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Clinical Trial Results:
Open, non-controlled, dose escalating Phase I trial to evaluate the pharmacokinetics, pharmacodynamics, tolerability and toxicity of Volasertib in paediatric patients from 2 years to less than 18 years of age with acute leukaemia or advanced solid tumour, for whom no effective treatment is known

Summary
EudraCT number	2013-001291-38
Trial protocol	DE IT CZ AT SK BE NL GB FR
Global end of trial date	31 Jan 2017

Results information
Results version number	v1
This version publication date	06 Aug 2017
First version publication date	06 Aug 2017
Other versions	v2

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

1230.27

ISRCTN number

US NCT number

NCT01971476

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000044-PIP20-13

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

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

Analysis stage

Final

Date of interim/final analysis

28 Feb 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Jun 2015

Global end of trial reached?

Yes

Global end of trial date

31 Jan 2017

Was the trial ended prematurely?

Main objective of the trial

The present trial was performed according to an open design to determine the Maximum Tolerable Dose (MTD) by evaluation of Dose-Limiting Toxicity (DLT) of Volasertib in paediatric leukaemia and solid tumours in the age group 2 to less than 12 and 12 to less than 18 years. A further objective was to collect data on safety, tolerability, toxicity, efficacy (preliminary activity), pharmacokinetics and pharmacodynamics of Volasertib in paediatric cancer patients.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. If a subject continued to take trial medication, close monitoring was adhered to and all adverse events recorded. Rules were implemented in all trials whereby doses would be reduced if required. Thereafter, if further events were reported, the subject would be withdrawn from the trial. Symptomatic treatment of tumour associated symptoms were allowed throughout.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Oct 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 13

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

Czech Republic: 2

Country: Number of subjects enrolled

United Kingdom: 2

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

In the age group 2 to <12 years, 12 patients were entered and treated. In the age group 12 to <18 years, 10 patients were entered and treated.

Screening details

In the age group 2 to <12 years, 15 patients were screened, with 3 screen failures. In the age group 12 to <18 years, 14 patients were screened, with 4 screen failures.

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

The study was non-controlled, non-randomised, open label.

Are arms mutually exclusive

Yes

2 to <12 years: Volasertib 200 mg/m2

Arm description

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Arm type

Experimental

Investigational medicinal product name

Volasertib 200 mg/m2

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

The patients were administered Volasertib 200 mg/m2 over approximately 1 hour on Day 1 of 14-day cycle.

2 to <12 years: Volasertib 250 mg/m2

Arm description

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Arm type

Experimental

Investigational medicinal product name

Volasertib 250 mg/m2

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

The patients were administered Volasertib 250 mg/m2 over approximately 1 hour on Day 1 of 14-day cycle.

2 to <12 years: Volasertib 300 mg/m2

Arm description

The patients were administered Volasertib 300 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Arm type

Experimental

Investigational medicinal product name

Volasertib 300 mg/m2

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

The patients were administered Volasertib 300 mg/m2 over approximately 1 hour on Day 1 of 14-day cycle.

12 to <18 years: Volasertib 200 mg/m2

Arm description

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Arm type

Experimental

Investigational medicinal product name

Volasertib 200 mg/m2

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

The patients were administered Volasertib 200 mg/m2 over approximately 1 hour on Day 1 of 14-day cycle.

12 to <18 years: Volasertib 250 mg/m2

Arm description

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Arm type

Experimental

Investigational medicinal product name

Volasertib 250 mg/m2

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

The patients were administered Volasertib 250 mg/m2 over approximately 1 hour on Day 1 of 14-day cycle.

