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Clinical Trial Results:
A Phase I Study of Sunitinib (SU11248), an Oral Multi-Targeted Tyrosine Kinase Inhibitor, in Children with Refractory Solid Tumors

Summary
EudraCT number	2012-000690-23
Trial protocol	Outside EU/EEA
Global end of trial date	12 Jul 2012

Results information
Results version number	v1(current)
This version publication date	14 Apr 2018
First version publication date	14 Apr 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ADVL0612;NCI-07-C-0220

ISRCTN number

US NCT number

NCT00387920

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 110017

Public contact

Biljana Georgievska, Childrens Oncology Group – Phase 1/Pilot Consortium, 001 6262411566, bgeorgievska@childrensoncologyrgroup.org

Scientific contact

Biljana Georgievska, Childrens Oncology Group – Phase 1/Pilot Consortium, 001 6262411566, bgeorgievska@childrensoncologyrgroup.org

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000342-PIP01-08

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

Yes

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

Analysis stage

Final

Date of interim/final analysis

18 Jun 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Jul 2012

Was the trial ended prematurely?

Main objective of the trial

- To determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose of sunitinib administered orally once daily for 28 days followed by 14 days rest period in children with refractory solid tumours. - To define and describe the toxicities of sunitinib administered on this schedule. - To characterize the pharmacokinetics of oral sunitinib in children with refractory solid tumours.

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 Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Dec 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

26 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 35

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

A total of 35 subjects were enrolled and treated in the study from 01-Dec-2007 to 12-Jul-2012.

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

Part A: Sunitinib 15 mg/m^2

Arm description

Subjects with recurrent or refractory solid tumour received 15 milligram per meter square (mg/m^2) of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Arm type

Experimental

Investigational medicinal product name

Sunitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects were administered 15 mg/m^2 capsule of sunitinib based on the body surface area (BSA) once daily.

Part A: Sunitinib 20 mg/m^2

Arm description

Subjects with recurrent or refractory solid tumour received 20 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Arm type

Experimental

Investigational medicinal product name

Sunitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects were administered 20 mg/m^2 capsule of sunitinib based on the BSA once daily.

Part B: Sunitinib 15 mg/m^2

Arm description

Subjects with recurrent or refractory solid tumour received 15 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Arm type

Experimental

Investigational medicinal product name

Sunitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects were administered 15 mg/m^2 capsule of sunitinib based on the BSA once daily.

Part B: Sunitinib 20 mg/m^2

Arm description

Subjects with recurrent or refractory solid tumour received 20 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Arm type

Experimental

Investigational medicinal product name

Sunitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects were administered 20 mg/m^2 capsule of sunitinib based on the BSA once daily.

Part C: Sunitinib 15 mg/m^2

Arm description

Subjects with recurrent or refractory solid tumour received 15 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Arm type

Experimental

Investigational medicinal product name

Sunitinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Subjects were administered 15 mg/m^2 sunitinib as a powder sprinkled on applesauce or yogurt as per BSA once daily.

Number of subjects in period 1	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part B: Sunitinib 20 mg/m^2	Part C: Sunitinib 15 mg/m^2
Started	6	6	8	3	12
Completed	0	0	2	0	1
Not completed	6	6	6	3	11
Consent withdrawn by subject	-	-	1	1	2
Adverse event	2	3	1	-	1
Insufficient clinical response	4	3	4	2	8

Baseline characteristics

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Reporting group title

Part A: Sunitinib 15 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 15 milligram per meter square (mg/m^2) of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part A: Sunitinib 20 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 20 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part B: Sunitinib 15 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 15 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part B: Sunitinib 20 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 20 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part C: Sunitinib 15 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 15 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part B: Sunitinib 20 mg/m^2	Part C: Sunitinib 15 mg/m^2	Total
Number of subjects	6	6	8	3	12	35
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	16.3 ( 3.3 )	12.8 ( 1.9 )	10.5 ( 5.3 )	9.7 ( 3.5 )	12.1 ( 5.2 )	-
Gender categorical
Units: Subjects
Female	2	2	5	3	7	19
Male	4	4	3	0	5	16

End points

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Reporting group title

Part A: Sunitinib 15 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 15 milligram per meter square (mg/m^2) of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part A: Sunitinib 20 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 20 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part B: Sunitinib 15 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 15 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part B: Sunitinib 20 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 20 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part C: Sunitinib 15 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 15 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Subject analysis set title

