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Clinical Trial Results:
A Phase II Study of Dasatinib Therapy in Children and Adolescents with Ph+ Leukemia with Resistance or Intolerance to Imatinib.

Summary
EudraCT number	2008-002260-33
Trial protocol	IT ES FR NL GB DE Outside EU/EEA
Global end of trial date

Results information
Results version number	v1(current)
This version publication date	30 Dec 2017
First version publication date	30 Dec 2017
Other versions

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

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Trial information

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Sponsor protocol code

CA180-226

ISRCTN number

US NCT number

NCT00777036

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000567-PIP01-09

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

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

Yes

Analysis stage

Interim

Date of interim/final analysis

01 Sep 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Sep 2016

Global end of trial reached?

Main objective of the trial

The purpose of this study is to determine whether dasatinib is safe and effective in children and adolescents with newly diagnosed chronic myeloid leukemia (CML), or in children with Ph+ acute lymphoblastic leukemia (ALL), accelerated or blast phases CML who relapse after imatinib or who are resistant or intolerant to imatinib. The side effects of this oral investigational drug in children and adolescents will be evaluated

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Mar 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 1

Country: Number of subjects enrolled

Australia: 3

Country: Number of subjects enrolled

Brazil: 15

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

India: 19

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Mexico: 14

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

Romania: 3

Country: Number of subjects enrolled

Singapore: 2

Country: Number of subjects enrolled

South Africa: 5

Country: Number of subjects enrolled

Spain: 3

Country: Number of subjects enrolled

United States: 23

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

Russian Federation: 9

Country: Number of subjects enrolled

Korea, Republic of: 15

Worldwide total number of subjects

145

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

Subjects were enrolled at 80 sites (Argentina, Australia, Brazil, Canada, France, Germany, Great Britain, India, Italy, Korea, Mexico, Netherlands, Romania, Russia, Singapore, South Africa, Spain, and USA).

Screening details

A total of 145 Subjects were enrolled and 130 Subjects were treated in the study. Reasons for non-treatment include 2 withdrew consent, 1 died, 11 failed to meet study criteria, and 1 other non-specified.

Period 1 title

On Treatment

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1

Arm description

Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

Cohort 2

Arm description

Children and adolescents with Ph+ ALL, AP-CML or BP-CML who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dasatinib tablets at dose schedule of 80 mg/m2 QD, with a maximum dose of 140 mg QD for subjects with high BSA

Cohort 3

Arm description

Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dasatinib powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

Number of subjects in period 1 ^[1]	Cohort 1	Cohort 2	Cohort 3
Started	29	17	84
Completed	14	1	61
Not completed	15	16	23
Adverse event, serious fatal	-	2	-
Non-compliance with Study Drug	1	-	-
Consent withdrawn by subject	3	2	3
Reason Not Specified	4	7	12
Progressive Disease	5	4	6
Maximum Clinical Benefit	2	-	1
Failure to Meet Study Criteria	-	1	-
Study Drug Toxicity	-	-	1

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: A total of 145 subjects were enrolled and 130 subjects were treated in the study and included in the baseline period. Reasons for non-treatment include 2 withdrew consent, 1 died, 11 failed to meet study criteria, and 1 other non-specified.

Period 2 title

Follow-Up

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1

Arm description

Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

Cohort 2

Arm description

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dasatinib tablets at dose schedule of 80 mg/m2 QD, with a maximum dose of 140 mg QD for subjects with high BSA

Cohort 3

Arm description

Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Dasatinib tablets at 60 mg/m2 QD, with a maximum dose of 100 mg QD for subjects with high BSA

Number of subjects in period 2 ^[2]	Cohort 1	Cohort 2	Cohort 3
Started	14	13	23
Completed	9	5	19
Not completed	5	8	4
Adverse event, serious fatal	1	8	-
Consent withdrawn by subject	1	-	4
Reason Not Specified	2	-	-
Lost to follow-up	1	-	-

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all participants who discontinued treatment entered the follow-up period

Baseline characteristics

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Reporting group title

Cohort 1

Reporting group description

Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

Reporting group title

Cohort 2

Reporting group description

Reporting group title

Cohort 3

Reporting group description

Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

Reporting group values	Cohort 1	Cohort 2	Cohort 3	Total
Number of subjects	29	17	84	130
Age Categorical
Units: Subjects
< 2 years	1	0	2	3
>= 2 to < 7 years	3	2	10	15
>= 7 to < 12 years	6	6	28	40
>= 12 to < 18 years	17	9	44	70
>= 18 years	2	0	0	2
Age Continuous
Units: years
arithmetic mean (standard deviation)	12.60 ( 4.774 )	12.10 ( 3.680 )	11.95 ( 4.418 )	-
Gender, Male/Female
Units: Subjects
Female	16	9	39	64
Male	13	8	45	66
Race/Ethnicity, Customized
Units: Subjects
White	20	13	56	89
Black or African American	2	0	4	6
Asian	6	3	23	32
American Indian or Alaska Native	0	0	1	1
Other	1	1	0	2
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	2	0	5	7
Not Hispanic or Latino	4	0	20	24
Unknown or Not Reported	23	17	59	99

Subject analysis set title

Cohort 3a

Subject analysis set type

Sub-group analysis

Subject analysis set description

Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

Subject analysis set title

Cohort 3b

Subject analysis set type

Sub-group analysis

Subject analysis set description

Children and adolescents with CP-CML who were treatment-naive received dasatinib powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

Subject analysis sets values	Cohort 3a	Cohort 3b
Number of subjects	51	33
Age Categorical
Units: Subjects
< 2 years	1	1
>= 2 to < 7 years	5	5
>= 7 to < 12 years	16	12
>= 12 to < 18 years	29	15
>= 18 years	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	12.28 ( 4.084 )	11.44 ( 4.912 )
Gender, Male/Female
Units: Subjects
Female	25	14
Male	26	19
Race/Ethnicity, Customized
Units: Subjects
White	31	25
Black or African American	3	1
Asian	16	7
American Indian or Alaska Native	1	0
Other	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	4
Not Hispanic or Latino	13	7
Unknown or Not Reported	37	22

End points

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Reporting group title

Cohort 1

Reporting group description

Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

Reporting group title

Cohort 2

Reporting group description

Reporting group title

Cohort 3

Reporting group description

Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

Reporting group title

Cohort 1

Reporting group description

Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

Reporting group title

Cohort 2

Reporting group description

Reporting group title

Cohort 3

Reporting group description

Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD or powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

Subject analysis set title

Cohort 3a

Subject analysis set type

Sub-group analysis

Subject analysis set description

Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

Subject analysis set title

Cohort 3b

Subject analysis set type

Sub-group analysis

Subject analysis set description

Children and adolescents with CP-CML who were treatment-naive received dasatinib powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

Primary: Major Cytogenetic Response (MCyR) Rate

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End point title

Major Cytogenetic Response (MCyR) Rate ^[1] ^[2]

End point description

Major Cytogenetic Response (MCyR) rate is defined as the proportion of all treated subjects who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response, expressed as percentage. The denominator of the MCyR response rate consists of all treated subjects in Cohort 1, and the numerator is all subjects in Cohort 1 achieving MCyR. 95% confidence interval was calculated by Clopper-Pearson exact method.

