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Clinical Trial Results:
Phase 1 Study of SRC, ABL Tyrosine Kinase Inhibitor Dasatinib (BMS-354825) in Children and Adolescents with Relapsed or Refractory Leukemia

Summary
EudraCT number	2005-002882-35
Trial protocol	DE AT GB IT BE
Global end of trial date	22 May 2019

Results information
Results version number	v1(current)
This version publication date	21 Nov 2020
First version publication date	21 Nov 2020
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

CA180-018

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, 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

Final

Date of interim/final analysis

02 Dec 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 May 2011

Global end of trial reached?

Yes

Global end of trial date

22 May 2019

Was the trial ended prematurely?

Main objective of the trial

To establish, by stratum using a dose-finding design, a recommended Phase 2 dose of dasatinib (BMS-354825) in children and adolescents with relapsed or refractory leukemia.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Jan 2006

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

France: 15

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Netherlands: 13

Country: Number of subjects enrolled

United Kingdom: 11

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Stratum 1 - 18 were enrolled; 1 no longer met study criteria and was never treated Stratum 2/3 - 20 were enrolled;3 never treated(2 no longer met study criteria;1 withdrew consent) Stratum 4 - 25 were enrolled; 1 no longer met study criteria and was never treated

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose

Arm description

Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). Starting Dose Level of 60 mg/m^2; Escalated/Dose Level 2 of 80 mg/m^2. Once daily (QD), as long as clinical benefit was maintained.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

BMS-354825-03

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

5mg, 20mg and 50mg tablets

Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose

Arm description

Participants with imatinib-resistant or imatinib-intolerant Ph+ CML in accelerated phase (AP), or in myeloid blast phase (MBP), or in lymphoid blast phase (LBP); or relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL) after imatinib use; or second or subsequent relapse of Ph+ acute myeloid leukemia (AML). Starting Dose Level of 60 mg/m^2; Escalated/Dose level 2 of 80 mg/m^2. QD, as long as clinical benefit was maintained.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

BMS-354825-03

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

5mg, 20mg and 50mg tablets

Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose

Arm description

Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Starting Dose Level of 60 mg/m^2; Escalated/Dose level 2 of 80 mg/m^2, Escalated/Dose level 3 of 100 mg/m^2, and Escalated/Dose level 4 of 120 mg/m^2. QD, as long as clinical benefit was maintained.

Arm type

Experimental

Investigational medicinal product name

Dasatinib

Investigational medicinal product code

Other name

BMS-354825-03

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

5mg, 20mg and 50mg tablets

Number of subjects in period 1	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose
Started	17	17	24
Completed	17	17	24

Baseline characteristics

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Reporting group title

Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose

Reporting group description

Reporting group title

Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose

Reporting group description

Reporting group title

Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose

Reporting group description

Reporting group values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose	Total
Number of subjects	17	17	24	58
Age Categorical
Units: Participants
< 2 years	0	0	2	2
Between 2 and 6 years	2	5	7	14
Between 7 and 11 years	6	5	7	18
Between 12 and 18 years	9	7	7	23
> 18 years	0	0	1	1
Age Continuous
Units: years
arithmetic mean (standard deviation)	12.4 ( 4.1 )	9.7 ( 4.3 )	8.6 ( 5.6 )	-
Sex: Female, Male
Units:
Female	6	5	8	19
Male	11	12	16	39
Race/Ethnicity, Customized
Race only
Units: Subjects
White	16	15	21	52
Black/African American	0	0	1	1
Asian	1	1	1	3
Other	0	1	1	2
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	0
Not Hispanic or Latino	0	1	0	1
Unknown or Not Reported	17	16	24	57

Subject analysis set title

Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 80 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant or imatinib-intolerant Ph+ CML in accelerated phase (AP), or in myeloid blast phase (MBP), or in lymphoid blast phase (LBP); or relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL) after imatinib use; or second or subsequent relapse of Ph+ acute myeloid leukemia (AML). Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant or imatinib-intolerant Ph+ CML in accelerated phase (AP), or in myeloid blast phase (MBP), or in lymphoid blast phase (LBP); or relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL) after imatinib use; or second or subsequent relapse of Ph+ acute myeloid leukemia (AML). Dasatinib 80 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Dasatinib 80 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 80 mg/m^2, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Ph+ chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 80 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum1 Ph+ CP-CML (Dasatinib 60 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2 QD Starting Dose