Number of subjects in period 1 ^[1]	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Started	3	3	6	6	4
Completed	0	0	0	0	0
Not completed	3	3	6	6	4
Other reason not defined above	-	1	-	-	-
Dose Limiting Toxicity (DLT)	-	-	-	-	1
Non-fatal Adverse Event (AE)	-	-	-	-	1
Progressive disease/relapse	3	2	6	6	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

Baseline characteristics

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Reporting group title

2 to <12 years: Volasertib 200 mg/m2

Reporting group description

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

2 to <12 years: Volasertib 250 mg/m2

Reporting group description

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

2 to <12 years: Volasertib 300 mg/m2

Reporting group description

The patients were administered Volasertib 300 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

12 to <18 years: Volasertib 200 mg/m2

Reporting group description

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

12 to <18 years: Volasertib 250 mg/m2

Reporting group description

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2	Total
Number of subjects	3	3	6	6	4	22
Age categorical
Units: Subjects
Age Continuous
Treated Set: The treated set consisted of all patients who have received at least 1 dose of trial medication at the time of clinical cut-off.
Units: Years
arithmetic mean (standard deviation)	7 ( 3.6 )	6.3 ( 3.1 )	7 ( 3.3 )	14.3 ( 2.3 )	15.8 ( 1.5 )	-
Gender categorical
Units: Subjects
Female	1	2	3	2	0	8
Male	2	1	3	4	4	14

End points

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Reporting group title

2 to <12 years: Volasertib 200 mg/m2

Reporting group description

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

2 to <12 years: Volasertib 250 mg/m2

Reporting group description

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

2 to <12 years: Volasertib 300 mg/m2

Reporting group description

The patients were administered Volasertib 300 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

12 to <18 years: Volasertib 200 mg/m2

Reporting group description

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

12 to <18 years: Volasertib 250 mg/m2

Reporting group description

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Primary: Number of Participants with Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)

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End point title

Number of Participants with Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) ^[1]

End point description

This outcome measure presents number of participants with DLTs in the first cycle for the determination of MTD. DLTs were defined as drug related Common Terminology Criteria for Adverse Events (CTCAE) ≥Grade 3 (haematological and nonhaematological) Adverse Events (AEs) with the exception of a) Reduced blood cell count (any grade) without associated clinical complications qualifying for DLT. b) Febrile neutropenia Grade 3. c) Infection Grade 3 with neutrophil count <1000/mm3. d) Uric acid Grade ≥3. e) Nausea, vomiting and/or diarrhoea managed by adequate therapy (i.e. recovery to CTCAE Grade ≤2). Treated Set (TS): The treated set consisted of all patients who have received at least 1 dose of trial medication at the time of clinical cut-off.

End point type

Primary

End point timeframe

Up to 14 days.

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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	3 ^[2]	3 ^[3]	6 ^[4]	6 ^[5]	4 ^[6]
Units: Participants
number (not applicable)	0	0	0	0	2

Notes
[2] - TS
[3] - TS
[4] - TS
[5] - TS
[6] - TS

No statistical analyses for this end point

Primary: Maximum Tolerated Dose of Volasertib

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End point title

Maximum Tolerated Dose of Volasertib ^[7]

End point description

This outcome measure presents MTD of Volasertib. The MTD was defined as the highest dose level at which DLTs were reported in not more than 1 in 6 evaluable patients during Cycle 1. 99999: The recommended dose for Volasertib in patients of 2 to <12 years of age was 300 mg/m2. 99999: The MTD for Volasertib in patients of 12 to <18 years of age was 200 mg/m2.

End point type

Primary

End point timeframe

Up to 14 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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	3 ^[8]	3 ^[9]	6 ^[10]	6 ^[11]	4 ^[12]
Units: mg
number (not applicable)	99999	99999	99999	99999	99999

Notes
[8] - TS
[9] - TS
[10] - TS
[11] - TS
[12] - TS

No statistical analyses for this end point

Secondary: Number of Patients with Hepatic Injury Defined as Adverse Events of Special Interest (AESI)

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End point title

Number of Patients with Hepatic Injury Defined as Adverse Events of Special Interest (AESI)

End point description

This outcome measure presents number of patients with hepatic injury defined as AESI. Hepatic injury was defined by the following alterations of liver parameters: an elevation of (Aspartate Transaminase) AST and/or (Alanine Transaminase) ALT >3x Upper Limit of Normal (ULN) combined with an elevation of total bilirubin >2x ULN measured in the same blood sample.

End point type

Secondary

End point timeframe

Up to 879 days.