End point type

Primary

End point timeframe

From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

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 only planned to analyze select arms
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was only planned to analyze select arms

End point values	Cohort 1
Number of subjects analysed	29
Units: percentage of subjects
number (confidence interval 95%)	89.7 (72.6 to 97.8)

No statistical analyses for this end point

Primary: Complete Hematologic Response (CHR) Rate

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End point title

Complete Hematologic Response (CHR) Rate ^[3] ^[4]

End point description

Complete Hematologic Response (CHR) rate is defined as the proportion of all treated subjects who achieve a confirmed CHR while on-study, expressed as percentage. CHR is defined as including no more than 5% blasts in bone marrow and normal white blood cell count without blasts in peripheral blood, expressed as percentage. The denominator of the CHR response rate consists of all treated subjects in Cohort 2, and the numerator is all subjects in Cohort 2 achieving CHR. 95% confidence interval was calculated by Clopper-Pearson exact method.

End point type

Primary

End point timeframe

From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were planned for this endpoint
[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: This endpoint was only planned to analyze select arms

End point values	Cohort 2
Number of subjects analysed	17
Units: percentage of subjects
number (confidence interval 95%)	29.4 (10.3 to 56.0)

No statistical analyses for this end point

Primary: Complete Cytogenetic Response (CCyR) Rate

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End point title

Complete Cytogenetic Response (CCyR) Rate ^[5] ^[6]

End point description

Complete Cytogenetic Response (CCyR) rate is defined as the proportion of all treated subjects who achieve a CCyR while on-study, expressed as a percentage. CCyR rate is defined as 0% Ph+ metaphases in at least 20 metaphases in bone marrow. The denominator of the CCyR response rate consists of all treated subjects in Cohort 3, and the numerator is all subjects in Cohort 3 achieving CCyR. 95% confidence interval was calculated by Clopper-Pearson exact method.

End point type

Primary

End point timeframe

From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were planned for this endpoint
[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: This endpoint was only planned to analyze select arms

End point values	Cohort 3
Number of subjects analysed	84
Units: percentage of subjects
number (confidence interval 95%)	94.0 (86.7 to 98.0)

No statistical analyses for this end point

Secondary: Major Cytogenetic Response (MCyR) Rate in Cohort 2

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End point title

Major Cytogenetic Response (MCyR) Rate in Cohort 2 ^[7]

End point description

Major Cytogenetic Response (MCyR) rate was defined as the proportion of all treated subjects who achieved a complete (0%) or partial (1%-35% Ph+ metaphases in at least 20 metaphases in bone marrow) cytogenetic response. The percentage of treated subjects in each arm with MCyR is reported.

End point type

Secondary

End point timeframe

From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

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: This endpoint was only planned to analyze select arms

End point values	Cohort 2
Number of subjects analysed	17
Units: percent of subjects
number (confidence interval 95%)	58.8 (32.9 to 81.6)

No statistical analyses for this end point

Secondary: Complete Hematologic Response (CHR) Rate in Cohorts 1 and 3

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End point title

Complete Hematologic Response (CHR) Rate in Cohorts 1 and 3 ^[8]

End point description

Complete Hematologic Response (CHR) rate defined as the proportion of all treated subjects who achieve a confirmed CHR while on-study. CHR is defined as including no more than 5% blasts in bone marrow and normal white blood cell count without blasts in peripheral blood. The percentage of treated subjects in each arm with CHR is reported.

End point type

Secondary

End point timeframe

From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

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: This endpoint was only planned to analyze select arms

End point values	Cohort 1	Cohort 3
Number of subjects analysed	29	84
Units: percentage of subjects
number (confidence interval 95%)	93.1 (77.2 to 99.2)	96.4 (89.9 to 99.3)

No statistical analyses for this end point

Secondary: Rate of Best Cytogenetic Response

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End point title

Rate of Best Cytogenetic Response

End point description

The number of subjects achieving their best on-study cytogenetic response was reported as a percentage of all treated subjects in that arm.

End point type

Secondary

End point timeframe

From first dose of study therapy until 30 days after last dose (Assessed up to September 2016, approximately 90 months)

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	29	17	84	51	33
Units: percentage of subjects
number (not applicable)
Complete (0%)	82.8	29.4	94.0	96.1	90.9
Partial (>0% - 35%)	6.9	23.5	2.4	2.0	3.0
Minor (>35% - 65%)	3.4	0	0	0	0
Minimal (>65% - 95%)	3.4	0	1.2	2.0	0
No Response (>95% - 100%)	0	5.9	0	0	0
Unable to Determine	3.4	41.2	2.4	0	6.1

No statistical analyses for this end point

Secondary: Time to Major Cytogenetic Response (MCyR)

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End point title

Time to Major Cytogenetic Response (MCyR)

End point description

Time to MCyR is defined as the time from first dose of dasatinib until the first day MCyR criteria are met, computed only for subjects whose best response is MCyR.

End point type

Secondary

End point timeframe

From first dose until MCyR criteria are met (assessed up to September 2016, approximately 90 months)

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	26	9	81	50	31
Units: months
median (confidence interval 95%)	3.1 (2.8 to 4.1)	1.6 (0.5 to 5.7)	3.0 (2.9 to 4.3)	3.3 (2.9 to 5.6)	3.0 (2.8 to 5.0)

No statistical analyses for this end point

Secondary: Duration of Major Cytogenetic Response (MCyR)

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End point title

Duration of Major Cytogenetic Response (MCyR)

End point description

Duration of MCyR will be computed from the first day criteria are met for MCyR until the date PD is reported (or treatment is discontinued for PD) or death. Subjects who neither discontinue due to PD nor die will be censored on the date of their last hematologic or cytogenetic assessment, whichever comes last. Only subjects with MCyR were analyzed.

End point type

Secondary

End point timeframe

From first day criteria are met for MCyR until the date PD is reported or death (assessed up to September 2016, approximately 90 months)

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	26	9	81	50	31
Units: months
median (confidence interval 95%)	99999 (54.9 to 99999)	11.2 (0.3 to 99999)	99999 (52.7 to 99999)	99999 (52.7 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Time to Complete Cytogenetic Response (CCyR)

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End point title

Time to Complete Cytogenetic Response (CCyR)

End point description

Time to CCyR is defined as the time from first dose of dasatinib until the first day CCyR criteria are met, computed only for subjects whose best response is CCyR.