Part B: Sunitinib (All subjects)

Subject analysis set type

Full analysis

Subject analysis set description

Subjects with recurrent or refractory solid tumour received either 15 or 20 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Primary: Maximum Tolerated Dose (MTD)

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End point title

Maximum Tolerated Dose (MTD) ^[1]

End point description

The MTD was defined as the highest dose at which no more than 1 of 6 participants or no more than 1 of 3 participants experienced a dose Limiting Toxicity (DLT). DLT defined as any of the following occurring during cycle 1 of part 1 of study, Hematologic toxicity: Any grade 4 or higher hematologic adverse event, Grade 4 thrombocytopenia or neutropenia. Nonhematologic toxicity: grade 3 non-hemotologic toxicity except grade 3 or higher laboratory AE which was asymptomatic and rapidly reversible adverse events (returned to baseline or to grade 1 or lower within 7 days), Grade 3 nausea and vomiting of less than (<)3 days, Grade 3 fever of <5 days, Grade 3 aspartate transminase, alanine transminase and biluribin (returned to grade 2 or lower within 7 days). Grades based on NCICTC for Adverse Events version 4.03. Per-protocol set included all enrolled subjects who received at least one dose of study drug.

End point type

Primary

End point timeframe

Cycle 1 (Day 1 up to Day 42)

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: Part B 20 mg/m^2 was evaluated and exceed MTD due to 2 out of 3 patients with DLT, then MTD was established at the lower level as 15 mg /m^2.

End point values	Part B: Sunitinib (All subjects)
Number of subjects analysed	11
Units: mg per meter square
number (not applicable)	15

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

End point description

An AE was any untoward medical occurrence in a subject who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; lack of efficacy in an approved indication. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state. Per-protocol set included all enrolled subjects who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (maximum duration: Part A: 4 cycles, Part B: 9 cycles, Part C: 18 cycles)

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part B: Sunitinib 20 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	6	6	8	3	12
Units: Subjects
AEs	6	6	8	3	12
SAEs	3	3	3	3	6

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment Related Adverse Events

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End point title

Number of Subjects With Treatment Related Adverse Events

End point description

Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. Relatedness to study drug was assessed by the investigator. Per protocol set included all enrolled subjects who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (maximum duration: Part A: 4 cycles, Part B: 9 cycles, Part C: 18 cycles)

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part B: Sunitinib 20 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	6	6	8	3	12
Units: Subjects	6	6	8	3	12

No statistical analyses for this end point

Secondary: Number of Subjects With Adverse Events (AEs) According to Maximum Severity

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End point title

Number of Subjects With Adverse Events (AEs) According to Maximum Severity

End point description

An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Grade 1 =mild; Grade 2 =moderate; within normal limits, Grade 3 =severe or medically significant but not immediately life-threatening; Grade 4 =life-threatening or disabling; urgent intervention indicated; Grade 5 =death. Per protocol set included all enrolled subjects who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (maximum duration: Part A: 4 cycles, Part B: 9 cycles, Part C: 18 cycles)

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part B: Sunitinib 20 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	6	6	8	3	12
Units: Subjects
Grade 1	0	0	2	0	0
Grade 2	1	1	2	0	1
Grade 3	4	4	3	1	7
Grade 4	1	1	1	1	0
Grade 5	0	0	0	1	4

No statistical analyses for this end point

Secondary: Number of subjects with Laboratory Abnormalities By Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological and Chemistry Test Abnormalities

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End point title

Number of subjects with Laboratory Abnormalities By Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological and Chemistry Test Abnormalities