Subject analysis set type

Full analysis

Subject analysis set description

Stratum 1 (Ph+ CP-CML): Participants with imatinib-resistant Ph+ CML in CP; Stratum 2/3 (PH+ ALL OR AP/BP-CML): Participants with imatinib-resistant or imatinib-intolerant Ph+ CML in AP, or in MBP, or in LBP; or relapsed or refractory Ph+ ALL after imatinib use; or second or subsequent relapse of Ph+ AML; Stratum 4 (PH- ALL/AML): Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Strata 1, 2/3, and 4: 60 mg/m^2 starting dose; 80 mg/m^2 escalated/dose level 2; Stratum 4: 100 mg/m^2 escalated/dose level 3 and 120 mg/m^2 escalated/dose level 4. QD, as long as clinical benefit was observed.

Subject analysis set title

Dasatinib 60 mg/m^2 QD Starting Dose

Subject analysis set type

Full analysis

Subject analysis set description

Stratum 1 (Ph+ CP-CML): Participants with imatinib-resistant Ph+ CML in CP; Stratum 2/3 (PH+ ALL OR AP/BP-CML): Participants with imatinib-resistant or imatinib-intolerant Ph+ CML in AP, or in MBP, or in LBP; or relapsed or refractory Ph+ ALL after imatinib use; or second or subsequent relapse of Ph+ AML; Stratum 4 (PH- ALL/AML): Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Strata 1, 2/3, and 4: 60 mg/m^2 starting dose; 80 mg/m^2 escalated/dose level 2; Stratum 4: 100 mg/m^2 escalated/dose level 3 and 120 mg/m^2 escalated/dose level 4. QD, as long as clinical benefit was observed.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 80 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 80 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 120 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 120 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 80 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 120 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 80 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 80 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 120 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis sets values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Dasatinib 60 mg/m^2 QD Starting Dose	Dasatinib 60 mg/m^2 QD Starting Dose	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2	Dasatinib 60 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2
Number of subjects	11	6	8	9	6	6	6	6	6	6	11	53	53	20	25	19	10	19	18	9	18	20	15	8	16	13	21	14	4	10	6	1
Age Categorical
Units: Participants
< 2 years
Between 2 and 6 years
Between 7 and 11 years
Between 12 and 18 years
> 18 years
Age Continuous
Units: years
arithmetic mean (standard deviation)	( )	( )	( )	( )	( )	( )	( )	( )	( )	6 ( )	90.9 ( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )
Sex: Female, Male
Units:
Female
Male
Race/Ethnicity, Customized
Race only
Units: Subjects
White
Black/African American
Asian
Other
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino
Not Hispanic or Latino
Unknown or Not Reported

End points

Top of page

Reporting group title

Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose

Reporting group description

Reporting group title

Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose

Reporting group description

Reporting group title

Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose

Reporting group description

Subject analysis set title

Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 80 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant or imatinib-intolerant Ph+ CML in accelerated phase (AP), or in myeloid blast phase (MBP), or in lymphoid blast phase (LBP); or relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL) after imatinib use; or second or subsequent relapse of Ph+ acute myeloid leukemia (AML). Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant or imatinib-intolerant Ph+ CML in accelerated phase (AP), or in myeloid blast phase (MBP), or in lymphoid blast phase (LBP); or relapsed or refractory Ph+ acute lymphoblastic leukemia (ALL) after imatinib use; or second or subsequent relapse of Ph+ acute myeloid leukemia (AML). Dasatinib 80 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Dasatinib 80 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 80 mg/m^2, as long as clinical benefit was maintained.

Subject analysis set title

Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Ph+ chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 80 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Stratum1 Ph+ CP-CML (Dasatinib 60 mg/m^2)

Subject analysis set type

Full analysis

Subject analysis set description

Participants with imatinib-resistant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2 QD Starting Dose

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Dasatinib 60 mg/m^2 QD Starting Dose

Subject analysis set type

Full analysis

Subject analysis set description

Stratum 1 (Ph+ CP-CML): Participants with imatinib-resistant Ph+ CML in CP; Stratum 2/3 (PH+ ALL OR AP/BP-CML): Participants with imatinib-resistant or imatinib-intolerant Ph+ CML in AP, or in MBP, or in LBP; or relapsed or refractory Ph+ ALL after imatinib use; or second or subsequent relapse of Ph+ AML; Stratum 4 (PH- ALL/AML): Participants with second or subsequent relapse of Ph- ALL or Ph- AML. Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Strata 1, 2/3, and 4: 60 mg/m^2 starting dose; 80 mg/m^2 escalated/dose level 2; Stratum 4: 100 mg/m^2 escalated/dose level 3 and 120 mg/m^2 escalated/dose level 4. QD, as long as clinical benefit was observed.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 80 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 120 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 120 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 80 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 120 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 80 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 60 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Dasatinib 60 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 80 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Dasatinib 100 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 100 mg/m^2 QD, as long as clinical benefit was maintained.