End point type

Secondary

End point timeframe

From first dose until CCyR criteria are met, assessed up to September 2016 (approximately 90 months)

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	24	7	79	49	30
Units: months
median (confidence interval 95%)	3.9 (2.8 to 5.6)	1.6 (0.5 to 5.7)	5.6 (5.0 to 6.0)	5.7 (3.7 to 6.2)	5.6 (3.1 to 6.0)

No statistical analyses for this end point

Secondary: Duration of Complete Cytogenetic Response (CCyR)

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End point title

Duration of Complete Cytogenetic Response (CCyR)

End point description

Duration of CCyR will be computed from the first day criteria are met for CCyR until the date PD is reported (or treatment is discontinued for PD) or death. Subjects who neither discontinue due to PD nor die will be censored on the date of their last hematologic or cytogenetic assessment, whichever comes last.

End point type

Secondary

End point timeframe

From first day criteria are met for CCyR until the date of progressive disease or death (assessed up to September 2016, approximately 90 months)

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	24	5	79	49	30
Units: months
median (confidence interval 95%)	99999 (54.9 to 99999)	99999 (1.0 to 99999)	99999 (49.9 to 99999)	99999 (49.9 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS) Rate at 2 years

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End point title

Progression-Free Survival (PFS) Rate at 2 years

End point description

PFS is defined as time from the first dosing date until the time PD is first documented by the investigator or death. Subjects who die without a reported date of progression will be considered to have progressed on the date of death. Subjects who neither progress nor die will be censored on the date of their last cytogenetic or hematologic assessment. The percentages of progression-free subjects at 2 years are based on Kaplan-Meier estimation.

End point type

Secondary

End point timeframe

2 years

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	29	17	84	51	33
Units: percentage
median (confidence interval 95%)	81.7 (61.4 to 92.0)	20.5 (3.7 to 46.4)	95.1 (87.4 to 98.1)	94.0 (82.6 to 98.0)	96.8 (79.2 to 99.5)

No statistical analyses for this end point

Secondary: Time to Complete Hematologic Response (CHR)

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End point title

Time to Complete Hematologic Response (CHR)

End point description

Time to CHR is defined as the time from first dose of dasatinib until the first day CHR criteria are met, provided they are confirmed 4 weeks later, computed only for subjects whose best response is CHR.

End point type

Secondary

End point timeframe

From first dose until CHR criteria are met, assessed up to September 2016 (approximately 90 months)

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	27	5	81	51	30
Units: months
median (confidence interval 95%)	0.7 (0.5 to 1.8)	2.5 (0.5 to 2.8)	1.2 (0.9 to 1.4)	1.2 (0.9 to 1.4)	1.0 (0.7 to 1.8)

No statistical analyses for this end point

Secondary: Duration of Complete Hemotologic Response (CHR)

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End point title

Duration of Complete Hemotologic Response (CHR)

End point description

Duration of CHR will be computed from the first day all criteria are met for CHR, provided they are confirmed 4 weeks later, until the date progressive disease (PD) is reported (or treatment is discontinued for PD) or death. Subjects who neither discontinue due to PD nor die will be censored on the date of their last hematologic assessment. Only subjects with CHR were analyzed.

End point type

Secondary

End point timeframe

From first day criteria are met for CHR until date of disease progression or death (assessed up to September 2016, approximately 90 months)

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	27	5	81	51	30
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (1.9 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Disease-Free Survival Rate at 2 years

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End point title

Disease-Free Survival Rate at 2 years

End point description

Disease free survival is defined as time from CCyR for Subjects with newly diagnosed chronic phase CML and for Subjects with chronic phase CML who are resistant or intolerant to imatinib (cohort 3 and cohort 1), and as time from CHR for Subjects with advanced phase CML and PH + ALL (cohort 2) until the time progression is first documented by the investigator or death from any cause. The percentages of disease-free subjects at 2 years are based on Kaplan-Meier estimation.

End point type

Secondary

End point timeframe

2 years

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	24	5	79	49	30
Units: percentage
median (confidence interval 95%)	86.9 (64.6 to 95.6)	60.0 (12.6 to 88.2)	98.7 (91.2 to 99.8)	97.9 (86.1 to 99.7)	100 (100 to 100)

No statistical analyses for this end point

Secondary: Overall Survival (OS) Rate at 2 years

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End point title

Overall Survival (OS) Rate at 2 years

End point description

OS is defined as time from the first dosing date until the time of death. All subjects will be followed yearly for survival for up to 5 years after treatment discontinuation. Subjects who have not died or who are lost to follow-up will be censored on the last date the subject is known to be alive. The percentages of surviving participants at 2 years are based on Kaplan-Meier estimation.

End point type

Secondary

End point timeframe

2 years

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	29	17	84	51	33
Units: percentage
median (confidence interval 95%)	96.4 (77.2 to 99.5)	32.2 (10.6 to 56.4)	100 (100 to 100)	100 (100 to 100)	100 (100 to 100)

No statistical analyses for this end point

Secondary: Major Molecular Response (MMR) Rate

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End point title

Major Molecular Response (MMR) Rate

End point description

Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). MMR for subjects with the p210 BCR-ABL transcript variant was defined as a ratio BCR-ABL/ABL <= 10-3 or 0.1% on the international scale. In this study, ABL was used as the control-gene. For a subject with the p190 BCR-ABL transcript variant (occurring in Cohort 2 only), on-study assessments were compared to the participant’s individual baseline BCR-ABL/ABL ratio and a reduction to < 0.1% or a 3-log reduction from baseline was considered an MMR.

End point type

Secondary

End point timeframe

From date of first treatment to date of MMR (assessed up to September 2016, approximately 90 months)

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	29	17	84	51	33
Units: percentage of subjects
number (confidence interval 95%)	62.1 (42.3 to 79.3)	29.4 (10.3 to 56.0)	79.8 (69.6 to 87.7)	88.2 (76.1 to 95.6)	66.7 (48.2 to 82.0)

No statistical analyses for this end point

Secondary: Complete Molecular Response (CMR) Rate

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End point title

Complete Molecular Response (CMR) Rate

End point description

Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). CMR is defined as absence of BCR-ABL rearrangements by real-time qPCR analysis. The percentage of treated subjects with CMR is reported by arm.

End point type

Secondary

End point timeframe

From date of first treatment to date of CMR (assessed up to September 2016, approximately 90 months)

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	29	17	84	51	33
Units: percentage
number (confidence interval 95%)	24.1 (10.3 to 43.5)	17.6 (3.8 to 43.4)	29.8 (20.3 to 40.7)	43.1 (29.3 to 57.8)	9.1 (1.9 to 24.3)

No statistical analyses for this end point

Secondary: Major Cytogenetic Response (MCyR) Rate up to 2 years

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End point title

Major Cytogenetic Response (MCyR) Rate up to 2 years

End point description

End point type

Secondary

End point timeframe

24 months

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	29	17	84	51	33
Units: percentage of subjects
number (confidence interval 95%)
12 months	89.7 (72.6 to 97.8)	58.8 (32.9 to 81.6)	96.4 (89.9 to 99.3)	98.0 (89.6 to 100.0)	93.9 (79.8 to 99.3)
24 months	89.7 (72.6 to 97.8)	58.8 (32.9 to 81.6)	96.4 (89.9 to 99.3)	98.0 (89.6 to 100.0)	93.9 (79.8 to 99.3)

No statistical analyses for this end point

Secondary: Complete Cytogenetic Response (CCyR) Rate up to 2 years

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End point title

Complete Cytogenetic Response (CCyR) Rate up to 2 years

End point description

Complete Cytogenetic Response (CCyR) rate is defined as the proportion of all treated subjects who achieve a CCyR while on-study. CCyR rate is defined as 0% Ph+ metaphases in at least 20 metaphases in bone marrow. The percentage of treated subjects with CCyR is reported by arm.

