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Clinical Trial Results:
A Phase I Study of Ipilimumab (Anti-CTLA-4) in Children, Adolescents, and Young Adults with Treatment Refractory Cancer

Summary
EudraCT number	2012-001141-41
Trial protocol	Outside EU/EEA
Global end of trial date	13 Apr 2014

Results information
Results version number	v1(current)
This version publication date	10 Feb 2017
First version publication date	10 Feb 2017
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

CA184-070

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Division of Cancer Treatment and Diagnosis (DCTD)

Sponsor organisation address

9609 Medical Center Drive, Rockville, United States, 20892

Public contact

Melinda Merchant, MD, Division of Cancer Treatment and Diagnosis (DCTD), merchanm@mail.nih.gov

Scientific contact

Melinda Merchant, MD, Division of Cancer Treatment and Diagnosis (DCTD), merchanm@mail.nih.gov

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000117-PIP02-10 EMEA-000117-PIP01-07

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

13 Apr 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Apr 2014

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to determine the tolerance and toxicity profile of ipilimumab at a range of doses up to, but not exceeding, the highest dose tolerated in adults in subjects ≤ 21 years of age with untreatable, refractory or relapsed solid malignant tumors and to assess the pharmacokinetics (PK) of ipilimumab administered intravenously (IV) in subjects ≤21 years of age with solid tumors refractory to standard therapy.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Sep 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: 33

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

Screening details

33 subjects were enrolled at a total of 3 study sites. All enrolled subjects received at least one dose of Ipilimumab.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

1mg/kg Ipilimumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

YervoyBMS-734016

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

In vitro use

Dosage and administration details

Ipilimumab was administered IV over 90 minutes on Day 1 of each 21-day cycle for 4 cycles in the absence of dose-limiting toxicity (DLT) or disease progression. Subjects received no experimental drug therapy on Days 2 to 21 of cycles 1 through 4. From Cycle 5 onward (with Cycle 5 at Week 12), ipilimumab was administered approximately every 12 weeks (maintenance dosing). Subjects who entered the maintenance phase and had confirmed PD during the maintenance treatment were eligible to receive re-induction therapy using ipilimumab at the assigned dose and schedule specified in the protocol (Day 1 of a 21-day cycle for 4 cycles). Patients who stopped maintenance treatment because of a CR and subsequently had confirmed PD were eligible to receive re-induction as well. Subjects with an initial PR or CR or SD for at least 3 months, and subsequently had PD were also eligible for re-induction. Eligible patients could receive treatment/maintenance therapy until they met off-treatment criteria.

3mg/kg Ipilimumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

YervoyBMS-734016

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

In vitro use

Dosage and administration details

5mg/kg Ipilimumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

YervoyBMS-734016

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

In vitro use

Dosage and administration details

10mg/kg Ipilimumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

YervoyBMS-734016

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

In vitro use

Dosage and administration details

Number of subjects in period 1	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Started	3	3	14	13
Completed	0	0	0	0
Not completed	3	3	14	13
Adverse event, non-fatal	-	-	4	4
Death	-	-	-	1
Progressive Disease	3	3	8	8
Clinical Progression	-	-	1	-
Complicating Disease/Intercurrent Illness	-	-	1	-

Baseline characteristics

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Reporting group title

1mg/kg Ipilimumab

Reporting group description

Reporting group title

3mg/kg Ipilimumab

Reporting group description

Reporting group title

5mg/kg Ipilimumab

Reporting group description

Reporting group title

10mg/kg Ipilimumab

Reporting group description

Reporting group values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab	Total
Number of subjects	3	3	14	13	33
Age Categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	1	1	6	4	12
Adolescents (12-17 years)	0	1	5	7	13
Adults (18-64 years)	2	1	3	2	8
From 65-84 years	0	0	0	0	0
85 years and over	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	14.57 ( 10.54 )	12.57 ( 8.83 )	12.76 ( 5.67 )	14.18 ( 3.53 )	-
Gender Categorical
Units: Subjects
Female	2	1	13	3	19
Male	1	2	1	10	14

End points

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Reporting group title

1mg/kg Ipilimumab

Reporting group description

Reporting group title

3mg/kg Ipilimumab

Reporting group description

Reporting group title

5mg/kg Ipilimumab

Reporting group description

Reporting group title

10mg/kg Ipilimumab

Reporting group description

Primary: Number of subjects with drug-related adverse events, adverse events leading to discontinuation, drug-related adverse events leading to discontinuation, serious adverse events, drug-related serious adverse events, and immune-related adverse events.

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End point title

Number of subjects with drug-related adverse events, adverse events leading to discontinuation, drug-related adverse events leading to discontinuation, serious adverse events, drug-related serious adverse events, and immune-related adverse events. ^[1]

End point description

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling.