Subject analysis set title

Dasatinib 120 mg/m^2

Subject analysis set type

Full analysis

Subject analysis set description

Tablets, Oral; If necessary in participants who could not swallow, tablets were dispersed into 30 cc of 100% fruit juice with no preservatives (minute maid lemonade or orange juice or apple juice). Dasatinib 120 mg/m^2 QD, as long as clinical benefit was maintained.

Primary: Recommended Phase II Dose of Dasatinib in Children and Adolescents with Relapsed or Refractory Leukemia

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End point title

Recommended Phase II Dose of Dasatinib in Children and Adolescents with Relapsed or Refractory Leukemia ^[1]

End point description

The recommended phase 2 dasatinib dose was determined based on efficacy, safety, and pharmacokinetic data obtained at the prespecified dose levels. Note: 9999 = NA (not available)

End point type

Primary

End point timeframe

From the date of first dose to end-of-treatment (EOT) (Median duration of therapy in months: Stratum 1=24.11 [Range:2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38])

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

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose
Number of subjects analysed	17	17	24
Units: mg/m^2 QD	60	80	9999

No statistical analyses for this end point

Secondary: Number of Participants with Related Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

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End point title

Number of Participants with Related Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

End point description

AE: New untoward medical occurrence or worsening of a preexisting medical condition that does not have causal relationship with this treatment. SAE: Untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, drug dependency/abuse; life-threatening, an important medical event, a congenital anomaly/birth defect; requires inpatient hospitalization/prolongs existing hospitalization. Grade 3 = Severe; Grade 4 = Life-threatening or disabling.

End point type

Secondary

End point timeframe

From the date of first dose until at least 30 days after the last dose of study drug (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38])

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)
Number of subjects analysed	11	6	8	9	6	6	6	6
Units: participants
Drug-Related Deaths	0	0	0	0	0	0	0	0
Drug-Related SAEs	1	1	2	3	2	2	2	2
Drug-Related AEs Leading to Discontinuation	0	0	0	0	1	0	1	0
Grade 3/4 AEs	5	3	4	3	3	4	3	2

No statistical analyses for this end point

Secondary: Number of Participants with Dose-limiting Toxicity (DLT)

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End point title

Number of Participants with Dose-limiting Toxicity (DLT)

End point description

DLTs: AEs which were at least possibly drug-related occurring within first 3 weeks of dasatinib therapy (toxicities occurring after 21 days were also considered) and are:- --Any nonhematologic clinically-apparent toxicity of Grade(GR)≥3 occurring despite appropriate medical management and GR4 laboratory abnormality/GR3 lasting ≥7 days --GR4 neutropenia or thrombocytopenia lasting ≥7 days and not explained by the presence of leukemia after hematopoietic reconstitution --Any clinically important toxicity of GR≥2 requiring treatment discontinuation or interruption ≥7 days.

End point type

Secondary

End point timeframe

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)
Number of subjects analysed	11	6	8	9	6	6	6	6
Units: participants	0	0	0	0	1	0	0	1

No statistical analyses for this end point

Secondary: Number of Participants with Hematology Abnormalities by NCI CTCAE Version 3.0

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End point title

Number of Participants with Hematology Abnormalities by NCI CTCAE Version 3.0

End point description

GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. WBC: GR1=<LLN-3.0*10^9/L; GR2=<3.0-2.0*10^9/L; GR3=<2.0-1.0*10^9/L; GR4=<1.0*10^9/L. ANC: GR1=<LLN-1.5*10^9 /L; GR2=<1.5-1.0*10^9/L; GR3=<1.0-0.5*10^9/L; GR4=<0.5*10^9/L. Hemoglobin: GR1=<LLN-10.0g/dL; GR2=<10.0-8.0g/dL; GR3=<8.0-6.5g/dL; GR4=<6.5g/dL. Platelets: GR1=<LLN-75.0*10^9/L; GR2=<75.0-50.0*10^9/L; GR3=<50.0-25.0*10^9/L; GR4=<25.0*10^9/L.