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	3 ^[13]	3 ^[14]	6 ^[15]	6 ^[16]	4 ^[17]
Units: Participants
number (not applicable)
Total AEs in grouped category hepatic impairment	0	1	1	3	1
Alanine aminotransferase increased	0	1	0	2	0
Aspartate aminotransferase increased	0	1	0	0	0
Blood alkaline phosphatase increased	0	0	1	0	0
Metabolism and nutrition disorders	0	0	0	0	1
Hypoalbuminaemia	0	0	0	0	1
Hepatobiliary disorders	0	0	0	1	0
Hyperbilirubinaemia	0	0	0	1	0
Blood bilirubin increased	0	0	0	1	0
Gamma-glutamyltransferase increased	0	0	0	1	0

Notes
[13] - TS
[14] - TS
[15] - TS
[16] - TS
[17] - TS

No statistical analyses for this end point

Secondary: Number of Patients with Clinically Relevant Laboratory Value Changes of Calcium (hyper- and/or hypocalcaemia) as Judged by the Investigator and Reported as AEs, CTCAE Grade ≥3

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End point title

Number of Patients with Clinically Relevant Laboratory Value Changes of Calcium (hyper- and/or hypocalcaemia) as Judged by the Investigator and Reported as AEs, CTCAE Grade ≥3

End point description

This outcome measure presents number of patients with clinically relevant laboratory value changes of calcium (hyper- and/or hypocalcaemia) as judged by the investigator and reported as AEs, CTCAE Grade ≥3. CTCAE Grade 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE).

End point type

Secondary

End point timeframe

Up to 879 days.

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	3 ^[18]	3 ^[19]	6 ^[20]	6 ^[21]	4 ^[22]
Units: Participants
number (not applicable)
Total AEs clinically relevant changes of calcium	0	0	0	0	0
Metabolism and nutrition disorders	0	0	0	0	0
Hypocalcaemia	0	0	0	0	0
Hypercalcaemia	0	0	0	0	0

Notes
[18] - TS
[19] - TS
[20] - TS
[21] - TS
[22] - TS

No statistical analyses for this end point

Secondary: The Number of Patients with Changes in Cardiac Activity (prolonged QTc interval) Reported as Clinically Relevant Observations

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End point title

The Number of Patients with Changes in Cardiac Activity (prolonged QTc interval) Reported as Clinically Relevant Observations

End point description

This outcome measure presents the number of patients with changes in cardiac activity (prolonged QTc interval) reported as clinically relevant observations to assess cardiac activity based on Electrocardiogram (ECG) recordings (digital, triplicate) before and at the end of each Volasertib administration and at least at 2 more time-points within the first 24 hours after end of the first Volasertib administration. Two methods of heart rate correction of the QT interval were used: the fixed corrections QTcF (Fridericia's correction) and QTcB (Bazett's correction). SMQ: Standardised Medical Dictionary for Regulatory Activities (MedDRA) query.

End point type

Secondary

End point timeframe

Up to 879 days.

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	3 ^[23]	3 ^[24]	6 ^[25]	6 ^[26]	4 ^[27]
Units: Participants
number (not applicable)
Total AEs in the MedDRA SMQ of QT prolongation	0	0	1	2	1
Electrocardiogram QT prolonged	0	0	1	1	1
Cardiac disorders	0	0	0	1	0
Conduction disorder	0	0	0	1	0

Notes
[23] - TS
[24] - TS
[25] - TS
[26] - TS
[27] - TS

No statistical analyses for this end point

Secondary: Best Overall Response [in leukaemia patients]: (Complete Remission (CR)), CR with incomplete neutrophil or platelet recovery (CRi), Partial Remission (PR), Stable Disease (SD), Progressive Disease (PD) and Death in aplasia

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End point title

Best Overall Response [in leukaemia patients]: (Complete Remission (CR)), CR with incomplete neutrophil or platelet recovery (CRi), Partial Remission (PR), Stable Disease (SD), Progressive Disease (PD) and Death in aplasia

End point description

This outcome measure includes, CR: Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary (EM) disease; absolute neutrophil count ≥ 1.0 x 109/L (1000/μL); platelet count ≥80 x 109/L (80000/μL); independence of red blood cells transfusions. CRi: All CR criteria except for residual neutropenia (<1.0 x 109/L [1000/μL]) or thrombocytopenia (<800 x 109/L [80000/μL]), independence of red blood cell transfusions not required. PR: Decrease of bone marrow blast percentage to 5%-25%; decrease of pretreatment bone marrow (baseline) blast percentage by at least 50%; absence of EM disease. SD: Neither qualifies for CR, CRi, PR or PD. PD: At least one of the criteria a) 50% increase in bone marrow blast count over baseline b) 50% increase in peripheral blast count over baseline - evidence of new EM disease - clinically PD based on the judgment of the investigator. Death in aplasia: Deaths occurring ≥7 days after last administration of the trial drug while cytopenic.