End point type

Primary

End point timeframe

From first dose to 30 days after last dose

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	14	13
Units: subjects
Drug-related adverse events	3	3	12	12
Adverse events leading to discontinuation	0	0	4	4
Drug-related AEs leading to discontinuation	0	0	4	4
Serious adverse events	0	2	9	5
Drug-related serious adverse events	0	2	6	5
Immune-related adverse events	2	3	10	10

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - White Blood Cell Count

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End point title

Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - White Blood Cell Count ^[2]

End point description

Laboratory grades are based on Common Terminology Criteria for Adverse Events (CTC) version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 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: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	13
Units: subjects
Grade 0	2	2	9	9
Grade 1	1	1	2	3
Grade 2	0	0	2	0
Grade 3	0	0	0	1
Grade 4	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Absolute Neutrophil Count

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End point title

Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Absolute Neutrophil Count ^[3]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

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: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	12
Units: subjects
Grade 0	2	3	11	9
Grade 1	0	0	0	2
Grade 2	1	0	1	1
Grade 3	0	0	1	0
Grade 4	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Platelet Count

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End point title

Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Platelet Count ^[4]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	13
Units: subjects
Grade 0	3	1	8	10
Grade 1	0	2	5	3
Grade 2	0	0	0	0
Grade 3	0	0	0	0
Grade 4	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Hemoglobin

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End point title

Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Hemoglobin ^[5]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

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: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	13
Units: subjects
Grade 0	0	0	5	1
Grade 1	2	1	4	6
Grade 2	1	0	4	4
Grade 3	0	2	0	2
Grade 4	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Absolute Lymphocyte Count (ALC)

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End point title

Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Absolute Lymphocyte Count (ALC) ^[6]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

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: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	13
Units: subjects
Grade 0	3	1	5	4
Grade 1	0	0	2	2
Grade 2	0	2	4	6
Grade 3	0	0	2	0
Grade 4	0	0	0	1

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Alanine Aminotransferase (ALT)

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End point title

Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Alanine Aminotransferase (ALT) ^[7]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

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: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	13
Units: subjects
Grade 0	1	0	9	5
Grade 1	1	2	2	6
Grade 2	1	1	0	1
Grade 3	0	0	2	1
Grade 4	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Aspartate Aminotransferase (AST)

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End point title

Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Aspartate Aminotransferase (AST) ^[8]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	13
Units: subjects
Grade 0	2	0	11	6
Grade 1	0	3	0	4
Grade 2	1	0	1	2
Grade 3	0	0	1	1
Grade 4	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Total Bilibrubin

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End point title

Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Total Bilibrubin ^[9]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	13
Units: subjects
Grade 0	3	3	12	13
Grade 1	0	0	1	0
Grade 2	0	0	0	0
Grade 3	0	0	0	0
Grade 4	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Alkaline Phosphatase

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End point title

Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Alkaline Phosphatase ^[10]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	13
Units: subjects
Grade 0	1	2	9	9
Grade 1	2	1	2	4
Grade 2	0	0	1	0
Grade 3	0	0	1	0
Grade 4	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Renal Function Laboratory Results - Creatinine

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End point title

Number of Subjects with Worst CTC Grade of On-study Renal Function Laboratory Results - Creatinine ^[11]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	2	13	11
Units: subjects
Grade 0	3	2	13	10
Grade 1	0	0	0	1
Grade 2	0	0	0	0
Grade 3	0	0	0	0
Grade 4	0	0	0	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Serum Chemistry Laboratory Results - Lipase

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End point title

Number of Subjects with Worst CTC Grade of On-study Serum Chemistry Laboratory Results - Lipase ^[12]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	11	8
Units: subjects
Grade 0	2	3	9	8
Grade 1	0	0	0	0
Grade 2	0	0	1	0
Grade 3	1	0	0	0
Grade 4	0	0	1	0

No statistical analyses for this end point

Primary: Number of Subjects with Worst CTC Grade of On-study Serum Chemistry Laboratory Results - Amylase

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End point title

Number of Subjects with Worst CTC Grade of On-study Serum Chemistry Laboratory Results - Amylase ^[13]

End point description

Laboratory grades are based on CTC version 3.0 and 4.0. All treated subjects with evaluable laboratory results were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	11
Units: subjects
Grade 0	3	3	11	11
Grade 1	0	0	1	0
Grade 2	0	0	0	0
Grade 3	0	0	0	0
Grade 4	0	0	1	0

No statistical analyses for this end point

Primary: Number of On-study Deaths

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End point title

Number of On-study Deaths ^[14]

End point description

The total number of deaths due to any cause, that occurred within 30 days of last dose, was reported for each arm. All treated subjects were included in the analysis.

End point type

Primary

End point timeframe

From first dose to last dose plus 30 days

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	14	13
Units: subjects	0	0	1	1

No statistical analyses for this end point

Primary: Number of Deaths

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End point title

Number of Deaths ^[15]

End point description

The total number of deaths due to any cause, including deaths that occurred off-study, was reported for each arm. All treated subjects were included in the analysis.

