: On-treatment Progression-free Survival

Secondary: Part 2: On-treatment Progression-free Survival

Secondary: Part 2: Overall Survival

Secondary: Part 2: Overall Survival

Secondary: Number of Subjects with Adverse Events (AEs)

Secondary: Number of Subjects with Adverse Events (AEs)

Secondary: Number of Subjects with Grade 3 or Higher Laboratory Toxicities

Secondary: Number of Subjects with Grade 3 or Higher Laboratory Toxicities

Secondary: Number of Subjects With Antibody Formation to Panitumumab, Rilotumumab or Ganitumab

Secondary: Number of Subjects With Antibody Formation to Panitumumab, Rilotumumab or Ganitumab

Secondary: Part 1: Maximum Observed Drug Concentration (Cmax) and Minimum drug concentration (Cmin) for Panitumumab and Rilotumumab

Secondary: Part 1: Maximum Observed Drug Concentration (Cmax) and Minimum drug concentration (Cmin) for Panitumumab and Rilotumumab

Secondary: Part 1: Area Under the Drug Concentration-time Curve During a Dosing Interval (AUCtau) for Panitumumab and Rilotumumab

Secondary: Part 1: Area Under the Drug Concentration-time Curve During a Dosing Interval (AUCtau) for Panitumumab and Rilotumumab

Secondary: Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Panitumumab

Secondary: Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Panitumumab

Secondary: Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Panitumumab

Secondary: Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Panitumumab

Secondary: Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Rilotumumab

Secondary: Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Rilotumumab

Secondary: Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Rilotumumab

Secondary: Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Rilotumumab

Secondary: Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Ganitumab

Secondary: Part 2: Maximum Observed Drug Concentration During the Dosing Interval (Cmax) for Ganitumab

Secondary: Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Ganitumab

Secondary: Part 2: Minimum Observed Drug Concentration During the Dosing Interval (Cmin) for Ganitumab

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Randomized, Phase 1b/2 Trial of AMG 102 or AMG 479 in Combination with Panitumumab versus Panitumumab Alone in Subjects With Wild-Type KRAS Metastatic Colorectal Cancer