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Clinical Trial Results:
A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Panitumumab in Children with Solid Tumors

Summary
EudraCT number	2014-005190-36
Trial protocol	Outside EU/EEA
Global end of trial date	25 Mar 2015

Results information
Results version number	v1(current)
This version publication date	29 May 2016
First version publication date	29 May 2016
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

20050252

ISRCTN number

US NCT number

NCT00658658

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?

Yes

Analysis stage

Final

Date of interim/final analysis

25 Mar 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Mar 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to evaluate the safety and pharmacokinetics of up to 3 different dose schedules of panitumumab in pediatric patients with solid tumors.

Protection of trial subjects

This study was conducted in accordance with ICH GCP regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Mar 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 31

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was conducted at 7 centers in the United States. Participants were enrolled from 14 March 2008 to 4 March 2015.

Screening details

Three dose regimens were to be tested in pediatric patients stratified by age group (1 to 11 versus 12 to 17 years). Participants were enrolled sequentially into each dose group, beginning with the 2.5 mg/kg, 12 to 17 year old cohort, based upon demonstration of sufficient safety.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Age 12–17: 2.5 mg/kg QW

Arm description

Participants aged 12 to 17 years received panitumumab 2.5 mg/kg administered by intravenous (IV) infusion weekly (QW) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

Other name

Vectibix

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

Age 12–17: 6 mg/kg Q2W

Arm description

Participants aged 12 to 17 years received panitumumab 6 mg/kg administered by IV infusion every 2 weeks (Q2W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

Other name

Vectibix

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

Age 12–17: 9 mg/kg Q3W

Arm description

Participants aged 12 to 17 years received panitumumab 9 mg/kg administered by IV infusion every 3 weeks (Q3W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

Other name

Vectibix

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

Age 1–11: 2.5 mg/kg QW

Arm description

Participants aged 1 to 11 years received panitumumab 2.5 mg/kg administered by IV infusion QW until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

Other name

Vectibix

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

Age 1–11: 6 mg/kg Q2W

Arm description

Participants aged 1 to 11 years received panitumumab 6 mg/kg administered by IV infusion Q2W until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study.

Arm type

Experimental

Investigational medicinal product name

Panitumumab

Investigational medicinal product code

Other name

Vectibix

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Panitumumab administered by intravenous infusion over 60 minutes for doses ≤ 1000 mg and over 60 to 90 minutes for doses > 1000 mg.

Number of subjects in period 1	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Started	6	7	4	6	8
Completed	1	5	4	4	3
Not completed	5	2	0	2	5
Consent withdrawn by subject	-	1	-	-	-
Death	4	-	-	1	1
Other	-	-	-	-	1
Protocol-specified Criteria	1	-	-	-	-
Disease Progression	-	1	-	1	3

Baseline characteristics

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Reporting group title

Age 12–17: 2.5 mg/kg QW

Reporting group description

Reporting group title

Age 12–17: 6 mg/kg Q2W

Reporting group description

Reporting group title

Age 12–17: 9 mg/kg Q3W

Reporting group description

Reporting group title

Age 1–11: 2.5 mg/kg QW

Reporting group description

Reporting group title

Age 1–11: 6 mg/kg Q2W

Reporting group description

Reporting group values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W	Total
Number of subjects	6	7	4	6	8	31
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	6	8	14
Adolescents (12-17 years)	6	7	4	0	0	17
Adults (18-64 years)	0	0	0	0	0	0
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	13.2 ± 0.8	15.6 ± 1.5	15.8 ± 1.9	7.8 ± 3.1	8.4 ± 2.8	-
Gender, Male/Female
Units: participants
Female	3	1	3	3	4	14
Male	3	6	1	3	4	17
Race/Ethnicity, Customized
Units: Subjects
Asian	0	2	0	0	0	2
Black (or African American)	1	1	0	1	0	3
Hispanic or Latino	0	0	1	0	1	2
Other	0	0	0	1	0	1
White or Caucasian	5	4	3	4	7	23