End point type

Secondary

End point timeframe

Days 8, 15, 22, 29, 36, 43, then every 3 weeks, then every 3 months after 1 Year, EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38])

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)
Number of subjects analysed	11	6	8	9	6	6	6	6
Units: participants
WBC GR1	6	4	2	1	1	1	0	0
WBC GR2	0	1	3	3	0	1	1	1
WBC GR3	0	0	0	1	0	2	1	0
WBC GR4	0	0	1	3	2	2	3	1
ANC GR1	3	3	1	1	0	0	0	0
ANC GR2	4	0	2	2	1	0	0	0
ANC GR3	1	2	2	0	0	2	0	2
ANC GR4	0	1	3	4	4	4	6	3
Platelet GR1	4	4	0	2	0	0	0	0
Platelet GR2	0	1	0	2	1	0	0	0
Platelet GR3	2	0	4	1	0	1	1	1
Platelet GR4	0	0	4	3	4	5	5	5
Hemoglobin GR1	3	4	1	0	0	0	0	0
Hemoglobin GR2	4	1	5	3	2	3	3	3
Hemoglobin GR3	0	0	1	4	3	1	3	2
Hemoglobin GR4	0	0	1	0	0	2	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Serum Chemistry Abnormalities (calcium, magnesium, and phosphate) by NCI CTCAE Version 3.0

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End point title

Number of Participants with Serum Chemistry Abnormalities (calcium, magnesium, and phosphate) by NCI CTCAE Version 3.0

End point description

GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. Low calcium: GR1=<LLN–8.0 mg/dL, GR2=<8.0–7.0 mg/dL, GR3=<7.0–6.0 mg/dL, GR4=<6.0 mg/dL; Low magnesium: GR1=<LLN–1.2 mg/dL, GR2=<1.2–0.9 mg/dL, GR3=<0.9–0.7 mg/dL, GR4=<0.7 mg/dL; Low phosphate: GR1=<LLN – 2.5 mg/dL, GR2=<2.5 – 2.0 mg/dL, GR3=<2.0 – 1.0 mg/dL, GR4=<1.0 mg/dL.

End point type

Secondary

End point timeframe

Days 22 and 43, then every 12 weeks, then every 24 weeks after 24 months of treatment, EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38])

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)
Number of subjects analysed	11	6	8	9	6	6	6	6
Units: participants
Low Calcium GR1	3	0	2	2	2	0	1	0
Low Calcium GR2	0	0	1	1	0	2	2	1
Low Calcium GR3	0	0	0	0	0	0	1	0
Low Calcium GR4	0	0	0	0	0	0	0	0
Low magnesium GR1	1	1	5	0	1	0	4	1
Low Magnesium GR2	0	0	0	0	0	0	0	0
Low Magnesium GR3	0	0	0	0	0	0	0	0
Low Magnesium GR4	0	0	0	0	0	0	0	0
Low Phosphate GR1	2	1	2	2	0	2	2	1
Low Phosphate GR2	1	0	0	1	0	2	1	1
Low Phosphate GR3	0	0	0	0	1	0	1	1
Low Phosphate GR4	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Serum Chemistry Abnormalities (Liver and Renal Function) by NCI CTCAE Version 3.0

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End point title

Number of Participants with Serum Chemistry Abnormalities (Liver and Renal Function) by NCI CTCAE Version 3.0

End point description

GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. AST and ALT: GR1=>ULN-2.5*ULN; GR2=>2.5-5.0*ULN; GR3=>5.0-20.0*ULN; GR4:>20.0*ULN. Total bilirubin:GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3-10*ULN, GR4=>10*ULN. Creatinine: GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3.0-6.0*ULN, GR4=>6.0*ULN.