End point type

Secondary

End point timeframe

Up to 849 days.

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	2 ^[28]	2 ^[29]	0 ^[30]	2 ^[31]	1 ^[32]
Units: Participants
number (not applicable)
Complete remission	0	0		0	0
CRi*	0	0		0	0
Partial remission	0	0		0	0
Stable disease	2	2		1	0
Progressive disease	0	0		1	1
Death in aplasia	0	0		0	0
Not evaluable	0	0		0	0
Missing	0	0		0	0

Notes
[28] - TS
[29] - TS
[30] - TS No subjects analysed.
[31] - TS
[32] - TS

No statistical analyses for this end point

Secondary: Event-Free Survival (EFS) [in leukaemia patients]

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End point title

Event-Free Survival (EFS) [in leukaemia patients]

End point description

EFS was defined as the time from the first infusion of Volasertib to the date of PD or relapse, occurrence of secondary malignancy, or death from any cause, whichever occurred first. EFS was censored at the date of last disease assessment for patients who were not reported with PD, relapse, occurrence of secondary malignancy or death. 99999: Median EFS not estimated due to small number of patients per treatment arm.

End point type

Secondary

End point timeframe

Up to 849 days.

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	2 ^[33]	2 ^[34]	0 ^[35]	2 ^[36]	1 ^[37]
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	( to )	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[33] - TS
[34] - TS
[35] - TS
[36] - TS
[37] - TS

No statistical analyses for this end point

Secondary: Overall Survival (OS) [in leukaemia patients]

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End point title

Overall Survival (OS) [in leukaemia patients]

End point description

Overall survival was defined as time from first infusion of Volasertib to death from any cause. For patients who were lost to follow-up, OS were censored on the last date the patients were known to be alive. 99999: Median OS not estimated due to small number of patients per treatment arm.

End point type

Secondary

End point timeframe

Up to 849 days.

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	2 ^[38]	2 ^[39]	0 ^[40]	2 ^[41]	1 ^[42]
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	( to )	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[38] - TS
[39] - TS
[40] - TS No subjects analysed.
[41] - TS
[42] - TS

No statistical analyses for this end point

Secondary: Maximum Measured Concentration (Cmax, norm) of Volasertib

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End point title

Maximum Measured Concentration (Cmax, norm) of Volasertib

End point description

This outcome measure presents dose normalized maximum measured concentration of Volasertib in plasma (Cmax, norm). Pharmacokinetic Set (PKS): All evaluable patients were included in the PK analysis. A patient was considered to be not evaluable, if the patient had an important protocol violation relevant to the evaluation of PK or had insufficient data.

End point type

Secondary

End point timeframe

Cycle 1: -0:05 (hour/s: minute/s) before drug administration and 1:00, 1:30, 3:00, 24:00, 96:00, 216:00 after drug administration. Cycle >=2: -0:05 (hour/s: minute/s) before drug administration and 1:00 after drug administration.

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	3 ^[43]	3 ^[44]	6 ^[45]	6 ^[46]	4 ^[47]
Units: ng/mL/mg
geometric mean (geometric coefficient of variation)	5.34 ( 22 )	9.71 ( 128 )	3.6 ( 35.1 )	2.46 ( 54.9 )	2.5 ( 94.6 )

Notes
[43] - PKS
[44] - PKS
[45] - PKS
[46] - PKS
[47] - PKS

No statistical analyses for this end point

Secondary: Trough Concentration (Cpre, 2) of Volasertib

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End point title

Trough Concentration (Cpre, 2) of Volasertib

End point description

This outcome measure presents pre-dose concentration of Volasertib in plasma immediately before administration of the second dose (Cpre,2). The number of participants analysed are the number of participants with available data at the time-point of interest.