End points

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Reporting group title

Age 12–17: 2.5 mg/kg QW

Reporting group description

Reporting group title

Age 12–17: 6 mg/kg Q2W

Reporting group description

Reporting group title

Age 12–17: 9 mg/kg Q3W

Reporting group description

Reporting group title

Age 1–11: 2.5 mg/kg QW

Reporting group description

Reporting group title

Age 1–11: 6 mg/kg Q2W

Reporting group description

Primary: Number of Participants with Dose-limiting Toxicities (DLTs)

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End point title

Number of Participants with Dose-limiting Toxicities (DLTs) ^[1]

End point description

Any panitumumab related grade 3 or 4 hematologic or non-hematologic toxicity (graded according to the modified Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria) was considered a DLT with the exception of alopecia and fatigue. Hypomagnesemia, nausea, diarrhea, vomiting, and skin or nail toxicities constituted a DLT only of the following occured: • Grade 3 or 4 hypomagnesemia that persisted for at least 5 days despite maximal magnesium replacement; • Grade 3 or 4 diarrhea, nausea, or vomiting that persisted for at least 5 days despite maximum supportive therapy; • Grade 4 skin or nail toxicity. This analysis was perfored in the DLT Analysis Set which included all participants who received at least 1 dose of panitumumab and were evaluated for DLTs and completed at least 28 days (for the 2.5 and 6 mg/kg cohorts) or 21 days (for 9 mg/kg cohort) of therapy unless due to a DLT.

End point type

Primary

End point timeframe

28 days from initial administration of panitumumab for the 2.5 and 6 mg/kg cohorts and 21 days from first administration for the 9 mg/kg cohort.

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: A formal hypothesis was not tested in this study. All results are descriptive in nature.

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	4	5	4	4	5
Units: participants
number (not applicable)	1	0	0	1	3

No statistical analyses for this end point

Primary: Number of Participants with Adverse Events (AEs)

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End point title

Number of Participants with Adverse Events (AEs) ^[2]

End point description

A serious adverse event is defined as an AE that: • is fatal; • is life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • is a congenital anomaly/birth defect; • other significant medical hazard. The investigator assessed whether adverse events were related to panitumumab. The severity of adverse events was based on CTCAE version 3 (with the exception of skin- or nail-related toxicities which were graded using the CTCAE version 3.0 with modifications), according to the following: Grade 1 = Mild (aware of sign or symptom, but easily tolerated); Grade 2 = Moderate (discomfort enough to cause interference with usual activity); Grade 3 = Severe (incapacitating with inability to work or do usual activity); Grade 4 = Life-threatening or disabling; Grade 5 = Fatal. Adverse event analyses include all participants who received at least one dose of panitumumab.

End point type

Primary

End point timeframe

From first dose date to end of study date. The median duration of study was 47 days.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: A formal hypothesis was not tested in this study. All results are descriptive in nature.

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	6	7	4	6	8
Units: participants
number (not applicable)
Any adverse event	6	7	3	6	8
Serious adverse events	5	3	2	3	5
Treatment-related adverse event	5	5	3	5	6
Treatment-related serious adverse event	1	0	0	1	2
Withdrawals due to adverse event	0	0	0	0	0
Grade 1	5	7	3	6	6
Grade 2	5	6	3	4	7
Grade 3	4	5	2	4	6
Grade 4	4	0	0	1	2
Fatal	4	0	0	1	1

No statistical analyses for this end point

Primary: Maximum Observed Concentration (Cmax) of Panitumumab

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End point title

Maximum Observed Concentration (Cmax) of Panitumumab ^[3]

End point description

Panitumumab serum concentration was measured using an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) of the assay was 400 pg/mL. Concentrations below the LLOQ were set to zero. The Pharmacokinetic (PK) Analysis Set included all participants who received the correct dose of panitumumab and from whom the PK parameters could be assessed; "n" indicates the number of participants with available data for each time point. Standard deviation was not calculated when n < 3; "99999" is entered as a placeholder.