End point type

Secondary

End point timeframe

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)
Number of subjects analysed	11	6	8	9	6	6	6	6
Units: participants
AST GR1	1	3	5	3	1	4	2	2
AST GR2	0	0	2	1	1	1	1	1
AST GR3	0	0	1	2	1	1	0	0
AST GR4	0	0	0	0	0	0	0	0
High ALT GR1	4	4	4	2	0	2	3	2
High ALT GR2	0	0	2	1	1	2	1	0
High ALT GR3	0	0	1	0	1	2	0	1
High ALT GR4	0	0	0	2	0	0	0	0
Total Bilirubin GR1	2	0	1	1	0	1	2	0
Total Bilirubin GR2	0	1	0	0	1	2	1	1
Total Bilirubin GR3	1	0	0	0	0	0	0	0
Total Bilirubin GR4	0	0	0	0	0	0	0	0
High Serum Creatinine GR1	1	1	1	1	1	0	0	0
High Serum Creatinine GR2	0	0	1	0	0	0	1	0
High Serum Creatinine GR3	0	0	0	0	0	0	0	0
High Serum Creatinine GR4	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Major Cytogenetic Response (MCyR) at Any Time in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

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End point title

Number of Participants with Major Cytogenetic Response (MCyR) at Any Time in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

End point description

Cytogenetic responses were based on the karyotype analysis of the percentage of Ph+ metaphases among cells in metaphase on a BM sample. At least 20 metaphase cells from a BM sample were evaluated. MCyR: A cytogenetic response that is either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM.

End point type

Secondary

End point timeframe

Strata 1 and 2/3: At Week 7, 13, then every 12 weeks, and EOT; Stratum 2/3: Additionally at Week 4, 19, 31 (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72])

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	11	6	8	9
Units: participants	9	6	4	7

No statistical analyses for this end point

Secondary: Number of Participants with Major Cytogenetic Response (MCyR) in Stratum 1 (Ph+ CP-CML) Within First 12 and 24 Weeks

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End point title

Number of Participants with Major Cytogenetic Response (MCyR) in Stratum 1 (Ph+ CP-CML) Within First 12 and 24 Weeks

End point description

Cytogenetic responses were based on the karyotype analysis of the percentage of Ph+ metaphases among cells in metaphase on a BM sample. At least 20 metaphase cells from a BM sample were evaluated. MCyR: A cytogenetic response that was either CCyR or PCyR. CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM.

End point type

Secondary

End point timeframe

After completion of Week 12 and 24 (measured at Weeks 13 and 25)

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	11	6
Units: participants
MCyR within first 12 weeks	6	2
MCyR within first 24 weeks	9	5

No statistical analyses for this end point

Secondary: Best Cytogenetic Response (CyR) in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

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End point title

Best Cytogenetic Response (CyR) in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

End point description

Best CyR was assessed based on the percentages of Ph+ metaphases of ≥20 analyzed metaphases in BM sample. Participants with complete, partial, minor, minimal, or no CyR. Refer to Outcome Measure 7 for definitions of CCyR and PCyR. Minor CyR:>35%-65% Ph+ cells in metaphase in BM. Minimal CyR:>65%-95% Ph+ cells in metaphase in BM. No CyR:>95%-100% Ph+ cells in metaphase in BM. Unable to determine:Participants without valid cytogenetic assessment (i.e., at least 1 metaphase observed and number of Ph+ metaphases smaller than total number of metaphases [%Ph+ <100%]).

End point type

Secondary

End point timeframe

Strata 1 and 2/3: At Weeks 7, 13, then every 12 weeks, and EOT; Stratum 2/3: Additionally at Weeks 4, 19, 25, 31 (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72])

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	11	6	8	9
Units: participants
No Response (>95% - 100%)	1	0	0	1
Minimal (>65% - 95%)	0	0	0	0
Minor (>35% - 65%)	1	0	0	0
Partial (>0% - 35%)	1	0	0	0
Complete (0%)	8	6	4	8
Unable to determine	0	0	4	0

No statistical analyses for this end point

Secondary: Percentage of Participants with Complete Cytogenetic Response (CCyR) or Major Cytogenetic Response (MCyR) at Recommended Phase II Dose

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End point title

Percentage of Participants with Complete Cytogenetic Response (CCyR) or Major Cytogenetic Response (MCyR) at Recommended Phase II Dose

End point description

Cytogenetic responses were based on the karyotype analysis of the percentage of Ph+ metaphases among cells in metaphase on a BM sample. At least 20 metaphase cells from a BM sample were evaluated. MCyR: A cytogenetic response that was either CCyR or PCyR. CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM.