End point type

Secondary

End point timeframe

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	3 ^[48]	2 ^[49]	0 ^[50]	0 ^[51]	0 ^[52]
Units: ng/mL
geometric mean (geometric coefficient of variation)	1.48 ( 60.3 )	1.13 ( 17.6 )	( )	( )	( )

Notes
[48] - PKS
[49] - PKS
[50] - PKS No subjects analysed.
[51] - PKS No subjects analysed.
[52] - PKS No subjects analysed.

No statistical analyses for this end point

Secondary: Area Under the Concentration-Time Curve (AUC0-∞, norm) of Volasertib in Plasma

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End point title

Area Under the Concentration-Time Curve (AUC0-∞, norm) of Volasertib in Plasma

End point description

This outcome measure presents dose normalized area under the concentration-time curve of Volasertib in plasma over the time interval from zero extrapolated to infinity.

End point type

Secondary

End point timeframe

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	3 ^[53]	3 ^[54]	6 ^[55]	6 ^[56]	4 ^[57]
Units: ng*h/mL/mg
geometric mean (geometric coefficient of variation)	41.7 ( 40.1 )	51.2 ( 69.8 )	36.4 ( 28.2 )	28.6 ( 19 )	22.1 ( 37.9 )

Notes
[53] - PKS
[54] - PKS
[55] - PKS
[56] - PKS
[57] - PKS

No statistical analyses for this end point

Secondary: Half-Life (t1/2) of Volasertib

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End point title

Half-Life (t1/2) of Volasertib

End point description

This outcome measure presents half-life of Volasertib.

End point type

Secondary

End point timeframe

End point values	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2
Number of subjects analysed	3 ^[58]	3 ^[59]	6 ^[60]	6 ^[61]	4 ^[62]
Units: hx
geometric mean (geometric coefficient of variation)	102 ( 28.6 )	130 ( 14.1 )	54.8 ( 27.2 )	78.6 ( 27.3 )	52.7 ( 17.7 )

Notes
[58] - PKS
[59] - PKS
[60] - PKS
[61] - PKS
[62] - PKS

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first drug administration until 30 days after the last drug administration.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

2 to <12 years: Volasertib 200 mg/m2

Reporting group description

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

2 to <12 years: Volasertib 250 mg/m2

Reporting group description

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

2 to <12 years: Volasertib 300 mg/m2

Reporting group description

The patients were administered Volasertib 300 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

2 to <12 years: Volasertib Pooled Total

Reporting group description

The pooled total of patients administered Volasertib 200 mg/m2/250 mg/m2/300 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

12 to <18 years: Volasertib 200 mg/m2

Reporting group description

The patients were administered Volasertib 200 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Reporting group title

12 to <18 years: Volasertib 250 mg/m2

Reporting group description

The patients were administered Volasertib 250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 1-day cycle.

Reporting group title

12 to <18 years: Volasertib Pooled Total

Reporting group description

The pooled total of patients administered Volasertib 200 mg/m2/250 mg/m2 (solution for infusion) by intravenous infusion over approximately 1 hour on Day 1 of 14-day cycle.