End point description

Anemia(grade[g]1:Less than[<] Lower limit of normal[LLN] to 10gram per[/] deciliter[g/dL],g2:<10 to 8g/dL,g3:<8g/dL,g4:lifethreatening);platelet (g1:<LLN to 75*10^3/millimeter[mm]^3,g2:<75*10^3/mm^3 to 50*10^3/mm^3,g3:<50*10^3/mm^3 to 25*10^3/mm^3,g4:<25*10^3/mm^3); white blood cell count (WBC)(g1:<LLN to 3*10^3/mm^3,g2:<3*10^3 to 2*10^3/mm^3,g3:<2*10^3 to 1*10^3/mm^3,g4:<1*10^3/mm^3); ALT/AST(grade[g]1:>ULN-3*ULN,g2:>3-5*ULN,g3:>5-20*ULN,g4:>20*ULN);CR(g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-6*ULN,g4:>6*ULN); );bilirubin(total)(g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-10*ULN,g4:>10*ULN); hypophosphatemia(g1:<LLN-2.5mg/dL,g2:<2.5-2mg/dL,g3:<2-1mg/dL,g4:<1mg/dL);hypocalcemia(g1:<LLN-8mg/dL,g2:<8-7mg/dL,g3:<7-6mg/dL,g4:<6mg/dL);amylase,lipase(g1:>ULN-1.5*ULN,g2:>1.5-2.0*ULN,g3:>2.0-5.0*ULN;>5.0*ULN); hypercalcemia(g1:>ULN-11.5mg/dL,g2:>11.5-12.5mg/dL,g3:>12.5-13.5mg/dL,g4:>13.5mg/dL).Only categories with atleast 1 subject with abnormality are reported in this endpoint.Per protocol analysis set.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (maximum duration: Part A: 4 cycles, Part B: 9 cycles, Part C: 18 cycles)

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part B: Sunitinib 20 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	6	6	8	3	12
Units: Subjects
Anemia: Grade 2 (n =6,6,8,3,12)	0	2	0	0	0
Anemia: Grade 3 (n =6,6,8,3,12)	0	0	0	0	1
Platelets: Grade 2 (n =6,6,8,3,12)	0	2	0	0	1
WBC: Grade 2 (n =6,6,8,3,12)	1	1	0	0	3
WBC: Grade 3 (n =6,6,8,3,12)	0	3	0	0	0
Amylase: Grade 1 (n =6,6,8,3,12)	0	2	1	0	1
AST: Grade 1 (n =4,6,0,0,2)	2	5	99999	99999	1
Creatinine: Grade 1 (n =6,6,8,3,12)	5	6	6	3	10
Creatinine: Grade 2 (n =6,6,8,3,12)	0	0	2	0	0
Hypophosphatemia: Grade 1 (n =6,6,8,3,12)	1	4	1	0	1
Hypophosphatemia: Grade 2 (n =6,6,8,3,12)	0	1	0	0	0
Hypophosphatemia: Grade 3 (n =6,6,8,3,12)	1	0	1	0	0
Hypophosphatemia: Grade 4 (n =6,6,8,3,12)	0	0	0	0	0
Lipase: Grade 1 (n =6,6,8,3,12)	0	0	2	1	1
Lipase: Grade 2 (n =6,6,8,3,12)	0	1	0	0	1
Lipase: Grade 3 (n =6,6,8,3,12)	0	1	0	0	0
Hypercalcemia: Grade 1 (n =0,0,0,0,12)	99999	99999	99999	99999	3
Hypocalcemia: Grade 1 (n =0,0,0,0,4)	99999	99999	99999	99999	4

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of Sunitinib and its metabolite

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End point title

Maximum Observed Plasma Concentration (Cmax) of Sunitinib and its metabolite ^[2]

End point description

SU012662 was the metabolite of sunitinib. Pharmacokinetic (PK) population included all treated subjects who received at least one dose of study drug. Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0. Here, 99999 signifies data was not evaluable as only 1 subject was analyzed.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 24, 25, 26, 27, 28, 48, 49, 50, 51, 52 hours post-dose on Day 1 of Cycle 1

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	4	1	4	12
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
Sunitinib	15.2074 ( 16 )	99999 ( 99999 )	22.5757 ( 91 )	18.9275 ( 52 )
SU012662	2.42764 ( 54 )	99999 ( 99999 )	3.45750 ( 102 )	1.755 ( 13249 )

No statistical analyses for this end point

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sunitinib and its metabolite

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End point title

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sunitinib and its metabolite ^[3]

End point description

SU012662 was the metabolite of sunitinib. PK population included all treated subjects who received at least one dose of study drug. Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 24, 25, 26, 27, 28, 48, 49, 50, 51, 52 hours post-dose on Day 1 of Cycle 1