End point type

Secondary

End point timeframe

24 months

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	29	17	84	51	33
Units: percentage of subjects
number (confidence interval 95%)
12 months	75.9 (56.5 to 89.7)	41.2 (18.4 to 67.1)	92.9 (85.1 to 97.3)	96.1 (86.5 to 99.5)	87.9 (71.8 to 96.6)
24 months	82.8 (64.2 to 94.2)	41.2 (18.4 to 67.1)	94.0 (86.7 to 98.0)	96.1 (86.5 to 99.5)	90.9 (75.7 to 98.1)

No statistical analyses for this end point

Secondary: Major Molecular Response (MMR) Rate up to 2 years

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End point title

Major Molecular Response (MMR) Rate up to 2 years

End point description

Molecular response was assessed using BCR-ABL transcript levels measurement by real-time qPCR. MMR for Subjects with the p210 BCR-ABL transcript variant is defined according to the recommendations of Hughes et al. as a ratio BCR-ABL/ABL <= 10-3 or 0.1% on the international scale proposed by the authors. The standardized baseline, as established in the IRIS trial, is taken to represent 100% on the international scale and a 3-log reduction in ratio (BCR-ABL transcripts/ABL or BCR) from the standardized baseline (MMR) is fixed at 0.1%. In this study, ABL or other housekeeping gene, will be used as the control-gene. For a Subject with the p190 BCR-ABL transcript variant, on-study assessments will be compared to the Subject’s individual baseline BCR-ABL/ABL ratio and a reduction to < 0.1% or a 3-log reduction from baseline will be considered an MMR. The percentage of treated subjects with MMR is reported by arm.

End point type

Secondary

End point timeframe

24 months

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	29	17	84	51	33
Units: percentage of subjects
number (confidence interval 95%)
12 months	41.4 (23.5 to 61.1)	23.5 (6.8 to 49.9)	52.4 (41.2 to 63.4)	56.9 (42.2 to 70.7)	45.5 (28.1 to 63.6)
24 months	55.2 (35.7 to 73.6)	29.4 (10.3 to 56.0)	70.2 (59.3 to 79.7)	74.5 (60.4 to 85.7)	63.6 (45.1 to 79.6)

No statistical analyses for this end point

Secondary: Complete Molecular Response (CMR) Rate up to 2 years

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End point title

Complete Molecular Response (CMR) Rate up to 2 years

End point description

Molecular response was assessed using BCR-ABL transcript levels measurement by real-time quantitative polymerase chain reaction (qPCR). (CMR) is defined as absence of BCR-ABL rearrangements by real-time qPCR analysis. The percentage of treated subjects with CMR is reported by arm.

End point type

Secondary

End point timeframe

24 months

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 3a	Cohort 3b
Number of subjects analysed	29	17	84	51	33
Units: percentage
number (confidence interval 95%)
12 months	6.9 (0.8 to 22.8)	11.8 (1.5 to 36.4)	8.3 (3.4 to 16.4)	9.8 (3.3 to 21.4)	6.1 (0.7 to 20.2)
24 months	17.2 (5.8 to 35.8)	11.8 (1.5 to 36.4)	21.4 (13.2 to 31.7)	29.4 (17.5 to 43.8)	9.1 (1.9 to 24.3)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose of study drug until the last dose of study drug plus 30 days

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Cohort 3a

Reporting group description

Children and adolescents with CP-CML who were treatment-naive received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

Reporting group title

Cohort 3b

Reporting group description

Children and adolescents with CP-CML who were treatment-naive received dasatinib powder for oral suspension (PFOS) at 72 mg/m2 QD on a continuous oral regimen.

Reporting group title

Cohort 1

Reporting group description

Children and adolescents with CP-CML who were resistant or intolerant to imatinib received dasatinib tablets at 60 mg/m2 QD on a continuous oral regimen.

Reporting group title

Cohort 2 BP-CML

Reporting group description

Children and adolescents with BP-CML who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.

Reporting group title

Cohort 2 Ph+ ALL

Reporting group description

Children and adolescents with Ph+ ALL who were resistant or intolerant to, or relapsed after imatinib therapy received dasatinib tablets at a dose schedule of 80 mg/m2 QD on a continuous oral regimen.

Serious adverse events	Cohort 3a	Cohort 3b	Cohort 1	Cohort 2 BP-CML	Cohort 2 Ph+ ALL
Total subjects affected by serious adverse events
subjects affected / exposed	19 / 51 (37.25%)	9 / 33 (27.27%)	13 / 29 (44.83%)	7 / 8 (87.50%)	6 / 9 (66.67%)
number of deaths (all causes)	0	0	0	1	3
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia recurrent
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
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 / 1
Blast cell proliferation
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blast crisis in myelogenous leukaemia
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic myeloid leukaemia
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	1 / 29 (3.45%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukaemia
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukaemia recurrent
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	1 / 29 (3.45%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	2 / 8 (25.00%)	2 / 9 (22.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
Vascular disorders
Jugular vein thrombosis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Bone marrow transplant
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (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
General disorders and administration site conditions
Chills
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Fatigue
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (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
Pain
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 51 (3.92%)	3 / 33 (9.09%)	2 / 29 (6.90%)	2 / 8 (25.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (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
Reproductive system and breast disorders
Genital haemorrhage
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
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
Uterine haemorrhage
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (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
Pulmonary haemorrhage
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
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 / 1
Respiratory failure
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
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 / 1
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Personality change
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (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
Aspartate aminotransferase increased
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (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
White blood cell count decreased
subjects affected / exposed	2 / 51 (3.92%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Facial bones fracture
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gun shot wound
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 51 (1.96%)	1 / 33 (3.03%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Left ventricular dysfunction
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (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
Nervous system disorders
Arachnoiditis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial nerve disorder
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 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 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
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
Seizure
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (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
Syncope
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 51 (5.88%)	1 / 33 (3.03%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	6 / 7	0 / 1	4 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	2 / 51 (3.92%)	1 / 33 (3.03%)	0 / 29 (0.00%)	2 / 8 (25.00%)	3 / 9 (33.33%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	3 / 5	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Leukopenia
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	2 / 29 (6.90%)	2 / 8 (25.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	4 / 4	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 51 (3.92%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal ulcer
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (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
Colitis
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 51 (0.00%)	3 / 33 (9.09%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
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
Haematochezia
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (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
Rectal haemorrhage
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
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
Stomatitis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 51 (0.00%)	3 / 33 (9.09%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (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
Skin and subcutaneous tissue disorders
Rash maculo-papular
subjects affected / exposed	1 / 51 (1.96%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	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
Musculoskeletal and connective tissue disorders
Osteonecrosis
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacterial sepsis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
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
Gastroenteritis
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	2 / 29 (6.90%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myringitis
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	2 / 8 (25.00%)	0 / 9 (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
Otitis externa
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (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
Sepsis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Upper aerodigestive tract infection
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
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 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 51 (3.92%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 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: 5%