Serious adverse events	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	2 to <12 years: Volasertib Pooled Total	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2	12 to <18 years: Volasertib Pooled Total
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	5 / 6 (83.33%)	7 / 12 (58.33%)	6 / 6 (100.00%)	4 / 4 (100.00%)	10 / 10 (100.00%)
number of deaths (all causes)	3	3	6	12	5	4	9
number of deaths resulting from adverse events	0	0	0	0	0	1	1
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	2 / 12 (16.67%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 1	0 / 0	0 / 1
Injury, poisoning and procedural complications
Lower limb fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tongue injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Haemorrhage intracranial
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	1 / 1	1 / 1
Headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 4 (50.00%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraplegia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Bone marrow toxicity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 6 (50.00%)	5 / 12 (41.67%)	2 / 6 (33.33%)	2 / 4 (50.00%)	4 / 10 (40.00%)
occurrences causally related to treatment / all	3 / 3	1 / 1	3 / 3	7 / 7	1 / 2	2 / 2	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess neck
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	2 to <12 years: Volasertib 200 mg/m2	2 to <12 years: Volasertib 250 mg/m2	2 to <12 years: Volasertib 300 mg/m2	2 to <12 years: Volasertib Pooled Total	12 to <18 years: Volasertib 200 mg/m2	12 to <18 years: Volasertib 250 mg/m2	12 to <18 years: Volasertib Pooled Total
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	6 / 6 (100.00%)	12 / 12 (100.00%)	6 / 6 (100.00%)	3 / 4 (75.00%)	9 / 10 (90.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	2	2
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	1	3	4
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Fatigue
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 12 (16.67%)	1 / 6 (16.67%)	2 / 4 (50.00%)	3 / 10 (30.00%)
occurrences all number	1	0	1	2	1	2	3
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	4	4
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Pyrexia
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 12 (16.67%)	1 / 6 (16.67%)	2 / 4 (50.00%)	3 / 10 (30.00%)
occurrences all number	2	0	0	2	3	2	5
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	1	0	3	3
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 4 (50.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	0	4	4
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Respiratory disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Alanine aminotransferase decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)	2 / 6 (33.33%)	0 / 4 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	1	0	1	2	0	2
Antithrombin III decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Blood creatine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Blood creatine phosphokinase MB increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	2	0	2
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Blood creatinine increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 12 (16.67%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	1	2	2	0	2
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	2	0	2
Blood phosphorus decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	1	1	2
Blood pressure increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Body temperature increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	2	0	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	1	0	15	15
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Haemoglobin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
International normalised ratio increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Lymphocyte count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 12 (16.67%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	1	0	1	2	1	23	24
Neutrophil count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	1	0	0	1	1	23	24
Platelet count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 12 (16.67%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	1	0	1	2	1	22	23
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
White blood cell count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 12 (16.67%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	1	0	1	2	1	18	19
Injury, poisoning and procedural complications
Allergic transfusion reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Cardiac disorders
Conduction disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	12	1	0	1
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Nervous system disorders
Cranial nerve disorder
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Dysaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Headache
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	2 / 4 (50.00%)	3 / 10 (30.00%)
occurrences all number	2	0	0	2	2	10	12
IIIrd nerve disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	6	6
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	3 / 6 (50.00%)	6 / 12 (50.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	3 / 10 (30.00%)
occurrences all number	1	2	3	6	2	4	6
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	1	6	0	6
Lymphadenopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Neutropenia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 6 (50.00%)	4 / 12 (33.33%)	3 / 6 (50.00%)	1 / 4 (25.00%)	4 / 10 (40.00%)
occurrences all number	2	0	3	5	14	1	15
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 6 (16.67%)	3 / 12 (25.00%)	3 / 6 (50.00%)	1 / 4 (25.00%)	4 / 10 (40.00%)
occurrences all number	0	2	1	3	4	1	5
Eye disorders
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 6 (33.33%)	3 / 12 (25.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	3 / 10 (30.00%)
occurrences all number	0	1	4	5	2	11	13
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Anal inflammation
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Aphthous ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Constipation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	2 / 6 (33.33%)	0 / 4 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	2	0	2
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	2 / 12 (16.67%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	2	1	3	0	15	15
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Glossodynia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Nausea
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 12 (16.67%)	2 / 6 (33.33%)	2 / 4 (50.00%)	4 / 10 (40.00%)
occurrences all number	2	0	1	3	3	4	7
Oral pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 6 (33.33%)	3 / 12 (25.00%)	2 / 6 (33.33%)	3 / 4 (75.00%)	5 / 10 (50.00%)
occurrences all number	1	0	2	3	2	5	7
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	2	0	0	0
Exfoliative rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Ingrowing nail
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Mechanical urticaria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Petechiae
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	1	0	1	1
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	0	1	0	1	2	4	6
Rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Scar pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Renal and urinary disorders
Oliguria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Urinary retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	1	1	2
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Groin pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 4 (50.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	0	2	2
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Infections and infestations
Anal abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Conjunctivitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Oropharyngeal candidiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	3	3
Stoma site infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 6 (33.33%)	3 / 12 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	2	3	0	0	0
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	2 / 6 (33.33%)	0 / 4 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	2	0	2
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	0	0	2	2	1	5	6
Hyperkalaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	1	0	1	1
Hyperuricaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	1	0	1
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	2	0	0	0
Hypoglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	1	1
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	1	0	1	1
Hyponatraemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 12 (16.67%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 10 (20.00%)
occurrences all number	2	0	1	3	1	7	8
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0