End point type

Primary

End point timeframe

First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively).

Notes
[3] - 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: A formal hypothesis was not tested in this study. All results are descriptive in nature.

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	6	7	3	4	7
Units: μg/mL
arithmetic mean (standard deviation)
First Dose (n=6, 7, 3, 4, 7)	52.8 ± 11.4	161 ± 41.2	205 ± 45.9	42.9 ± 8.51	120 ± 29.4
Third Dose (n=3, 5, 1, 3, 2)	76.6 ± 21.1	187 ± 45.2	327 ± 99999	60.8 ± 15.7	126 ± 99999

No statistical analyses for this end point

Primary: Minimum Observed Concentration (Cmin) of Panitumumab

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End point title

Minimum Observed Concentration (Cmin) of Panitumumab ^[4]

End point description

Standard deviation was not calculated when n < 3; "99999" is entered as a placeholder.

End point type

Primary

End point timeframe

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: A formal hypothesis was not tested in this study. All results are descriptive in nature.

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	4	7	2	4	5
Units: μg/mL
arithmetic mean (standard deviation)
First Dose (n=4, 7, 2, 4, 5)	6.62 ± 6.83	24.7 ± 18.6	35.3 ± 99999	4.87 ± 3.64	19.7 ± 15.5
Third Dose (n=3, 5, 0, 3, 2)	24.2 ± 22.9	48.1 ± 25.1	99999 ± 99999	17.3 ± 8.83	26.1 ± 99999

No statistical analyses for this end point

Primary: Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab

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End point title

Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab ^[5]

End point description

The area under the serum concentration-time curve from time zero to the end of the dosing interval (AUCtau), estimated using the linear trapezoidal method. Standard deviation was not calculated when n < 3; "99999" is entered as a placeholder.

End point type

Primary

End point timeframe

Notes
[5] - 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: A formal hypothesis was not tested in this study. All results are descriptive in nature.

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	4	7	2	4	5
Units: day*μg/mL
arithmetic mean (standard deviation)
First Dose (n=4, 7, 2, 4, 5)	167 ± 86.1	1040 ± 357	1580 ± 99999	127 ± 37.9	708 ± 247
Third Dose (n=3, 5, 0, 3, 2)	306 ± 178	1330 ± 357	99999 ± 99999	255 ± 70.7	754 ± 99999

No statistical analyses for this end point

Primary: Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab

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End point title

Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab ^[6]

End point description

Standard deviation was not calculated when n < 3; "99999" is entered as placeholder.

End point type

Primary

End point timeframe

Notes
[6] - 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: A formal hypothesis was not tested in this study. All results are descriptive in nature.

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	2	5	1	3	3
Units: days
arithmetic mean (standard deviation)
First Dose (n=2, 5, 1, 3, 3)	1.33 ± 99999	4.49 ± 1.09	4.27 ± 99999	2.11 ± 0.913	4.23 ± 1.64
Third Dose (n=2, 2, 0, 1, 1)	2.94 ± 99999	4.98 ± 99999	99999 ± 99999	3.07 ± 99999	4.91 ± 99999

No statistical analyses for this end point

Primary: Serum Clearance (CL) of Panitumumab

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End point title

Serum Clearance (CL) of Panitumumab ^[7]

End point description

Standard deviation was not calculated when n < 3; "99999" is entered as a placeholder.

End point type

Primary

End point timeframe

Notes
[7] - 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: A formal hypothesis was not tested in this study. All results are descriptive in nature.