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	4	1	4	12
Units: Hour
median (full range (min-max))
Sunitinib	7.00 (4.00 to 48.0)	8.00 (8.00 to 8.00)	7.00 (2.00 to 8.00)	4.00 (4.00 to 8.00)
SU012662	28.0 (6.00 to 48.0)	8.00 (8.00 to 8.00)	7.00 (4.00 to 8.00)	6.00 (4.00 to 24.0)

No statistical analyses for this end point

Secondary: Time to the last quantifiable Time Point (Tlast) of Sunitinib and its metabolite

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End point title

Time to the last quantifiable Time Point (Tlast) of Sunitinib and its metabolite ^[4]

End point description

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 24, 25, 26, 27, 28, 48, 49, 50, 51, 52 hours post-dose on Day 1 of Cycle 1

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	4	1	4	12
Units: Hour
median (full range (min-max))
Sunitinib	48.0 (48.0 to 48.0)	48.0 (48.0 to 48.0)	48.0 (48.0 to 48.0)	48.0 (48.0 to 48.0)
SU012662	48.0 (48.0 to 48.0)	48.0 (48.0 to 48.0)	48.0 (24.0 to 48.0)	48.0 (48.0 to 48.0)

No statistical analyses for this end point

Secondary: Area Under The Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration of Sunitinib and its metabolite

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End point title

Area Under The Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration of Sunitinib and its metabolite ^[5]

End point description

AUC (last) is the area under the plasma concentration versus time curve from time zero (pre-dose) to last quantifiable concentration. SU012662 was the metabolite of sunitinib. PK population included all treated subjects who received at least one dose of study drug. Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0. Here, 99999 signifies data was not evaluable as only 1 subject was analyzed.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 24, 25, 26, 27, 28, 48, 49, 50, 51, 52 hours post-dose on Day 1 of Cycle 1

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	4	1	4	12
Units: Nanogramhour per milliliter (nghr/mL)
geometric mean (geometric coefficient of variation)
Sunitinib	457.425 ( 8 )	99999 ( 99999 )	546.296 ( 70 )	481.659 ( 50 )
SU012662	80.5142 ( 38 )	99999 ( 99999 )	106.070 ( 119 )	46.7130 ( 519121 )

No statistical analyses for this end point

Secondary: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Sunitinib and its metabolite

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End point title

Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Sunitinib and its metabolite ^[6]

End point description

AUC (0-24) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose. SU012662 was the metabolite of sunitinib. PK population included all treated subjects who received at least one dose of study drug. Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0. Here, 99999 signifies data was not evaluable as only 1 subject was analyzed.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 24 hours post-dose on Day 1 of Cycle 1

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	4	1	4	12
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Sunitinib	241.643 ( 15 )	99999 ( 99999 )	351.002 ( 73 )	312.669 ( 50 )
SU012662	33.8460 ( 25 )	99999 ( 99999 )	63.9279 ( 91 )	25.7630 ( 253329 )

No statistical analyses for this end point

Secondary: Area Under The Plasma Concentration-Time Curve From Time 0 to 48 Hours (AUC [0-48]) of Sunitinib and its metabolite

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End point title

Area Under The Plasma Concentration-Time Curve From Time 0 to 48 Hours (AUC [0-48]) of Sunitinib and its metabolite ^[7]

End point description

AUC (0-48) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 48 hours post-dose. SU012662 was the metabolite of sunitinib. PK population included all treated subjects who received at least one dose of study drug. Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 24, 25, 26, 27, 28, 48 hours post-dose on Day 1 of Cycle 1

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	4	1	4	12
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Sunitinib	457.425 ( 8 )	99999 ( 99999 )	546.296 ( 70 )	481.659 ( 50 )
SU012662	80.5142 ( 38 )	99999 ( 99999 )	118.128 ( 93 )	46.7130 ( 519121 )

No statistical analyses for this end point

Secondary: Area Under The Plasma Concentration-Time Curve From Time Zero to Infinity of Sunitinib and its metabolite

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End point title

Area Under The Plasma Concentration-Time Curve From Time Zero to Infinity of Sunitinib and its metabolite ^[8]