Non-serious adverse events	Cohort 3a	Cohort 3b	Cohort 1	Cohort 2 BP-CML	Cohort 2 Ph+ ALL
Total subjects affected by non serious adverse events
subjects affected / exposed	50 / 51 (98.04%)	33 / 33 (100.00%)	27 / 29 (93.10%)	7 / 8 (87.50%)	9 / 9 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	3 / 51 (5.88%)	3 / 33 (9.09%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	4	1	0	0
Vascular disorders
Haematoma
subjects affected / exposed	2 / 51 (3.92%)	3 / 33 (9.09%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	5	1	0	0
Hot flush
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1
Hypertension
subjects affected / exposed	5 / 51 (9.80%)	4 / 33 (12.12%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	6	5	1	0	0
Thrombophlebitis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	4	0
Phlebitis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1
Chest pain
subjects affected / exposed	2 / 51 (3.92%)	0 / 33 (0.00%)	3 / 29 (10.34%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	0	4	0	0
Chills
subjects affected / exposed	0 / 51 (0.00%)	3 / 33 (9.09%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	3	1	0	0
Fatigue
subjects affected / exposed	10 / 51 (19.61%)	7 / 33 (21.21%)	8 / 29 (27.59%)	1 / 8 (12.50%)	2 / 9 (22.22%)
occurrences all number	22	18	14	1	2
Influenza like illness
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0
Malaise
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	0	4
Mass
subjects affected / exposed	1 / 51 (1.96%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	3	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	1 / 29 (3.45%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	2	1	5	0
Non-Cardiac chest pain
subjects affected / exposed	3 / 51 (5.88%)	3 / 33 (9.09%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	3	0	0	0
Oedema peripheral
subjects affected / exposed	2 / 51 (3.92%)	1 / 33 (3.03%)	3 / 29 (10.34%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	2	1	3	1	0
Pain
subjects affected / exposed	6 / 51 (11.76%)	5 / 33 (15.15%)	3 / 29 (10.34%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences all number	9	7	3	1	2
Peripheral swelling
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0
Pyrexia
subjects affected / exposed	23 / 51 (45.10%)	10 / 33 (30.30%)	14 / 29 (48.28%)	1 / 8 (12.50%)	5 / 9 (55.56%)
occurrences all number	77	22	46	1	12
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0
Hypersensitivity
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	5	0	0
Reproductive system and breast disorders
Breast mass
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	1 / 29 (3.45%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	1	0	1	1	0
Dysmenorrhoea
subjects affected / exposed	4 / 51 (7.84%)	1 / 33 (3.03%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	14	1	3	0	0
Menstruation irregular
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0
Vaginal discharge
subjects affected / exposed	3 / 51 (5.88%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	5	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	16 / 51 (31.37%)	9 / 33 (27.27%)	13 / 29 (44.83%)	1 / 8 (12.50%)	4 / 9 (44.44%)
occurrences all number	38	20	25	6	5
Dyspnoea
subjects affected / exposed	4 / 51 (7.84%)	2 / 33 (6.06%)	3 / 29 (10.34%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	6	2	7	1	0
Epistaxis
subjects affected / exposed	5 / 51 (9.80%)	4 / 33 (12.12%)	3 / 29 (10.34%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	5	4	4	0	1
Nasal congestion
subjects affected / exposed	3 / 51 (5.88%)	2 / 33 (6.06%)	3 / 29 (10.34%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	4	4	5	0	0
Oropharyngeal pain
subjects affected / exposed	10 / 51 (19.61%)	11 / 33 (33.33%)	6 / 29 (20.69%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	16	18	10	1	0
Pharyngeal erythema
subjects affected / exposed	3 / 51 (5.88%)	5 / 33 (15.15%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	5	8	0	0	0
Productive cough
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	1	0	0	2	0
Respiratory failure
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1
Respiratory tract congestion
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	3	0	0	0
Rhinalgia
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1
Rhinitis allergic
subjects affected / exposed	3 / 51 (5.88%)	3 / 33 (9.09%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	3	2	0	0
Rhinorrhoea
subjects affected / exposed	11 / 51 (21.57%)	4 / 33 (12.12%)	3 / 29 (10.34%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences all number	15	6	4	1	1
Wheezing
subjects affected / exposed	3 / 51 (5.88%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	3	2	0	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	2 / 51 (3.92%)	3 / 33 (9.09%)	2 / 29 (6.90%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences all number	2	3	3	1	2
Depression
subjects affected / exposed	4 / 51 (7.84%)	1 / 33 (3.03%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	4	1	1	0	0
Insomnia
subjects affected / exposed	3 / 51 (5.88%)	2 / 33 (6.06%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	2	2	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 51 (5.88%)	4 / 33 (12.12%)	4 / 29 (13.79%)	3 / 8 (37.50%)	1 / 9 (11.11%)
occurrences all number	5	6	5	6	1
Aspartate aminotransferase increased
subjects affected / exposed	3 / 51 (5.88%)	3 / 33 (9.09%)	3 / 29 (10.34%)	2 / 8 (25.00%)	0 / 9 (0.00%)
occurrences all number	3	4	3	3	0
Blood creatinine increased
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	1	0	2	0
Blood lactate dehydrogenase increased
subjects affected / exposed	2 / 51 (3.92%)	4 / 33 (12.12%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	4	5	0	6	0
Blood phosphorus decreased
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1
Blood urea increased
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	1	0	2	0
Gamma-Glutamyltransferase increased
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 51 (0.00%)	5 / 33 (15.15%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	8	1	0	0
Neutrophil count decreased
subjects affected / exposed	1 / 51 (1.96%)	5 / 33 (15.15%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	6	0	0	0
Platelet count decreased
subjects affected / exposed	2 / 51 (3.92%)	11 / 33 (33.33%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	19	1	0	0
Weight decreased
subjects affected / exposed	3 / 51 (5.88%)	1 / 33 (3.03%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	1	1	0	0
Weight increased
subjects affected / exposed	3 / 51 (5.88%)	3 / 33 (9.09%)	2 / 29 (6.90%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	3	5	2	1	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	2	0	0
Contusion
subjects affected / exposed	3 / 51 (5.88%)	4 / 33 (12.12%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	6	8	3	0	0
Foot fracture
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1
Procedural pain
subjects affected / exposed	2 / 51 (3.92%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	5	0	0	0
Sunburn
subjects affected / exposed	1 / 51 (1.96%)	1 / 33 (3.03%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	2	0	0
Nervous system disorders
Arachnoiditis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Brain oedema
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Dizziness
subjects affected / exposed	12 / 51 (23.53%)	3 / 33 (9.09%)	2 / 29 (6.90%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	19	4	3	2	0
Dysgeusia
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1
Facial paralysis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Headache
subjects affected / exposed	24 / 51 (47.06%)	15 / 33 (45.45%)	17 / 29 (58.62%)	3 / 8 (37.50%)	5 / 9 (55.56%)
occurrences all number	82	25	52	16	9
Neuropathy peripheral
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Paraesthesia
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	5 / 29 (17.24%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	5	0	0
Somnolence
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	10 / 51 (19.61%)	5 / 33 (15.15%)	2 / 29 (6.90%)	2 / 8 (25.00%)	2 / 9 (22.22%)
occurrences all number	16	16	6	5	3
Febrile neutropenia
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	1	0	0	1
Haemoglobinaemia
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	0
Leukopenia
subjects affected / exposed	3 / 51 (5.88%)	2 / 33 (6.06%)	2 / 29 (6.90%)	2 / 8 (25.00%)	0 / 9 (0.00%)
occurrences all number	6	13	2	3	0
Lymphadenopathy
subjects affected / exposed	1 / 51 (1.96%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	2	0	0	0
Lymphopenia
subjects affected / exposed	1 / 51 (1.96%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	1	2	0	3	0
Neutropenia
subjects affected / exposed	17 / 51 (33.33%)	8 / 33 (24.24%)	6 / 29 (20.69%)	4 / 8 (50.00%)	3 / 9 (33.33%)
occurrences all number	35	21	14	9	8
Pancytopenia
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1
Thrombocytopenia
subjects affected / exposed	13 / 51 (25.49%)	7 / 33 (21.21%)	5 / 29 (17.24%)	4 / 8 (50.00%)	4 / 9 (44.44%)
occurrences all number	22	17	7	12	5
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	7 / 51 (13.73%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	8	3	0	0	0
Hypoacusis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Eye disorders
Dry eye
subjects affected / exposed	1 / 51 (1.96%)	2 / 33 (6.06%)	1 / 29 (3.45%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	3	2	1	1	0
Eye oedema
subjects affected / exposed	1 / 51 (1.96%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	4	0	0	0
Eye pain
subjects affected / exposed	3 / 51 (5.88%)	1 / 33 (3.03%)	3 / 29 (10.34%)	0 / 8 (0.00%)	2 / 9 (22.22%)
occurrences all number	4	1	3	0	2
Periorbital oedema
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0
Vision blurred
subjects affected / exposed	3 / 51 (5.88%)	1 / 33 (3.03%)	1 / 29 (3.45%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	3	1	1	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	18 / 51 (35.29%)	7 / 33 (21.21%)	10 / 29 (34.48%)	1 / 8 (12.50%)	2 / 9 (22.22%)
occurrences all number	42	12	37	1	4
Abdominal pain upper
subjects affected / exposed	12 / 51 (23.53%)	4 / 33 (12.12%)	8 / 29 (27.59%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	32	9	16	0	0
Anal fissure
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	1	0	1	0
Anal ulcer
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Colitis