End point type

Primary

End point timeframe

From Study Initiation to Study Closure (Approximately 67 months)

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	14	13
Units: subjects	3	3	5	4

No statistical analyses for this end point

Primary: Geometric Mean of Derived Maximum Plasma Concentration (Cmax) Parameters of Ipilimumab

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End point title

Geometric Mean of Derived Maximum Plasma Concentration (Cmax) Parameters of Ipilimumab ^[16]

End point description

Pharmacokinetic parameters were derived from plasma concentration vs time data for ipilimumab. Geometric Means for Cmax were reported in micrograms per milliliter (ug/mL) by arm and age cohort. All treated subjects with evaluable PK profiles were included in the analysis.

End point type

Primary

End point timeframe

5 time points from Day 1 through Day 15

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	13	13
Units: ug/mL
geometric mean (geometric coefficient of variation)
Age < 12 years	17.3 ( 99999 )	51.86 ( 17.4 )	93.35 ( 13.43 )	193.4 ( 16.93 )
Age >= 12 years	20.62 ( 12.37 )	81.5 ( 99999 )	90.56 ( 25.15 )	203.3 ( 22.21 )

No statistical analyses for this end point

Primary: Geometric Mean of Derived AUC(0-T) Parameters of Ipilimumab

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End point title

Geometric Mean of Derived AUC(0-T) Parameters of Ipilimumab ^[17]

End point description

Pharmacokinetic parameters were derived from plasma concentration vs time data for ipilimumab. Geometric Means for AUC(0-T) were reported in microgram hours per milliliter (ug*hr/mL) by arm and age cohort. All treated subjects with evaluable PK profiles were included in the analysis.

End point type

Primary

End point timeframe

5 time points from Day 1 through Day 15

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	12	11
Units: ug*hr/mL
geometric mean (geometric coefficient of variation)
Age < 12 years	2119.5 ( 99999 )	4300.3 ( 11.95 )	15752.2 ( 26.94 )	33697.8 ( 34.79 )
Age >= 12 years	1200.6 ( 259.62 )	12735.9 ( 99999 )	11109.9 ( 65.93 )	35983.6 ( 12.9 )

No statistical analyses for this end point

Primary: Geometric Mean of Derived AUC(0-21) Parameters of Ipilimumab

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End point title

Geometric Mean of Derived AUC(0-21) Parameters of Ipilimumab ^[18]

End point description

End point type

Primary

End point timeframe

5 time points from Day 1 through Day 15

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	12	11
Units: ug*hr/mL
geometric mean (geometric coefficient of variation)
Age < 12 years	2554.4 ( 99999 )	5273.1 ( 16.41 )	16317.5 ( 19.84 )	37053.1 ( 17.54 )
Age >= 12 years	1356.9 ( 347.6 )	16484.1 ( 99999 )	12681.1 ( 72.51 )	36751.3 ( 13.59 )

No statistical analyses for this end point

Primary: Geometric Mean of Derived AUC(INF) Parameters of Ipilimumab

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End point title

Geometric Mean of Derived AUC(INF) Parameters of Ipilimumab ^[19]

End point description

Pharmacokinetic parameters were derived from plasma concentration vs time data for ipilimumab. Geometric Means for AUC(INF) were reported in microgram hours per milliliter (ug*hr/mL) by arm and age cohort. All treated subjects with evaluable PK profiles were included in the analysis.

End point type

Primary

End point timeframe

5 time points from Day 1 through Day 15

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	2	3	10	11
Units: ug*hr/mL
geometric mean (geometric coefficient of variation)
Age < 12 years	3126.3 ( 99999 )	5913.1 ( 7.79 )	24676.8 ( 38.72 )	56313.1 ( 27.35 )
Age >= 12 years	6542.7 ( 99999 )	25105.7 ( 99999 )	23170.9 ( 53.14 )	52666.3 ( 24.27 )

No statistical analyses for this end point

Primary: Geometric Mean of Derived Total Body Clearance (CL) Parameters of Ipilimumab

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End point title

Geometric Mean of Derived Total Body Clearance (CL) Parameters of Ipilimumab ^[20]

End point description

Pharmacokinetic parameters were derived from plasma concentration vs time data for ipilimumab. Geometric Means for CL were reported in milliliter per hour per kilogram (mL/hr/kg) by arm and age cohort. All treated subjects with evaluable PK profiles were included in the analysis.

End point type

Primary

End point timeframe

5 time points from Day 1 through Day 15

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	2	3	10	11
Units: mL/hr/kg
geometric mean (geometric coefficient of variation)
Age <12 years	0.32 ( 99999 )	0.51 ( 7.79 )	0.2 ( 38.72 )	0.18 ( 27.35 )
Age >= 12 years	0.15 ( 99999 )	0.12 ( 99999 )	0.22 ( 53.14 )	0.19 ( 24.27 )

No statistical analyses for this end point

Primary: Geometric Mean of Derived Volume of Distribution at Steady State (Vss) Parameters of Ipilimumab

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End point title

Geometric Mean of Derived Volume of Distribution at Steady State (Vss) Parameters of Ipilimumab ^[21]

End point description

Pharmacokinetic parameters were derived from plasma concentration vs time data for ipilimumab. Geometric Means for Vss were reported in liters per kilogram (L/kg) by arm and age cohort. All treated subjects with evaluable PK profiles were included in the analysis.