End point description

AUC (inf) is the area under the plasma concentration versus time curve from time zero (pre-dose) extrapolated to infinity. SU012662 was the metabolite of Sunitinib. PK population included all treated subjects who received at least one dose of study drug. Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0. Here, number of subjects analyzed (N) signifies number of subjects evaluable for this endpoint and n signifies number of subjects evaluable at specified time points only. Here, 99999 signifies data was not evaluable as only 1 subject was analyzed.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 24, 25, 26, 27, 28, 48, 49, 50, 51, 52 hours post-dose on Day 1 of Cycle 1

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	3	1	4	12
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Sunitinib (n =3, 1, 4, 12)	1410.56 ( 167 )	99999 ( 99999 )	848.275 ( 101 )	658.225 ( 54 )
SU012662 (n =1, 1, 3, 8)	99999 ( 99999 )	99999 ( 99999 )	1078.81 ( 133 )	402.415 ( 74 )

No statistical analyses for this end point

Secondary: Terminal Elimination Half-Life (t1/2) of Sunitinib and its metabolite

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End point title

Terminal Elimination Half-Life (t1/2) of Sunitinib and its metabolite ^[9]

End point description

Terminal elimination (plasma decay) half-life is the time measured for the plasma concentration to decrease by one half. SU012662 was the metabolite of sunitinib. PK population included all treated subjects who received at least one dose of study drug. Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0. Here, N signifies number of subjects evaluable for this endpoint and n signifies number of subjects evaluable at specified time points only. Here, 99999 signifies data was not evaluable as only 1 subject was analyzed.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 2, 4, 6, 8, 10, 24, 25, 26, 27, 28, 48, 49, 50, 51, 52 hours post-dose on Day 1 of Cycle 1

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for part B: 20 mg/m^2 arm was not evaluable as the plasma concentration for this arm at the pre-specified time points was 0.

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	3	1	4	12
Units: Hour
arithmetic mean (standard deviation)
Sunitinib (n =3, 1, 4, 12)	115.2 ( 143.65 )	99999 ( 99999 )	33.08 ( 28.975 )	24.05 ( 8.2705 )
SU012662 (n =1, 1, 3, 8)	99999 ( 99999 )	99999 ( 99999 )	502.6 ( 726.21 )	85.79 ( 108.94 )

No statistical analyses for this end point

Secondary: Percentage of Subjects With Objective Response

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End point title

Percentage of Subjects With Objective Response

End point description

Percentage of subjects with confirmed complete response (CR) and partial response (PR) were based on RECIST v1.1. CR: Disappearance of all non-nodal target and non-target lesions, including target and non-target lymph nodes reduction to <10 millimeter (mm) in short axis. No new lesions and disappearance of all non-target lesions. PR: >= 30% decrease in sum of diameters of target lesions, compared to the sum at baseline. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. Full analysis set included all enrolled subjects regardless of the treatment received.

End point type

Secondary

End point timeframe

From Day 28 of cycle 1 up to Day 14 of cycle 18

End point values	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part B: Sunitinib 20 mg/m^2	Part C: Sunitinib 15 mg/m^2
Number of subjects analysed	6	6	8	3	12
Units: Percentage of subjects
number (confidence interval 95%)
CR + PR	0 (0.0 to 45.9)	0 (0.0 to 45.9)	0 (0.0 to 36.9)	0 (0.0 to 70.8)	0 (0.0 to 26.5)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to 30 days after last dose of study drug (maximum duration: Part A: 4 cycles, Part B: 9 cycles, Part C: 18 cycles)

Adverse event reporting additional description

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

15.1

Reporting group title

Part A: Sunitinib 15 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 15 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part A: Sunitinib 20 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 20 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part B: Sunitinib 15 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 15 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part B: Sunitinib 20 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 20 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Reporting group title

Part C: Sunitinib 15 mg/m^2

Reporting group description

Subjects with recurrent or refractory solid tumour received 15 mg/m^2 of sunitinib orally, once daily for 28 days in each cycle of 42 days.