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	3	5	1	4	3
Units: mL/day/kg
arithmetic mean (standard deviation)
First Dose (n=3, 5, 1, 4, 3)	19.8 ± 8.57	6.38 ± 0.466	7.15 ± 99999	18.7 ± 6.35	8.06 ± 1.4
Third Dose (n=3, 5, 0, 3, 2)	9.92 ± 4.4	4.69 ± 1	99999 ± 99999	10.1 ± 2.44	8.05 ± 99999

No statistical analyses for this end point

Secondary: Number of Participants who Developed Antibodies to Panitumumab

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End point title

Number of Participants who Developed Antibodies to Panitumumab

End point description

Three validated assays were used to detect the presence of anti-panitumumab antibodies. Two screening immunoassays, an acid-dissociation enzyme-linked immunosorbent assay (ELISA) and a Biacore-based biosensor assay, were used to detect antibodies capable of binding to panitumumab. All samples confirmed to be positive by drug specificity in either screening immunoassay were further tested for neutralizing antibodies in a cell-based epidermal growth factor receptor (EGFR) phosphorylation bioassay. The number of participants who developed antibodies to panitumumab is the number of participants with a non-positive (including missing) antibody result at baseline and a positive antibody result at any post-baseline time point. This analysis includes all participants who received at least 1 dose of panitumumab and who had at least one post-baseline immunoassay result.

End point type

Secondary

End point timeframe

Before panitumumab administration on Day 1, Day 43, Day 169 and 30 days after last dose for all cohorts.

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	4	5	4	3	4
Units: participants
number (not applicable)
Binding antibodies	1	0	0	2	0
Neutralizing antibodies	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants with an Objective Response

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End point title

Percentage of Participants with an Objective Response

End point description

Disease assessments were based on investigator review of scans using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria. Objective ersponse is defined as a best response of either complete response (CR) or partial response (PR). Participants with no post-baseline assessments were considered non-responders. CR or PR was confirmed no less than 4-weeks after the criteria for response were first met. CR: Disappearance of all target and non-target lesions, normalization of tumor markers and no new lesions. PR: At least 30% decrease in the size of target lesions, no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions, persistence of 1 or more non-target lesion(s) not qualifying for either CR or progressive disease (PD) or/and maintenance of tumor marker level above normal limits and no new lesions. Analysis includes all participants with baseline measurable disease who received at least 1 dose of panitumumab.

End point type

Secondary

End point timeframe

Tumor response was assessed every 8 weeks through week 48 and every 3 months thereafter until disease progression or end of study. The data cut-off for the analysis was 17 June 2015; median duration of study was 47 days.

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	4	3	4	2	3
Units: percentage of participants
number (confidence interval 95%)	0 (0 to 60.24)	0 (0 to 70.76)	0 (0 to 60.24)	0 (0 to 84.19)	0 (0 to 70.76)

No statistical analyses for this end point

Secondary: Percentage of Participants with Disease Control

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End point title

Percentage of Participants with Disease Control

End point description

Disease assessments were based on investigator review of scans using modified RECIST version 1.0 criteria. A participant was considered to have disease control if their best response is either a complete or partial response, or stable disease (SD). Participants without a post-baseline assessment were considered to not have disease control. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. A best overall response of SD requires a visit response of SD or better, no earlier than 49 days after the date of enrollment. Stable disease: Neither sufficient shrinkage of target lesions to qualify for a PR nor sufficient increase to qualify for PD and no progression of existing non-target lesions and no new lesions. Analysis includes all participants with baseline measurable disease who received at least 1 dose of panitumumab.