End point type

Primary

End point timeframe

5 time points from Day 1 through Day 15

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	2	3	10	11
Units: L/kg
geometric mean (geometric coefficient of variation)
Age < 12 years	0.1 ( 99999 )	0.12 ( 57.1 )	0.09 ( 5.07 )	0.08 ( 6.41 )
Age >= 12 years	0.08 ( 99999 )	0.06 ( 99999 )	0.07 ( 16.75 )	0.08 ( 24.18 )

No statistical analyses for this end point

Primary: Mean Terminal Elimination Half-life (T-half) of Ipilimumab

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End point title

Mean Terminal Elimination Half-life (T-half) of Ipilimumab ^[22]

End point description

Pharmacokinetic parameters were derived from plasma concentration vs time data for ipilimumab. Mean T-half was reported in days by arm and age cohort. All treated subjects with evaluable PK profiles were included in the analysis.

End point type

Primary

End point timeframe

5 time points from Day 1 through Day 15

Notes
[22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	2	3	10	11
Units: days
arithmetic mean (standard deviation)
Age < 12 years	8.87 ( 99999 )	7.01 ( 3.07 )	14.33 ( 5.3 )	14.05 ( 3.44 )
Age >= 12 years	14.72 ( 99999 )	13.79 ( 99999 )	9.82 ( 5.09 )	12.74 ( 5.07 )

No statistical analyses for this end point

Primary: Mean Time to Maximum Concentration (Tmax) of Ipilimumab

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End point title

Mean Time to Maximum Concentration (Tmax) of Ipilimumab ^[23]

End point description

Pharmacokinetic parameters were derived from plasma concentration vs time data for ipilimumab. Mean Tmax was reported in hours by arm and age cohort. All treated subjects with evaluable PK profiles were included in the analysis.

End point type

Primary

End point timeframe

5 time points from Day 1 through Day 15

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were reported for this endpoint.

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	10	11
Units: hours
arithmetic mean (standard deviation)
Age < 12 years	1.58 ( 99999 )	2.44 ( 0.96 )	1.81 ( 0.35 )	1.64 ( 0.14 )
Age >= 12 years	1.69 ( 0.09 )	1.93 ( 99999 )	1.56 ( 0.11 )	1.56 ( 0.06 )

No statistical analyses for this end point

Secondary: Best Overall Response

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End point title

Best Overall Response

End point description

COMPLETE RESPONSE: Disappearance of all non-measurable/non-target lesions and normalization of tumor marker levels. PARTIAL RESPONSE: Cannot be determined in patients with non-measureable disease. STABLE DISEASE: Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. PROGRESSIVE DISEASE: Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

End point type

Secondary

End point timeframe

From first dose until disease progression/recurrence

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	3	3	14	13
Units: subjects
Complete Response	0	0	0	0
Partial Response	0	0	0	0
Stable Disease	0	1	5	5
Progressive Disease	3	2	5	6
Not Applicable	0	0	1	1
Not Assessed	0	0	3	1

No statistical analyses for this end point

Secondary: Mean Change from Baseline in Activated CD4+ and CD8+ T Cells

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End point title

Mean Change from Baseline in Activated CD4+ and CD8+ T Cells

End point description

Assessments of the absolute number of activated CD4+ and CD8+ T cells in peripheral blood and change from baseline by study day were made on Day 1 of Cycle 1, and Day 1 of Cycle 2. Mean percent changes from baseline are presented by arm.

End point type

Secondary

End point timeframe

Day 1 of Cycle 1 to Day 1 of Cycle 2 (Days 1 to 22)

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	0 ^[24]	0 ^[25]	9	9
Units: Percent change from baseline
arithmetic mean (standard deviation)
Activated CD4 T Cells	( )	( )	22 ( 36.82 )	27 ( 63.21 )
Activated CD8 T Cells	( )	( )	1.6 ( 48.02 )	-10.5 ( 65.03 )

Notes
[24] - Summary statistics were not presented due to the limited number of subjects in this cohort.
[25] - Summary statistics were not presented due to the limited number of subjects in this cohort.

No statistical analyses for this end point

Secondary: Mean Change from Baseline in Absolutle Lymphocyte Count (ALC)

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End point title

Mean Change from Baseline in Absolutle Lymphocyte Count (ALC)

End point description

Absolute Lymphocyte Counts were evaluated in treated subjects. Mean percent changes from baseline to Day 1 of Cycle 2 are presented by arm.