Serious adverse events	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part B: Sunitinib 20 mg/m^2	Part C: Sunitinib 15 mg/m^2
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 6 (50.00%)	3 / 6 (50.00%)	3 / 8 (37.50%)	3 / 3 (100.00%)	6 / 12 (50.00%)
number of deaths (all causes)	0	0	0	1	2
number of deaths resulting from adverse events	0	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Shunt malfunction
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (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
Wound dehiscence
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Vascular disorders
Flushing
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (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
Cardiac failure
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (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
Left ventricular dysfunction
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Convulsion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (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
Depressed level of consciousness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Glossopharyngeal nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Haemorrhage intracranial
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vagus nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 12 (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
Peripheral motor neuropathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (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
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Flatulence
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (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
Pneumatosis intestinalis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (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
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Aspiration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 3 (66.67%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Proteinuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Nephrolithiasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	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
Decreased appetite
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
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
Hyperuricaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 12 (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
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (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
Hypophosphataemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Part A: Sunitinib 15 mg/m^2	Part A: Sunitinib 20 mg/m^2	Part B: Sunitinib 15 mg/m^2	Part B: Sunitinib 20 mg/m^2	Part C: Sunitinib 15 mg/m^2
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	6 / 6 (100.00%)	8 / 8 (100.00%)	3 / 3 (100.00%)	12 / 12 (100.00%)
Vascular disorders
Flushing
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	3 / 8 (37.50%)	2 / 3 (66.67%)	5 / 12 (41.67%)
occurrences all number	0	0	9	2	10
Hypotension
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	1	0	0	1
General disorders and administration site conditions
Chills
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0
Death
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Face oedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	1
Fatigue
subjects affected / exposed	3 / 6 (50.00%)	1 / 6 (16.67%)	2 / 8 (25.00%)	1 / 3 (33.33%)	8 / 12 (66.67%)
occurrences all number	4	1	2	1	12
Gait disturbance
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0
Ill-defined disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0
Non-cardiac chest pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0
Pain
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	2	0	1	0	2
Pyrexia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	1	1	1	0	4
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Bronchospasm
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0
Cough
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	1 / 8 (12.50%)	1 / 3 (33.33%)	2 / 12 (16.67%)
occurrences all number	2	2	1	1	3
Dyspnoea
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	2	0	0	0	1
Epistaxis
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 3 (33.33%)	2 / 12 (16.67%)
occurrences all number	1	1	0	1	2
Hypoxia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	1	0	0
Pleural effusion
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0
Respiratory disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Rhinitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Anxiety
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	2
Confusional state
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Depression
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Insomnia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	1	0	0	0	4
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	2 / 8 (25.00%)	1 / 3 (33.33%)	6 / 12 (50.00%)
occurrences all number	2	3	6	1	13
Amylase increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	2	1	0	2
Aspartate aminotransferase increased
subjects affected / exposed	3 / 6 (50.00%)	4 / 6 (66.67%)	3 / 8 (37.50%)	1 / 3 (33.33%)	3 / 12 (25.00%)
occurrences all number	3	6	4	2	3
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	2	0	0	0	4
Blood antidiuretic hormone abnormal
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Blood cholesterol increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	3
Blood creatinine increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)
occurrences all number	0	1	0	1	2
Blood thyroid stimulating hormone
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0
Blood urea
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Lipase increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 8 (25.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	0	2	2	0	3
Lymphocyte count decreased
subjects affected / exposed	4 / 6 (66.67%)	2 / 6 (33.33%)	2 / 8 (25.00%)	1 / 3 (33.33%)	6 / 12 (50.00%)
occurrences all number	7	2	2	1	12
Neutrophil count decreased
subjects affected / exposed	3 / 6 (50.00%)	5 / 6 (83.33%)	4 / 8 (50.00%)	0 / 3 (0.00%)	6 / 12 (50.00%)
occurrences all number	4	7	12	0	20
Platelet count decreased
subjects affected / exposed	5 / 6 (83.33%)	4 / 6 (66.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)
occurrences all number	5	6	0	0	13
Weight decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
White blood cell count decreased
subjects affected / exposed	4 / 6 (66.67%)	5 / 6 (83.33%)	3 / 8 (37.50%)	1 / 3 (33.33%)	6 / 12 (50.00%)
occurrences all number	5	7	12	1	24
Blood bilirubin increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Injury
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Wound
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Left ventricular dysfunction
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Sinus bradycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Sinus tachycardia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	1	0	0	0	3
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	3
Ataxia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 3 (66.67%)	3 / 12 (25.00%)
occurrences all number	0	0	0	2	3
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	0	0	6	0	4
Drooling