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Were there any global substantial amendments to the protocol? Yes

08 May 2014

One global amendment to the Clinical Trial Protocol (CTP) was issued before Database Lock (DBL)(08 May 2014); it was implemented only after approval of the Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)/Competent Authorities. The major changes were: • the alignment of the new reporting times for concomitant medication and Adverse Events (AEs), • a change in time for the End of Treatment (EoT) visit, to align the CTP with the Case Report Form (CRF) and to ensure that the residual effect period could be applied, • the addition of blood pressure and heart rate measurements during infusion of Volasertib, as requested by the German competent authority, • the addition of echocardiography after every 4th treatment cycle, as requested by Medicines and Healthcare products Regulatory Agency, United Kingdom (UK), • a change in wording for clarification: left ventricular ejection fraction <25% updated to left ventricular shortening fraction <30%, • an update of exclusion criterion 18 regarding the contraception, according to the Investigator’s Brochure (IB) of Volasertib, • to clarify that bone marrow sampling was not required if Progressive Disease (PD) was diagnosed due to increased peripheral blasts, evidence of new extramedullary disease or clinical PD based on the investigator's judgement, • the clarification of reporting of clinically relevant Electro Cardio Gram (ECG) findings.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)

Primary: Number of Participants with Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)

Primary: Maximum Tolerated Dose of Volasertib

Primary: Maximum Tolerated Dose of Volasertib

Secondary: Number of Patients with Hepatic Injury Defined as Adverse Events of Special Interest (AESI)

Secondary: Number of Patients with Hepatic Injury Defined as Adverse Events of Special Interest (AESI)

Secondary: Number of Patients with Clinically Relevant Laboratory Value Changes of Calcium (hyper- and/or hypocalcaemia) as Judged by the Investigator and Reported as AEs, CTCAE Grade ≥3

Secondary: Number of Patients with Clinically Relevant Laboratory Value Changes of Calcium (hyper- and/or hypocalcaemia) as Judged by the Investigator and Reported as AEs, CTCAE Grade ≥3

Secondary: The Number of Patients with Changes in Cardiac Activity (prolonged QTc interval) Reported as Clinically Relevant Observations

Secondary: The Number of Patients with Changes in Cardiac Activity (prolonged QTc interval) Reported as Clinically Relevant Observations

Secondary: Best Overall Response [in leukaemia patients]: (Complete Remission (CR)), CR with incomplete neutrophil or platelet recovery (CRi), Partial Remission (PR), Stable Disease (SD), Progressive Disease (PD) and Death in aplasia

Secondary: Best Overall Response [in leukaemia patients]: (Complete Remission (CR)), CR with incomplete neutrophil or platelet recovery (CRi), Partial Remission (PR), Stable Disease (SD), Progressive Disease (PD) and Death in aplasia

Secondary: Event-Free Survival (EFS) [in leukaemia patients]

Secondary: Event-Free Survival (EFS) [in leukaemia patients]

Secondary: Overall Survival (OS) [in leukaemia patients]

Secondary: Overall Survival (OS) [in leukaemia patients]

Secondary: Maximum Measured Concentration (Cmax, norm) of Volasertib

Secondary: Maximum Measured Concentration (Cmax, norm) of Volasertib

Secondary: Trough Concentration (Cpre, 2) of Volasertib

Secondary: Trough Concentration (Cpre, 2) of Volasertib

Secondary: Area Under the Concentration-Time Curve (AUC0-∞, norm) of Volasertib in Plasma

Secondary: Area Under the Concentration-Time Curve (AUC0-∞, norm) of Volasertib in Plasma

Secondary: Half-Life (t1/2) of Volasertib

Secondary: Half-Life (t1/2) of Volasertib

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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