subjects affected / exposed	3 / 51 (5.88%)	1 / 33 (3.03%)	1 / 29 (3.45%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences all number	7	2	1	1	1
Constipation
subjects affected / exposed	9 / 51 (17.65%)	5 / 33 (15.15%)	4 / 29 (13.79%)	2 / 8 (25.00%)	0 / 9 (0.00%)
occurrences all number	11	6	4	5	0
Diarrhoea
subjects affected / exposed	27 / 51 (52.94%)	12 / 33 (36.36%)	17 / 29 (58.62%)	3 / 8 (37.50%)	3 / 9 (33.33%)
occurrences all number	87	21	72	3	6
Dyspepsia
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	2	0	0
Flatulence
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	2	0	0
Gastritis
subjects affected / exposed	6 / 51 (11.76%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	9	1	0	0	0
Gingival bleeding
subjects affected / exposed	2 / 51 (3.92%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	2	0	0
Mouth ulceration
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	3	1	0	0
Nausea
subjects affected / exposed	20 / 51 (39.22%)	10 / 33 (30.30%)	11 / 29 (37.93%)	3 / 8 (37.50%)	2 / 9 (22.22%)
occurrences all number	38	24	28	3	3
Oral pain
subjects affected / exposed	2 / 51 (3.92%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	2	0	0	0
Stomatitis
subjects affected / exposed	2 / 51 (3.92%)	4 / 33 (12.12%)	0 / 29 (0.00%)	2 / 8 (25.00%)	1 / 9 (11.11%)
occurrences all number	2	17	0	2	1
Tongue ulceration
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	3	0	1	0
Toothache
subjects affected / exposed	4 / 51 (7.84%)	1 / 33 (3.03%)	3 / 29 (10.34%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	4	1	5	0	1
Vomiting
subjects affected / exposed	22 / 51 (43.14%)	11 / 33 (33.33%)	15 / 29 (51.72%)	3 / 8 (37.50%)	3 / 9 (33.33%)
occurrences all number	55	30	45	14	5
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 51 (1.96%)	7 / 33 (21.21%)	3 / 29 (10.34%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	7	5	0	1
Alopecia
subjects affected / exposed	5 / 51 (9.80%)	1 / 33 (3.03%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	6	1	2	0	0
Dermatitis acneiform
subjects affected / exposed	2 / 51 (3.92%)	2 / 33 (6.06%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	2	2	0	0
Dry skin
subjects affected / exposed	2 / 51 (3.92%)	0 / 33 (0.00%)	4 / 29 (13.79%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	2	0	6	0	1
Eczema
subjects affected / exposed	1 / 51 (1.96%)	1 / 33 (3.03%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	2	0	0
Erythema
subjects affected / exposed	4 / 51 (7.84%)	2 / 33 (6.06%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	4	4	2	0	0
Papule
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	0	1
Petechiae
subjects affected / exposed	1 / 51 (1.96%)	1 / 33 (3.03%)	1 / 29 (3.45%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	4	3	1	0	1
Pruritus
subjects affected / exposed	7 / 51 (13.73%)	4 / 33 (12.12%)	5 / 29 (17.24%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	8	4	5	0	0
Rash
subjects affected / exposed	14 / 51 (27.45%)	11 / 33 (33.33%)	8 / 29 (27.59%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences all number	19	25	11	1	1
Rash erythematous
subjects affected / exposed	3 / 51 (5.88%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	4	0	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 51 (0.00%)	3 / 33 (9.09%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	3	1	0	0
Rash papular
subjects affected / exposed	3 / 51 (5.88%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	3	1	0	0	1
Skin exfoliation
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	1	0	1
Skin hypopigmentation
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	2	0	1
Skin induration
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	1
Urticaria
subjects affected / exposed	3 / 51 (5.88%)	3 / 33 (9.09%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	4	6	2	0	0
Xeroderma
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	4 / 51 (7.84%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	5	1	0	1	0
Urinary incontinence
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 51 (21.57%)	6 / 33 (18.18%)	6 / 29 (20.69%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences all number	22	7	15	1	1
Back pain
subjects affected / exposed	7 / 51 (13.73%)	6 / 33 (18.18%)	4 / 29 (13.79%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	14	6	6	1	0
Bone pain
subjects affected / exposed	5 / 51 (9.80%)	0 / 33 (0.00%)	1 / 29 (3.45%)	1 / 8 (12.50%)	3 / 9 (33.33%)
occurrences all number	5	0	1	1	3
Coccydynia
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0
Groin pain
subjects affected / exposed	3 / 51 (5.88%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	1	0	1
Musculoskeletal chest pain
subjects affected / exposed	1 / 51 (1.96%)	4 / 33 (12.12%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	4	1	0	0
Musculoskeletal pain
subjects affected / exposed	5 / 51 (9.80%)	7 / 33 (21.21%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	9	7	4	0	0
Musculoskeletal stiffness
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	0
Myalgia
subjects affected / exposed	3 / 51 (5.88%)	6 / 33 (18.18%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	9	10	0	0
Neck pain
subjects affected / exposed	2 / 51 (3.92%)	2 / 33 (6.06%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	2	3	0	1	0
Pain in extremity
subjects affected / exposed	11 / 51 (21.57%)	14 / 33 (42.42%)	15 / 29 (51.72%)	2 / 8 (25.00%)	0 / 9 (0.00%)
occurrences all number	24	26	23	2	0
Pain in jaw
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	3 / 29 (10.34%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	3	0	0
Tendonitis
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0
Infections and infestations
Abscess
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1	2
Bronchitis
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	3 / 29 (10.34%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	3	0	0
Cellulitis
subjects affected / exposed	3 / 51 (5.88%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	0	1	0	0
Conjunctivitis
subjects affected / exposed	2 / 51 (3.92%)	2 / 33 (6.06%)	3 / 29 (10.34%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	2	3	0	0
Ear infection
subjects affected / exposed	5 / 51 (9.80%)	3 / 33 (9.09%)	1 / 29 (3.45%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	10	5	2	0	1
Febrile infection
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Folliculitis
subjects affected / exposed	2 / 51 (3.92%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	2	0	0	0
Gastroenteritis
subjects affected / exposed	7 / 51 (13.73%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences all number	12	0	0	1	1
Gastroenteritis viral
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	2 / 29 (6.90%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	3	0	0
Gingivitis
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	1 / 29 (3.45%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	1	0	1	1	0
Herpes virus infection
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Hordeolum
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	2 / 29 (6.90%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	1	3	0	1
Influenza
subjects affected / exposed	6 / 51 (11.76%)	1 / 33 (3.03%)	3 / 29 (10.34%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	14	1	3	0	0
Localised infection
subjects affected / exposed	1 / 51 (1.96%)	2 / 33 (6.06%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	2	1	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0
Nasopharyngitis
subjects affected / exposed	10 / 51 (19.61%)	4 / 33 (12.12%)	7 / 29 (24.14%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	16	8	9	0	0
Oral herpes
subjects affected / exposed	4 / 51 (7.84%)	1 / 33 (3.03%)	0 / 29 (0.00%)	2 / 8 (25.00%)	0 / 9 (0.00%)
occurrences all number	4	1	0	3	0
Otitis media
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	1 / 29 (3.45%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	1	1	0
Pharyngitis
subjects affected / exposed	6 / 51 (11.76%)	1 / 33 (3.03%)	2 / 29 (6.90%)	2 / 8 (25.00%)	2 / 9 (22.22%)
occurrences all number	8	1	2	3	3
Rhinitis
subjects affected / exposed	7 / 51 (13.73%)	4 / 33 (12.12%)	3 / 29 (10.34%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	10	6	3	0	1
Sinusitis
subjects affected / exposed	3 / 51 (5.88%)	2 / 33 (6.06%)	4 / 29 (13.79%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	8	2	4	0	1
Tonsillitis
subjects affected / exposed	3 / 51 (5.88%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	3	1	0	1	0
Tooth infection
subjects affected / exposed	3 / 51 (5.88%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	16 / 51 (31.37%)	11 / 33 (33.33%)	9 / 29 (31.03%)	1 / 8 (12.50%)	1 / 9 (11.11%)
occurrences all number	30	25	23	1	2
Viral infection
subjects affected / exposed	3 / 51 (5.88%)	0 / 33 (0.00%)	3 / 29 (10.34%)	0 / 8 (0.00%)	1 / 9 (11.11%)
occurrences all number	3	0	3	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 51 (7.84%)	1 / 33 (3.03%)	2 / 29 (6.90%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	8	1	2	2	0
Fluid retention
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	3	0	0	0
Hypercalcaemia
subjects affected / exposed	0 / 51 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0
Hyperkalaemia
subjects affected / exposed	0 / 51 (0.00%)	3 / 33 (9.09%)	0 / 29 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	7	0	0	0
Hypermagnesaemia
subjects affected / exposed	1 / 51 (1.96%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	2	2	0	3	0
Hypernatraemia
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0
Hyperphosphataemia
subjects affected / exposed	0 / 51 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	1	0	2	0
Hyperuricaemia
subjects affected / exposed	0 / 51 (0.00%)	4 / 33 (12.12%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	4	0	6	0
Hypoalbuminaemia
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	1	0	0	4	0
Hypocalcaemia
subjects affected / exposed	2 / 51 (3.92%)	3 / 33 (9.09%)	2 / 29 (6.90%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	2	3	2	3	0
Hypokalaemia
subjects affected / exposed	2 / 51 (3.92%)	1 / 33 (3.03%)	0 / 29 (0.00%)	2 / 8 (25.00%)	1 / 9 (11.11%)
occurrences all number	2	1	0	5	1
Hypomagnesaemia
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	1	0	0	2	0
Hyponatraemia
subjects affected / exposed	1 / 51 (1.96%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	0
Hypophosphataemia
subjects affected / exposed	0 / 51 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