End point type

Secondary

End point timeframe

Day 1 of Cycle 1 to Day 1 of Cycle 2 (Days 1 to 22)

End point values	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Number of subjects analysed	0 ^[26]	0 ^[27]	9	9
Units: Percent change from baseline
arithmetic mean (standard deviation)	( )	( )	8.5 ( 16.84 )	15.6 ( 52.15 )

Notes
[26] - Summary statistics were not presented due to the limited number of subjects in this cohort.
[27] - Summary statistics were not presented due to the limited number of subjects in this cohort.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose to last dose plus 30 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

1mg/kg Ipilimumab

Reporting group description

Reporting group title

3mg/kg Ipilimumab

Reporting group description

Reporting group title

5mg/kg Ipilimumab

Reporting group description

Reporting group title

10mg/kg Ipilimumab

Reporting group description

Serious adverse events	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	9 / 14 (64.29%)	5 / 13 (38.46%)
number of deaths (all causes)	0	0	1	1
number of deaths resulting from adverse events	0	0	0	0
Investigations
Amylase Increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lipase Increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood Creatine Phosphokinase Increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 14 (14.29%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Autoimmune Disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 14 (14.29%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic Reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vision Blurred
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Device Related Infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper Respiratory Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	1mg/kg Ipilimumab	3mg/kg Ipilimumab	5mg/kg Ipilimumab	10mg/kg Ipilimumab
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	14 / 14 (100.00%)	13 / 13 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	1	4	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1
Hot Flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Lymphoedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	3 / 3 (100.00%)	2 / 14 (14.29%)	6 / 13 (46.15%)
occurrences all number	0	4	3	8
Fatigue
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 14 (28.57%)	5 / 13 (38.46%)
occurrences all number	1	1	6	6
Pain
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	2 / 14 (14.29%)	1 / 13 (7.69%)
occurrences all number	2	1	3	1
Chills
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Death
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Disease Progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Influenza Like Illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Localised Oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Non-cardiac Chest Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Immune system disorders
Autoimmune Disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 14 (21.43%)	1 / 13 (7.69%)
occurrences all number	0	1	3	1
Anaphylactic Reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Reproductive system and breast disorders
Pelvic Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Perineal Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 14 (21.43%)	3 / 13 (23.08%)
occurrences all number	0	0	5	3
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 14 (14.29%)	2 / 13 (15.38%)
occurrences all number	0	0	2	2
Rhinitis Allergic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	2	0	1	1
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	2 / 13 (15.38%)
occurrences all number	0	0	1	2
Nasal Congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	2 / 13 (15.38%)
occurrences all number	0	0	1	2
Oropharyngeal Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	0	1	2
Bronchospasm
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Pleural Effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Rhinorrhoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	3 / 13 (23.08%)
occurrences all number	0	0	0	3
Investigations
Activated partial thromboplastin time ratio increased
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	5 / 14 (35.71%)	7 / 13 (53.85%)
occurrences all number	1	4	7	11
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	7 / 14 (50.00%)	8 / 13 (61.54%)
occurrences all number	0	2	10	10
White blood cell count decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 14 (21.43%)	3 / 13 (23.08%)
occurrences all number	1	1	9	4
Alanine Aminotransferase Increased
subjects affected / exposed	2 / 3 (66.67%)	3 / 3 (100.00%)	4 / 14 (28.57%)	3 / 13 (23.08%)
occurrences all number	2	3	6	3
Aspartate Aminotransferase Increased
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 14 (14.29%)	6 / 13 (46.15%)
occurrences all number	1	2	4	7
Blood Alkaline Phosphatase Increased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 14 (21.43%)	2 / 13 (15.38%)
occurrences all number	2	2	5	2
Neutrophil Count Decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 14 (21.43%)	2 / 13 (15.38%)
occurrences all number	1	0	6	4
Haemoglobin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	2 / 13 (15.38%)
occurrences all number	0	0	3	3
Platelet Count Decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	3 / 14 (21.43%)	1 / 13 (7.69%)
occurrences all number	0	2	3	1
Blood Bicarbonate Decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 14 (14.29%)	0 / 13 (0.00%)
occurrences all number	2	0	3	0
International Normalised Ratio Increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)
occurrences all number	0	0	0	5
Blood Creatinine Increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)
occurrences all number	0	0	0	3
Lipase Increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 14 (14.29%)	0 / 13 (0.00%)
occurrences all number	1	0	2	0
Amylase Increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 14 (14.29%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0
Blood Creatine Phosphokinase Increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)
occurrences all number	0	0	0	2
Weight Decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 14 (14.29%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0
Blood Bilirubin Increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Blood Creatinine Decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Blood Growth Hormone Abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Blood Prolactin Abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Electrocardiogram T Wave Inversion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Lymphocyte Count Increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Streptococcus Test Positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0
Arthropod Bite
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0
Tracheal Haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Cardiac disorders
Sinus Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	1	3	1
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	0	1	1
Nervous system disorders
Headache
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 14 (28.57%)	5 / 13 (38.46%)
occurrences all number	2	0	5	5
Peripheral Sensory Neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)
occurrences all number	0	0	0	2
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 3 (66.67%)	2 / 3 (66.67%)	7 / 14 (50.00%)	7 / 13 (53.85%)
occurrences all number	2	3	16	8
Eosinophilia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Ear and labyrinth disorders
Ear Discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Eye disorders
Vision Blurred
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 14 (21.43%)	0 / 13 (0.00%)
occurrences all number	0	0	3	0
Eye Swelling
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	1	0	0
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	5 / 14 (35.71%)	5 / 13 (38.46%)
occurrences all number	0	1	14	8
Nausea
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	3 / 14 (21.43%)	6 / 13 (46.15%)
occurrences all number	2	1	3	9
Abdominal Pain
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	4 / 14 (28.57%)	4 / 13 (30.77%)
occurrences all number	1	2	4	5
Vomiting
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	2 / 14 (14.29%)	5 / 13 (38.46%)
occurrences all number	2	1	2	7
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 14 (14.29%)	3 / 13 (23.08%)
occurrences all number	0	0	2	3
Abdominal Pain Upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Flatulence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Lower Gastrointestinal Haemorrhage
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0
Pancreatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Rectal Haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 14 (14.29%)	2 / 13 (15.38%)
occurrences all number	1	0	2	2
Dry Skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 14 (14.29%)	1 / 13 (7.69%)
occurrences all number	0	0	2	2
Rash Maculo-Papular
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 14 (14.29%)	0 / 13 (0.00%)
occurrences all number	1	1	2	0
Dermatitis Acneiform
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	0	1	1
Urticaria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)
occurrences all number	0	0	0	2
Blister
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0
Erythema Multiforme
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Kertosis Pilaris
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Skin Hyperpigmentation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Renal and urinary disorders
Proteinuria
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	1	2	3	0
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	0	4	1
Chromaturia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	3	0
Haemoglobinuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Polyuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Endocrine disorders
Diabetes Insipidus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Hypophysitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 14 (14.29%)	2 / 13 (15.38%)
occurrences all number	0	0	3	2
Pain in Extremity
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 14 (14.29%)	2 / 13 (15.38%)
occurrences all number	1	0	2	2
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	3 / 13 (23.08%)
occurrences all number	0	0	1	3
Musculoskeletal Chest Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	1	1	1
Flank Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)
occurrences all number	0	0	0	2
Neck Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	0	1	1
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Muscular Weakness
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Musculoskeletal Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Osteoporosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Infections and infestations
Oral Herpes
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	1	1	0
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	0	1	1
Device Related Infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	1	0	0
Respiratory Syncytial Virus Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Skin Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0
Viral Upper Respiratory Tract Infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 14 (0.00%)	0 / 13 (0.00%)
occurrences all number	1	0	0	0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	6 / 14 (42.86%)	4 / 13 (30.77%)
occurrences all number	1	2	8	5
Hypermagnesaemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	4 / 14 (28.57%)	3 / 13 (23.08%)
occurrences all number	1	3	5	3
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	3 / 14 (21.43%)	5 / 13 (38.46%)
occurrences all number	0	3	3	5
Hypokalaemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 14 (14.29%)	3 / 13 (23.08%)
occurrences all number	1	2	3	4
Hypophosphataemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 14 (14.29%)	2 / 13 (15.38%)
occurrences all number	2	2	2	4
Hyperglycaemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 14 (7.14%)	3 / 13 (23.08%)
occurrences all number	1	3	1	4
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 14 (14.29%)	3 / 13 (23.08%)
occurrences all number	0	0	3	3
Decreased Appetite
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 14 (7.14%)	3 / 13 (23.08%)
occurrences all number	1	0	1	3
Hypoglycaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 14 (0.00%)	2 / 13 (15.38%)
occurrences all number	1	0	0	3
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	1	1	3
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	2
Hyperkalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 14 (7.14%)	1 / 13 (7.69%)
occurrences all number	0	0	1	1
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Hypertriglyceridaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1
Hyperuricaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 14 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