End point type

Secondary

End point timeframe

End point values	Age 12–17: 2.5 mg/kg QW	Age 12–17: 6 mg/kg Q2W	Age 12–17: 9 mg/kg Q3W	Age 1–11: 2.5 mg/kg QW	Age 1–11: 6 mg/kg Q2W
Number of subjects analysed	4	3	4	2	3
Units: percentage of participants
number (confidence interval 95%)	0 (0 to 60.24)	33.33 (0.84 to 90.57)	0 (0 to 60.24)	50 (1.26 to 98.74)	66.67 (9.43 to 99.16)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose date to end of study date. The median duration of study is 47 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Age 12–17: 2.5 mg/kg QW

Reporting group description

Reporting group title

Age 12-17: 6 mg/kg Q2W

Reporting group description

Reporting group title

Age 12-17: 9 mg/kg Q3W

Reporting group description

Reporting group title

Age 1-11: 2.5 mg/kg QW

Reporting group description

Reporting group title

Age 1-11: 6 mg/kg Q2W

Reporting group description

Serious adverse events	Age 12–17: 2.5 mg/kg QW	Age 12-17: 6 mg/kg Q2W	Age 12-17: 9 mg/kg Q3W	Age 1-11: 2.5 mg/kg QW	Age 1-11: 6 mg/kg Q2W
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 6 (83.33%)	3 / 7 (42.86%)	2 / 4 (50.00%)	3 / 6 (50.00%)	5 / 8 (62.50%)
number of deaths (all causes)	4	0	0	1	1
number of deaths resulting from adverse events
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood urea increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	2 / 6 (33.33%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Osteosarcoma
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyosarcoma
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Apnoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchostenosis
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
Hypoxia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory acidosis
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Substance-induced psychotic disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oliguria
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Age 12–17: 2.5 mg/kg QW	Age 12-17: 6 mg/kg Q2W	Age 12-17: 9 mg/kg Q3W	Age 1-11: 2.5 mg/kg QW	Age 1-11: 6 mg/kg Q2W
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 6 (83.33%)	7 / 7 (100.00%)	3 / 4 (75.00%)	6 / 6 (100.00%)	7 / 8 (87.50%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Hypotension
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	1	0	0
Pallor
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0
Chills
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	1	0	1	0
Fatigue
subjects affected / exposed	1 / 6 (16.67%)	4 / 7 (57.14%)	2 / 4 (50.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)
occurrences all number	1	7	2	0	2
Hypothermia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Localised oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0
Mucosal inflammation
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Oedema
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	0	0	1
Oedema peripheral
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0	0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	1
Immune system disorders
Cytokine release syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0
Reproductive system and breast disorders
Acquired phimosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Cough
subjects affected / exposed	0 / 6 (0.00%)	3 / 7 (42.86%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	4	2	0	1
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 4 (50.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)
occurrences all number	0	0	2	1	1
Epistaxis
subjects affected / exposed	0 / 6 (0.00%)	2 / 7 (28.57%)	2 / 4 (50.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	2	0	0
Nasal congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0
Obstructive airways disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	1
Pleural effusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Respiratory distress
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Rhinitis allergic
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	2	0	0
Wheezing
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Psychiatric disorders
Abnormal behaviour
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Agitation
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	0	0	1
Anxiety
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)
occurrences all number	1	0	0	0	2
Confusional state
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	1	0	0
Depressed mood
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Depression
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Disorientation
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Irritability
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	1
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Blood albumin decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	0	0	1
Blood bicarbonate decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Blood creatinine
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Blood creatinine increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Blood lactate dehydrogenase decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Blood potassium decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	2
Haemoglobin
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	0	0	0	0
Haemoglobin decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	0	0	2
Heart rate increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	2
Neutrophil count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	0	0	0	2
Platelet count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	1	0	1
Temperature difference of extremities
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	2
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Contusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Infusion related reaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0
Skin abrasion
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Wound secretion
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0
Cardiac disorders
Arrhythmia supraventricular
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Bradycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Palpitations
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Sinus tachycardia
subjects affected / exposed	1 / 6 (16.67%)	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	1	1	0	1
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	2	0	2
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 6 (0.00%)	2 / 7 (28.57%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0	0
Cerebellar syndrome
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	4	0	1	0
Cognitive disorder
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Cranial nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	1
Headache