17 Dec 2009

The primary purpose of this amendment is to include a new cohort of pediatric subjects with newly diagnosed treatment-naive chronic phase chronic myelogenous leukemia (CP-CML) in this trial (Cohort #3) and to align the protocol with the Pediatric Investigational Plan (PIP). The changes include the following: - Expand the primary objective to include Cohort #3 - Clarify the study duration and drug dispensation. - Established a data monitoring committee (DMC). - In order to improve safety, subjects who have a dose escalation will also be required to have another ECG performed if one was not previously done at that dose. - In order to improve safety, Cohort #3 subjects are required to have ECGs and echocardiograms performed yearly. - Expand the dose selection rationale. - Expand and update safety and efficacy summaries. - Clarify inclusion criteria for all cohorts. - Clarify the resistance criteria for Ph+ ALL. - Clarify the dose escalation criteria for Cohort #2. - Clarify the exclusion criteria for subjects with extramedullary disease to include subjects with isolated CNS involvement. - Add the T315I mutation to the exclusion criteria. - Add hypersensitivity to the active substance or to any of the excipients to the exclusion criteria. - Add patients with hereditary problems of galactose intolerance or Lapp lactase deficiency or glucose-galactose malabsorption to the exclusion criteria. - Clarify statistical definitions, including the definitions for progression-free survival (PFS) and disease-free survival (DFS). - Clarification as to the mode of drug administration. - Synchronized visit and assessment schedules (Table 6.1-1). - Change the molecular analysis schedule to coincide with scheduled visits. - Add the long-term follow-up plan for patients on protocol therapy. - Indicate the modalities of body surface area calculation in children. - Change in the medical monitor of the trial. - Correction of typographical errors.