30 May 2008

Archived biopsy specimen analysis applies to NCI subjects only; Clarification of urine test to include VMA and HVA combination test for subjects ≤14 years of age, and 24-hour test for subjects >14 years; Clarifications regarding endocrine testing and GH sampling, and regarding fasting for 12 hours prior to sample collection.

05 Mar 2009

Eligibility: changed lower limit for age from 3 to 2 years of age.

11 Mar 2009

Revised comprehensive adverse events and potential risks, and informed consent to include the modified risk information from CTEP. Additional eligibility criteria added to exclude subjects with autoimmune disease, including autoimmune hemolytic anemia, ulcerative and hemorrhagic colitis, endocrine disorders, sarcoid granuloma, myasthenia gravis, polymyositis, and Guillain-Barre syndrome. Clarified criteria for not receiving subsequent doses of ipilimumab if subjects experience:  Non-hematologic dose limiting toxicities  Immune-related adverse events possibly, probably or likely related to ipilimumab  Grade 1 or 2 colitis and/or diarrhea which cannot be ascribed to another etiology and is possibly, probably or likely related to ipilimumab  Grade 2 thyroid autoimmunity for Grade 2 uveitis  Grade 3 or greater skin-related adverse events (regardless of causality)

25 May 2009

Revised the number of planned doses cohorts in the Phase 1 portion of the study from 4 to 3 dose levels (removed the 2 mg/kg dose cohort). Due to this revision the total number of subjects to be accrued was changed from 30 to 27 subjects.