subjects affected / exposed	2 / 6 (33.33%)	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)
occurrences all number	2	4	1	0	3
Hemiplegia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	2	0
Hyperaesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Motor dysfunction
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	2
Nystagmus
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	1
Peripheral motor neuropathy
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)
occurrences all number	1	0	0	1	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	1	0	2
Phantom pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Pyramidal tract syndrome
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	4	0	0
Lymphadenopathy
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Lymphopenia
subjects affected / exposed	0 / 6 (0.00%)	2 / 7 (28.57%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	1	0	0
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	1	1	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0
Vertigo
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Eye disorders
Diplopia
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	2	0	0	1
Dry eye
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Erythema of eyelid
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Exophthalmos
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Lacrimation increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Vision blurred
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 6 (33.33%)	1 / 7 (14.29%)	2 / 4 (50.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	1	2	0	0
Change of bowel habit
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Constipation
subjects affected / exposed	3 / 6 (50.00%)	3 / 7 (42.86%)	1 / 4 (25.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	4	3	1	1	0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	3 / 8 (37.50%)
occurrences all number	0	0	0	0	3
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0
Gingival bleeding
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Gingival erythema
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Hypoaesthesia oral
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Nausea
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	3 / 8 (37.50%)
occurrences all number	1	0	2	0	4
Oral pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Stomatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	4 / 6 (66.67%)	1 / 8 (12.50%)
occurrences all number	0	0	4	5	1
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	1
Alopecia
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0	0
Decubitus ulcer
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Dermatitis acneiform
subjects affected / exposed	2 / 6 (33.33%)	5 / 7 (71.43%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	18	0	0	0
Dry skin
subjects affected / exposed	0 / 6 (0.00%)	4 / 7 (57.14%)	2 / 4 (50.00%)	1 / 6 (16.67%)	3 / 8 (37.50%)
occurrences all number	0	7	3	1	3
Erythema
subjects affected / exposed	2 / 6 (33.33%)	2 / 7 (28.57%)	0 / 4 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)
occurrences all number	3	2	0	4	0
Exfoliative rash
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	2 / 4 (50.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	2	3	0	1
Petechiae
subjects affected / exposed	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0
Pruritus
subjects affected / exposed	2 / 6 (33.33%)	2 / 7 (28.57%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	2	2	1	0	1
Purpura
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Rash
subjects affected / exposed	2 / 6 (33.33%)	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 6 (33.33%)	2 / 8 (25.00%)
occurrences all number	2	1	0	2	4
Rash erythematous
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0	0
Rash macular
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Rash papular
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0
Skin fissures
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Skin hypopigmentation
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	0	0	0	0
Urinary incontinence
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Urogenital haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Endocrine disorders
Cushingoid
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0
Bone atrophy
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Flank pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Fracture pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	2 / 7 (28.57%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	4	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)
occurrences all number	0	0	1	1	1
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Pain in extremity
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	1	0	1	1	0
Scoliosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Torticollis
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Infections and infestations
Cystitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0
Herpes virus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Influenza
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0	0
Oral fungal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0
Oral herpes
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Peritonitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Purulent discharge
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0
Rash pustular
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Sinusitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Streptococcal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Urinary tract infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Alkalosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1
Decreased appetite
subjects affected / exposed	2 / 6 (33.33%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)
occurrences all number	2	0	0	1	0
Dehydration
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)
occurrences all number	1	0	0	0	2
Hyperglycaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	0	0	1
Hyperkalaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	2 / 6 (33.33%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	3	0	0	0	0
Hypocalcaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	5	0	0
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0
Hypokalaemia
subjects affected / exposed	3 / 6 (50.00%)	0 / 7 (0.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)
occurrences all number	3	0	3	0	1
Hypomagnesaemia
subjects affected / exposed	1 / 6 (16.67%)	1 / 7 (14.29%)	2 / 4 (50.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)
occurrences all number	1	1	4	0	2
Hyponatraemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0
Hypophosphataemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	3	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