End point type

Secondary

End point timeframe

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	11	9
Units: percentage of participants
number (confidence interval 95%)
CCyR	72.7 (39.0 to 94.0)	88.9 (51.8 to 99.7)
MCyR	81.8 (48.2 to 97.7)	88.9 (51.8 to 99.7)

No statistical analyses for this end point

Secondary: Time to Major Cytogenetic Response (MCyR) in Responders: Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

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End point title

Time to Major Cytogenetic Response (MCyR) in Responders: Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML) ^[2]

End point description

Defined as time (in days) from the first dose of dasatinib until criteria were first met for MCyR. MCyR: A CyR that was either CCyR or PCyR. CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM. The Kaplan-Meier plot was used. A 2-sided, 95% confidence interval (CI) for the median was computed using the Brookmeyer and Crowley method.

End point type

Secondary

End point timeframe

Strata 1 and 2/3: At Weeks 7, 13, 25, 37, then every 12 weeks; Stratum 2/3: Additionally at Weeks 4, 19, 31; until first MCyR (maximum participant time to first MCyR of 92 days).

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose
Number of subjects analysed	15	12
Units: days
median (confidence interval 95%)	75.0 (43.0 to 92.0)	33.5 (22.0 to 43.0)

No statistical analyses for this end point

Secondary: Duration of Major Cytogenetic Response (MCyR) in Responders (Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML])

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End point title

Duration of Major Cytogenetic Response (MCyR) in Responders (Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML]) ^[3]

End point description

Defined as the time (in months) from the first day that all criteria were met for MCyR until the date of progression (based on the Investigator’s assessment) or death (for participants whose best responses were MCyR and CCyR respectively). MCyR: A cytogenetic response that was either CCyR or PCyR. CCyR: 0% Ph+ cells in metaphase in BM. PCyR: >0% to 35% Ph+ cells in metaphase in BM. The Kaplan-Meier plot was used. A 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method.

End point type

Secondary

End point timeframe

From the date of first MCyR assessment to date of progression, death, or last tumor assessment (maximum participant duration of response of 48.6 months)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose
Number of subjects analysed	15	12
Units: months
median (confidence interval 95%)	52.2 (10.0 to 56.1)	4.6 (1.2 to 17.4)

No statistical analyses for this end point

Secondary: Duration of Complete Cytogenetic Response (CCyR) in Responders: Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML]

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End point title

Duration of Complete Cytogenetic Response (CCyR) in Responders: Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML] ^[4]

End point description

Defined as time (in months) from the first day that all criteria were met for CCyR until the date of progression (based on the Investigator’s assessment) or death (for participants whose best response was CCyR). CCyR = 0% Ph+ metaphases of ≥ 20 analyzed metaphases in BM aspiration. The Kaplan-Meier plot was used. A 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method.

End point type

Secondary

End point timeframe

From the date of first CCyR assessment to date of progression, death, or last tumor assessment (maximum participant duration of response of 45.1 months)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose
Number of subjects analysed	14	12
Units: months
median (confidence interval 95%)	48.1 (10.0 to 56.1)	4.6 (1.2 to 17.4)

No statistical analyses for this end point

Secondary: Number of Participants with Major Hematologic Response (MaHR) at Any Time in Stratum 2/3 (Ph+ ALL or AP/BP-CML) and Stratum 4 (Ph- ALL/AML)

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End point title

Number of Participants with Major Hematologic Response (MaHR) at Any Time in Stratum 2/3 (Ph+ ALL or AP/BP-CML) and Stratum 4 (Ph- ALL/AML)

End point description

Defined as participants having as best response complete hematologic response (CHR) or CHR with incomplete platelet recovery (CHRp). Criteria: CHR-WBC in Peripheral Blood (PB):≤ULN; Immature cells in PB:No blasts, promyelocytes, myelocytes, metamyelocytes; Platelet count (untransfused):≥100,000/mm^3 and ≤450,000/mm^3; ANC:≥ 1000/mm^3; Blasts in BM:<5%; Extra medullary disease:No extramedullary leukemia, including no hepato or splenomegaly (regardless of CNS involvement). CHRp-CHR except platelet count (untransfused) & ANC:20,000/mm^3 ≤platelet <100,000/mm^3 & /or 500/mm^3 ≤ANC ≤1000/mm^3.