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0
Dysgeusia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	0	1	0	0	3
Facial nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	1	0	2
Glossopharyngeal nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	2
Head discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	2
Headache
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 8 (25.00%)	1 / 3 (33.33%)	4 / 12 (33.33%)
occurrences all number	0	2	2	1	8
Hemiparesis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	0	1
Hydrocephalus
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0
IIIrd nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0
Nervous system disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Nystagmus
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1	1
Peripheral motor neuropathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	1 / 12 (8.33%)
occurrences all number	0	0	1	1	2
Peripheral sensory neuropathy
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	0	1	0	2
Pyramidal tract syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	0	1
Tremor
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
VIth nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Vagus nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 6 (50.00%)	2 / 6 (33.33%)	2 / 8 (25.00%)	1 / 3 (33.33%)	6 / 12 (50.00%)
occurrences all number	5	2	5	1	17
Ear and labyrinth disorders
External ear pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	2
Eye disorders
Extraocular muscle paresis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Eye swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0
Lacrimation increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0
Vision blurred
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	0	0	2	0	3
Visual impairment
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Abdominal pain
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	2	0	1	0	3
Abdominal pain upper
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	1	0	0	0
Constipation
subjects affected / exposed	3 / 6 (50.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 3 (66.67%)	3 / 12 (25.00%)
occurrences all number	3	0	2	2	3
Diarrhoea
subjects affected / exposed	3 / 6 (50.00%)	1 / 6 (16.67%)	3 / 8 (37.50%)	1 / 3 (33.33%)	3 / 12 (25.00%)
occurrences all number	3	1	3	1	3
Dyspepsia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	0 / 12 (0.00%)
occurrences all number	0	0	2	1	0
Gingival pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	2
Nausea
subjects affected / exposed	3 / 6 (50.00%)	2 / 6 (33.33%)	2 / 8 (25.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)
occurrences all number	3	2	4	0	5
Proctalgia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0
Rectal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Small intestinal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Stomatitis
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	2	1	0	0
Vomiting
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	3 / 8 (37.50%)	0 / 3 (0.00%)	4 / 12 (33.33%)
occurrences all number	3	3	3	0	5
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Dry skin
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	1	1	0	2
Erythema multiforme
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Hyperhidrosis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	1
Onychomadesis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0
Pain of skin
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Pruritus
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Purpura
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Rash maculo-papular
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 3 (33.33%)	2 / 12 (16.67%)
occurrences all number	0	1	1	1	3
Skin discolouration
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Skin hypopigmentation
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 8 (25.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	2	0	0
Renal and urinary disorders
Chromaturia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Dysuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Haematuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	2	0	0
Haemoglobinuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	2
Proteinuria
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	1	0	0	10
Urinary retention
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	2
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	2
Hypothyroidism
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	2	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	1	4	0	1
Back pain
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	2 / 12 (16.67%)
occurrences all number	3	0	1	1	3
Joint effusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Muscular weakness
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	2
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1	1
Neck pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	0
Pain in extremity
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 3 (33.33%)	1 / 12 (8.33%)
occurrences all number	0	1	1	1	1
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0
Cystitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0
Lip infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0
Sinusitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	2
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 3 (33.33%)	2 / 12 (16.67%)
occurrences all number	0	2	1	1	3
Decreased appetite
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 3 (66.67%)	1 / 12 (8.33%)
occurrences all number	2	1	0	2	1
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	1 / 12 (8.33%)
occurrences all number	0	0	1	1	1
Hypercalcaemia
subjects affected / exposed	4 / 6 (66.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	5 / 12 (41.67%)
occurrences all number	5	1	0	0	8
Hyperglycaemia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 3 (33.33%)	4 / 12 (33.33%)
occurrences all number	1	1	1	1	7
Hyperkalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	3 / 12 (25.00%)
occurrences all number	0	0	3	1	3
Hypermagnesaemia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 3 (33.33%)	6 / 12 (50.00%)
occurrences all number	1	1	1	1	9
Hypernatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	4	0	1
Hypertriglyceridaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	3
Hyperuricaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	0	1	0	2
Hypoalbuminaemia
subjects affected / exposed	3 / 6 (50.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	1 / 3 (33.33%)	2 / 12 (16.67%)
occurrences all number	3	2	0	1	2
Hypocalcaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	4 / 12 (33.33%)
occurrences all number	0	0	0	0	7
Hypochloraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	2
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	0	2	0	0	3
Hypokalaemia
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 3 (33.33%)	4 / 12 (33.33%)
occurrences all number	2	1	0	2	8
Hypomagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	1	1	0	3
Hyponatraemia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)
occurrences all number	1	1	0	0	8
Hypophosphataemia
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	4 / 8 (50.00%)	1 / 3 (33.33%)	2 / 12 (16.67%)
occurrences all number	2	1	5	1	2