04 Oct 2010

The primary purpose of this amendment is to provide updated information regarding the use of dasatinib for first line treatment in adults with chronic phase CML as further justification to study the same patient population in children and adolescents (cohort #3). The changes include the following: - Expand Rationale in Section 1.3.1 - Revised estimated number of sites - Separated diagnosis criteria for cohort #3 for clarity - Clarified diagnosis criteria for cohort #2 - Revised resistance criteria to cap previous imatinib dose at 400 mg/day for subjects with high BSAs - Corrected multiple typographical errors - Clarified footnotes in flow chart

12 Jun 2012

The primary purpose of this amendment is to clarify the objective of estimating the complete cytogenetic response (CCyR) rate to dasatinib therapy in children and adolescents with newly diagnosed CP-CML who are treatment-naive. Additional changes to the protocol include: - Modify Definition of Complete and Major Molecular Response - Define disease free survival for each cohort - Addition of exploratory objective and endpoints for growth and development and bone mineral content - Primary and Secondary Endpoint Clarification - Clarification of Efficacy Analyses - Administrative Changes

13 Dec 2012

The purpose of this amendment is to expand cohort 3 to include a sub-cohort of 30 pediatric subjects < 18 years of age with treatment naive chronic phase CML who will receive dasatinib powder for oral suspension (PFOS). This increase in subject number will change our current plan to treat at least 50 newly diagnosed CP- CML pediatric subjects to 80 subjects in cohort 3. Subjects will be required to take the PFOS for a minimum of 12 months, during which data will be collected. We will assess the PK of dasatinib following oral administration of the PFOS in this sub-cohort. Hematologic, cytogenetic, and molecular responses by 12 months will be reported for the sub-cohort taking standard tablets, the sub-cohort using PFOS, and in Cohort 3 as a whole. Similarly, safety analysis will also be reported for both sub-cohorts (taking the standard tablets and PFOS) and in the cohort as a whole. We will also assess the taste properties of the PFOS formulation. This data collected and analyzed on this expanded cohort will be used support registration of the dasatinib PFOS in pediatric subjects. The dose of dasatinib when administered in PFOS formulation will be increased by 20% from the tablet dose, i.e, a dose of 72mg/m2 in this expanded cohort. The purpose of such dose adjustment is to match the exposure of the PFOS formulation to the reference tablet in order to maintain a desired efficacy. It was based on the findings from a bioequivalent study, which showed that AUC(INF) of the PFOS formulation was 19.2% lower compared to the reference tablet.

18 Jul 2013

The purpose of this amendment is to permanently close Cohort 2 to further enrollment and update the WOCBP guidelines.

24 Oct 2013

The purpose of this amendment is to correct the criteria for women of child bearing potential (WOCBP) and remove information on post menopausal women.

13 Apr 2016

This amendment: 1) adds testing for Hepatitis B virus (HBV) and 2) updates recommendations for methods of contraception and reemphasizes the need for contraception.

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 II Study of Dasatinib Therapy in Children and Adolescents with Ph+ Leukemia with Resistance or Intolerance to Imatinib.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Major Cytogenetic Response (MCyR) Rate

Primary: Major Cytogenetic Response (MCyR) Rate

Primary: Complete Hematologic Response (CHR) Rate

Primary: Complete Hematologic Response (CHR) Rate

Primary: Complete Cytogenetic Response (CCyR) Rate

Primary: Complete Cytogenetic Response (CCyR) Rate

Secondary: Major Cytogenetic Response (MCyR) Rate in Cohort 2

Secondary: Major Cytogenetic Response (MCyR) Rate in Cohort 2

Secondary: Complete Hematologic Response (CHR) Rate in Cohorts 1 and 3

Secondary: Complete Hematologic Response (CHR) Rate in Cohorts 1 and 3

Secondary: Rate of Best Cytogenetic Response

Secondary: Rate of Best Cytogenetic Response

Secondary: Time to Major Cytogenetic Response (MCyR)

Secondary: Time to Major Cytogenetic Response (MCyR)

Secondary: Duration of Major Cytogenetic Response (MCyR)

Secondary: Duration of Major Cytogenetic Response (MCyR)

Secondary: Time to Complete Cytogenetic Response (CCyR)

Secondary: Time to Complete Cytogenetic Response (CCyR)

Secondary: Duration of Complete Cytogenetic Response (CCyR)

Secondary: Duration of Complete Cytogenetic Response (CCyR)

Secondary: Progression-Free Survival (PFS) Rate at 2 years

Secondary: Progression-Free Survival (PFS) Rate at 2 years

Secondary: Time to Complete Hematologic Response (CHR)

Secondary: Time to Complete Hematologic Response (CHR)

Secondary: Duration of Complete Hemotologic Response (CHR)

Secondary: Duration of Complete Hemotologic Response (CHR)

Secondary: Disease-Free Survival Rate at 2 years

Secondary: Disease-Free Survival Rate at 2 years

Secondary: Overall Survival (OS) Rate at 2 years

Secondary: Overall Survival (OS) Rate at 2 years

Secondary: Major Molecular Response (MMR) Rate

Secondary: Major Molecular Response (MMR) Rate

Secondary: Complete Molecular Response (CMR) Rate

Secondary: Complete Molecular Response (CMR) Rate

Secondary: Major Cytogenetic Response (MCyR) Rate up to 2 years

Secondary: Major Cytogenetic Response (MCyR) Rate up to 2 years

Secondary: Complete Cytogenetic Response (CCyR) Rate up to 2 years

Secondary: Complete Cytogenetic Response (CCyR) Rate up to 2 years

Secondary: Major Molecular Response (MMR) Rate up to 2 years

Secondary: Major Molecular Response (MMR) Rate up to 2 years

Secondary: Complete Molecular Response (CMR) Rate up to 2 years

Secondary: Complete Molecular Response (CMR) Rate up to 2 years

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase II Study of Dasatinib Therapy in Children and Adolescents with Ph+ Leukemia with Resistance or Intolerance to Imatinib.