22 Jul 2009

Revised exclusion criteria: Treatment with myeloid growth factors (sargramostim or filgastrim) within 72 hours prior study entry

26 Jan 2010

Revised exclusion criteria: No change in residual brain abnormality has been clarified to state no progression of residual brain abnormalities. Revised interval between surgery/radiotherapy and eligibility for subjects who have treated CNS metastases from 6 to 4 weeks. Pretreatment laboratories: Timing for obtaining pretreatment laboratory tests has been differentiated between those that should be collected within 72 hours (ie, hematology, LDH, ALT, AST, alkaline phosphatase, bilirubin (total and direct), BUN, creatinine, amylase, triglycerides, CPK, electrolytes, glucose, calcium, magnesium, phosphorus, uric acid, total protein and albumin) vs those collected within 4 weeks of therapy (ie, endocrine function tests, hepatitis serology, HLA typing, HAHA, anti HIV antibody and autoimmune profile (rheumatoid factor and ANA. Also for subjects with neuroblastoma: urine VMA and urine HVA, bone marrow biopsy and aspiration should be collected within 4 weeks of therapy. Baseline anti-HIV antibody added to baseline laboratory tests, to be obtained within 4 weeks of initiating the first cycle. Amylase, lipase and triglycerides have been separated from serum chemistry tests and are required to be drawn prior to every treatment cycle rather than at every laboratory draw (Cycle 1: Days 2, 4, 8, and 15, while on treatment).

15 Mar 2010

Eligibility: Removed positive ANA from eligibility exclusion criteria Changed language of Comprehensive Adverse Events and Potential Risk (CAEPR) list to reflect CTCAE version 4.0. In addition revised the risk profile of ipilimumab to CAEPR Version 2.3. Added dose level 4 (10 mg/kg) to the dose escalation schema. Added language to expand the cohort of subjects receiving the highest dose tolerated to include at least four subjects 12 years of age or older (to obtain additional data regarding tolerability). Under Statistical Considerations: the expected accrual for the dose escalation was increased from 15 to 18 subjects.

26 Apr 2010

Clarified that the dose escalation (Phase 1 part of this study):  consists of 4 and not 5 dose levels by removing the dose level -1 (0.5 mg/kg) cohort  expected number of subjects to be accrued in the dose escalation phase is 24 and not 18 subjects.

08 Jun 2010

Eligibility:  Baseline HIV and hepatitis serology changed from 4 to 12 weeks of initiation of first cycle.  For subjects who received irradiation (for CNS metastasis), time to have completed therapy changed from 4 weeks to 1 week prior to enrollment. Changed the location of where ipilimumab can be administered from and in-patient setting to an out-patient setting Changed the monitoring of vital signs at Cycle 1 from the first 24 hours to the first 6 hours. Revised algorithm for management and assessment of diarrhea, hepatoxicity, and general recommendations for the management of immune-related adverse events. Under ‘Background’ revised definition of high-risk neuroblastoma from >1 year to 18 months with metastatic disease. Clarified RECIST Criteria to state that tumor markers alone cannot be used to assess response with the exception or neuroblastoma.

01 Aug 2010

Changed CTCAE criteria to be used from version 3.0 to 4.0 with effective start date 01-Aug-2010. Cite version change under the following:  definitions of dose limiting toxicities  reporting changes in blood pressure  off-treatment criteria  toxicity criteria

27 Aug 2010

Removed vital signs monitoring at 8, 16, and 24 hours after ipilimumab administration.

07 Feb 2011

Added normal ranges for non-hematologic dose limiting toxicities for ALT, AST, and GGT. For alkaline phosphatase, normal ranges by age and gender were added.

01 Sep 2011

Removed exclusion criterion “subjects requiring supplemental oxygen”

28 Sep 2011

Updated the risk information for ipilimumab per CAEPR version 2.4. New risk:  rare but serious bleeding disorder cause by autoantibodies  potentially life threatening condition affecting less than 10% of the skin in which cell deaths causes epidermis (outer layer) to separate from dermis (middle layer) Increased risk attribution:  inability of the adrenal glands to produce a normal quantity of hormones  abnormally high or abnormally low levels of thyroid gland hormone  changed from ‘reported but undetermined’ to ‘rare but serious’: inflammation of the heart muscle

30 Nov 2011

Expanded the cohort of subjects at the highest maximum tolerated dose (5 mg/kg) to include 6 subjects <12 years of age. Revised inclusion criterion: hematologic function of transfusion independent platelet count from ≥75,000 μL to ≥50,000μL. normal bilirubin from ‘direct’ to ‘total’ Revised overall study design to allow maintenance therapy past 2 years provided that subjects continue to experience clinical benefit. Added section describing ipilimumab treatment during maintenance in those subjects who undergo resection and malignant metastases during this phase.