More information

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Were there any global substantial amendments to the protocol? Yes

10 Mar 2008

1.The study was amended due to cardiac toxicity of sunitinib to exclude subjects who were previously treated with potentially cardiotoxic therapies including anthracyclines or radiotherapy involving the heart. 2.Subjects with CNS tumors were allowed to enroll on study. 3.Updated Comprehensive Adverse Events and Potential Risks (CAEPR) for sunitinib and additional potential surrogate biomarkers related to angiogenesis.

25 Feb 2009

The CAEPR version was updated. The risks section of the informed consent was also updated to match those described in the new CAEPR.

28 Dec 2009

A new Part (Part C) was added to the study to evaluate the PK of sunitinib when the capsule contents were sprinkled over applesauce or yogurt. The sunitinib dose administered in this component of the trial was the RP2D of 15 mg/m 2 /day given orally once daily. The background section had been modified to describe the rationale for this amendment.

08 Mar 2010

The Language added to the protocol and the informed consent addressing risks to the caregiver preparing the powder formulation of sunitinib. Since the risks of sunitinib to an unborn baby were not known, pregnant women should have not prepared the sunitinib.

06 Oct 2010

Eligibility criteria was clarified in the protocol to limit enrollment to subjects with solid tumors or CNS tumors without imaging evidence of current or prior intracranial hemorrhage on appropriate MRI imaging sequences.

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 Sunitinib (SU11248), an Oral Multi-Targeted Tyrosine Kinase Inhibitor, in Children with Refractory Solid Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximum Tolerated Dose (MTD)

Primary: Maximum Tolerated Dose (MTD)

Secondary: Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Subjects With Treatment Related Adverse Events

Secondary: Number of Subjects With Treatment Related Adverse Events

Secondary: Number of Subjects With Adverse Events (AEs) According to Maximum Severity

Secondary: Number of Subjects With Adverse Events (AEs) According to Maximum Severity

Secondary: Number of subjects with Laboratory Abnormalities By Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological and Chemistry Test Abnormalities

Secondary: Number of subjects with Laboratory Abnormalities By Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological and Chemistry Test Abnormalities

Secondary: Maximum Observed Plasma Concentration (Cmax) of Sunitinib and its metabolite

Secondary: Maximum Observed Plasma Concentration (Cmax) of Sunitinib and its metabolite

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sunitinib and its metabolite

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sunitinib and its metabolite

Secondary: Time to the last quantifiable Time Point (Tlast) of Sunitinib and its metabolite

Secondary: Time to the last quantifiable Time Point (Tlast) of Sunitinib and its metabolite

Secondary: Area Under The Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration of Sunitinib and its metabolite

Secondary: Area Under The Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration of Sunitinib and its metabolite

Secondary: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Sunitinib and its metabolite

Secondary: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Sunitinib and its metabolite

Secondary: Area Under The Plasma Concentration-Time Curve From Time 0 to 48 Hours (AUC [0-48]) of Sunitinib and its metabolite

Secondary: Area Under The Plasma Concentration-Time Curve From Time 0 to 48 Hours (AUC [0-48]) of Sunitinib and its metabolite

Secondary: Area Under The Plasma Concentration-Time Curve From Time Zero to Infinity of Sunitinib and its metabolite

Secondary: Area Under The Plasma Concentration-Time Curve From Time Zero to Infinity of Sunitinib and its metabolite

Secondary: Terminal Elimination Half-Life (t1/2) of Sunitinib and its metabolite

Secondary: Terminal Elimination Half-Life (t1/2) of Sunitinib and its metabolite

Secondary: Percentage of Subjects With Objective Response

Secondary: Percentage of Subjects With Objective Response

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase I Study of Sunitinib (SU11248), an Oral Multi-Targeted Tyrosine Kinase Inhibitor, in Children with Refractory Solid Tumors