02 Mar 2011

- Removed the requirement for epidermal growth factor receptor (EGFR) immunohistochemical staining of tumor tissue prior to enrollment, but rather allow the central EGFR testing to be performed within 4 weeks after enrollment. - Updated the eligibility criteria to state that male subjects of reproductive potential were no longer required to use contraception precautions during the study and female subjects of childbearing potential were required to use adequate contraception precautions during treatment and for 2 months after the end of treatment. - Updated the interruption of panitumumab infusion to be consistent with the most recent guidelines regarding the management of panitumumab-related infusion reactions. - Deleted the instructions to allow treatment of subjects with central nervous system (CNS) disease only with stable glucocorticoid dosing. The dose of glucocorticoid to manage CNS disease may change while subjects are on the study. - Updated study procedures to specify that any blood and/or tumor tissue sample collected according to the Schedule of Assessments may be analyzed for any of the tests outlined in the protocol and for any tests necessary to minimize risks to study subjects. In addition, if informed consent is provided by the subject, Amgen may do additional testing on remaining samples. - Updated the Screening section to clarify that tumor tissue samples for EGFR testing should be submitted to the designated central laboratory within 4 weeks after enrollment. - Updated the End of Study Visit section to clarify that in case a subject tests positive for human antipanitumumab antibodies (HAPA) at the end of study visit, additional serum samples will be drawn and tested every 3 months from the date that the site is informed by Amgen of the positive result until the HAPA result is negative, withdrawal of consent, death, or up to 1 year after the positive result has been reported, whichever occurs first.

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 Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Panitumumab in Children with Solid Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with Dose-limiting Toxicities (DLTs)

Primary: Number of Participants with Dose-limiting Toxicities (DLTs)

Primary: Number of Participants with Adverse Events (AEs)

Primary: Number of Participants with Adverse Events (AEs)

Primary: Maximum Observed Concentration (Cmax) of Panitumumab

Primary: Maximum Observed Concentration (Cmax) of Panitumumab

Primary: Minimum Observed Concentration (Cmin) of Panitumumab

Primary: Minimum Observed Concentration (Cmin) of Panitumumab

Primary: Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab

Primary: Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab

Primary: Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab

Primary: Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab

Primary: Serum Clearance (CL) of Panitumumab

Primary: Serum Clearance (CL) of Panitumumab

Secondary: Number of Participants who Developed Antibodies to Panitumumab

Secondary: Number of Participants who Developed Antibodies to Panitumumab

Secondary: Percentage of Participants with an Objective Response

Secondary: Percentage of Participants with an Objective Response

Secondary: Percentage of Participants with Disease Control

Secondary: Percentage of Participants with Disease Control

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
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Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Panitumumab in Children with Solid Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with Dose-limiting Toxicities (DLTs)

Primary: Number of Participants with Dose-limiting Toxicities (DLTs)

Primary: Number of Participants with Adverse Events (AEs)

Primary: Number of Participants with Adverse Events (AEs)

Primary: Maximum Observed Concentration (Cmax) of Panitumumab

Primary: Maximum Observed Concentration (Cmax) of Panitumumab

Primary: Minimum Observed Concentration (Cmin) of Panitumumab

Primary: Minimum Observed Concentration (Cmin) of Panitumumab

Primary: Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab

Primary: Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab

Primary: Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab

Primary: Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab

Primary: Serum Clearance (CL) of Panitumumab

Primary: Serum Clearance (CL) of Panitumumab

Secondary: Number of Participants who Developed Antibodies to Panitumumab

Secondary: Number of Participants who Developed Antibodies to Panitumumab

Secondary: Percentage of Participants with an Objective Response

Secondary: Percentage of Participants with an Objective Response

Secondary: Percentage of Participants with Disease Control

Secondary: Percentage of Participants with Disease Control

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Panitumumab in Children with Solid Tumors