16 Dec 2011

Added language to expand the number of subjects to be included in the planned cohort expansion of the 5 and 10 m/kg doses to include 6 subjects <12 years of age.

18 Jan 2012

Allowed subjects to receive reinduction with 4 doses of ipilimumab at assigned dose followed by another maintenance phase for subjects who have progressed during maintenance therapy.

17 May 2012

Eligibility: changed lower limit for age from 2 to 1 year of age.

25 Jun 2013

Eligibility: A subject with viral hepatitis or HIV was to be excluded from study, but serology was not required unless infection was clinically suspected

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 I Study of Ipilimumab (Anti-CTLA-4) in Children, Adolescents, and Young Adults with Treatment Refractory Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with drug-related adverse events, adverse events leading to discontinuation, drug-related adverse events leading to discontinuation, serious adverse events, drug-related serious adverse events, and immune-related adverse events.

Primary: Number of subjects with drug-related adverse events, adverse events leading to discontinuation, drug-related adverse events leading to discontinuation, serious adverse events, drug-related serious adverse events, and immune-related adverse events.

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - White Blood Cell Count

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - White Blood Cell Count

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Absolute Neutrophil Count

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Absolute Neutrophil Count

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Platelet Count

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Platelet Count

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Hemoglobin

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Hemoglobin

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Absolute Lymphocyte Count (ALC)

Primary: Number of Subjects with Worst CTC Grade of On-study Hematology Laboratory Results - Absolute Lymphocyte Count (ALC)

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Alanine Aminotransferase (ALT)

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Alanine Aminotransferase (ALT)

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Aspartate Aminotransferase (AST)

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Aspartate Aminotransferase (AST)

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Total Bilibrubin

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Total Bilibrubin

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Alkaline Phosphatase

Primary: Number of Subjects with Worst CTC Grade of On-study Liver Function Laboratory Results - Alkaline Phosphatase

Primary: Number of Subjects with Worst CTC Grade of On-study Renal Function Laboratory Results - Creatinine

Primary: Number of Subjects with Worst CTC Grade of On-study Renal Function Laboratory Results - Creatinine

Primary: Number of Subjects with Worst CTC Grade of On-study Serum Chemistry Laboratory Results - Lipase

Primary: Number of Subjects with Worst CTC Grade of On-study Serum Chemistry Laboratory Results - Lipase

Primary: Number of Subjects with Worst CTC Grade of On-study Serum Chemistry Laboratory Results - Amylase

Primary: Number of Subjects with Worst CTC Grade of On-study Serum Chemistry Laboratory Results - Amylase

Primary: Number of On-study Deaths

Primary: Number of On-study Deaths

Primary: Number of Deaths

Primary: Number of Deaths

Primary: Geometric Mean of Derived Maximum Plasma Concentration (Cmax) Parameters of Ipilimumab

Primary: Geometric Mean of Derived Maximum Plasma Concentration (Cmax) Parameters of Ipilimumab

Primary: Geometric Mean of Derived AUC(0-T) Parameters of Ipilimumab

Primary: Geometric Mean of Derived AUC(0-T) Parameters of Ipilimumab

Primary: Geometric Mean of Derived AUC(0-21) Parameters of Ipilimumab

Primary: Geometric Mean of Derived AUC(0-21) Parameters of Ipilimumab

Primary: Geometric Mean of Derived AUC(INF) Parameters of Ipilimumab

Primary: Geometric Mean of Derived AUC(INF) Parameters of Ipilimumab

Primary: Geometric Mean of Derived Total Body Clearance (CL) Parameters of Ipilimumab

Primary: Geometric Mean of Derived Total Body Clearance (CL) Parameters of Ipilimumab

Primary: Geometric Mean of Derived Volume of Distribution at Steady State (Vss) Parameters of Ipilimumab

Primary: Geometric Mean of Derived Volume of Distribution at Steady State (Vss) Parameters of Ipilimumab

Primary: Mean Terminal Elimination Half-life (T-half) of Ipilimumab

Primary: Mean Terminal Elimination Half-life (T-half) of Ipilimumab

Primary: Mean Time to Maximum Concentration (Tmax) of Ipilimumab

Primary: Mean Time to Maximum Concentration (Tmax) of Ipilimumab

Secondary: Best Overall Response

Secondary: Best Overall Response

Secondary: Mean Change from Baseline in Activated CD4+ and CD8+ T Cells

Secondary: Mean Change from Baseline in Activated CD4+ and CD8+ T Cells

Secondary: Mean Change from Baseline in Absolutle Lymphocyte Count (ALC)

Secondary: Mean Change from Baseline in Absolutle Lymphocyte Count (ALC)

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 Phase I Study of Ipilimumab (Anti-CTLA-4) in Children, Adolescents, and Young Adults with Treatment Refractory Cancer