End point type

Secondary

End point timeframe

Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 13, 19, 25, 31, 37; at Week 10 (only stratum 4); then every 12 weeks upto 24 months; then once/year; EOT(Median duration of therapy in months: Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38])

End point values	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)
Number of subjects analysed	8	9	6	6	6	6
Units: participants	2	6	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Major Hematologic Response (MaHR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML) Within First 6 and 24 Weeks

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End point title

Number of Participants with Major Hematologic Response (MaHR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML) Within First 6 and 24 Weeks

End point description

Defined as participants having as best response a CHR or CHRp. Criteria: CHR-WBC in PB:≤ULN; Immature cells in PB:No blasts, promyelocytes, myelocytes, metamyelocytes; Platelet count (untransfused):≥100,000/mm^3 and ≤450,000/mm^3; ANC:≥ 1000/mm^3; Blasts in BM:<5%; Extra medullary disease:No extramedullary leukemia, including no hepato or splenomegaly (regardless of CNS involvement). CHRp-CHR except platelet count (untransfused) and ANC:20,000/mm^3 ≤platelet <100,000/mm^3 and /or 500/mm^3 ≤ANC ≤1000/mm^3.

End point type

Secondary

End point timeframe

After completion of Week 6 and 24 (measured at weeks 7 and 25)

End point values	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	8	9
Units: participants
MaHR within first 6 weeks	2	5
MaHR within first 24 weeks	2	6

No statistical analyses for this end point

Secondary: Best Hematologic Response (HR) At Any Time: Stratum 1 (Ph+ CP-CML)

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End point title

Best Hematologic Response (HR) At Any Time: Stratum 1 (Ph+ CP-CML)

End point description

HR: Determined by complete blood count (CBC), differential, and platelet count (PLT). Criteria for complete hematologic response (CHR): WBC in PB: <10,000/mm^3; Immature cells in PB: No blasts or promyelocytes (myelocytes + metamyelocytes) <5%; Basophils in PB: <5%; Platelet count (untransfused): <450,000/mm^3; Extra medullary disease: No extramedullary leukemia, including no splenomegaly. Unconfirmed HR = All criteria met. Confirmed HR = Criteria for HR fulfilled again at least 28 days after they first met with no concomitant use of anagrelide or hydroxyurea during this interval.

End point type

Secondary

End point timeframe

Days 8, 15, 22, 29, 36, 43; Weeks 7, 13, 25, 37; then every 12 weeks upto 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63])

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	11	6
Units: participants
Best Confirmed HR-Complete	10	6
Best Confirmed HR-No Response	1	0
Best Unconfirmed Hematologic Response-Complete	10	6
Best Unconfirmed Hematologic Response-No Response	1	0

No statistical analyses for this end point

Secondary: Best Hematologic Response (HR) At Any Time: Stratum 2/3 (Ph+ ALL or AP/BP-CML)

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End point title

Best Hematologic Response (HR) At Any Time: Stratum 2/3 (Ph+ ALL or AP/BP-CML)

End point description

HR was determined by CBC, differential, and platelet count. Refer to outcome measure 15 for criteria for CHR and CHRp. Criteria for minor hematologic response (MiHR): CHRp except blasts in BM-≥5% and ≤15% blasts in BM. Unconfirmed HR = All criteria met. periph=peripheral. Confirmed HR = Criteria for HR fulfilled again at least 28 days after they first met with no concomitant use of anagrelide or hydroxyurea during this interval.

End point type

Secondary

End point timeframe

Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 13, 19, 25, 31, 37; then every 12 weeks up to 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 2/3=3.02 [Range: 0.53-37.72])

End point values	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	8	9
Units: participants
Best Confirmed HR-Complete	1	5
Best Confirmed HR-Complete except periph. recovery	1	1
Best Confirmed HR-No Response	6	3
Best Unconfirmed HR-Complete	3	7
Best Unconfirmed HR-Minor	0	1
Best Unconfirmed HR-No Response	5	1

No statistical analyses for this end point

Secondary: Best Hematologic Response (HR) At Any Time: Stratum 4 (Ph- ALL/AML)

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End point title

Best Hematologic Response (HR) At Any Time: Stratum 4 (Ph- ALL/AML)

End point description

HR was determined by CBC, differential, and platelet count. Unable to determine = Participants without any valid hematologic assessments.

End point type

Secondary

End point timeframe

Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 10, 13, 19, 25, 31, 37; then every 12 weeks upto 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 4=1.14 [Range: 0.03-3.38])

End point values	Stratum 4 Ph- ALL/AML (Dasatinib 60 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 80 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 100 mg/m^2)	Stratum 4 Ph- ALL/AML (Dasatinib 120 mg/m^2)
Number of subjects analysed	6	6	6	6
Units: participants
Best Confirmed HR-No Response	5	6	6	6
Best Confirmed HR-Unable to Determine	1	0	0	0
Best Unconfirmed HR-No Response	5	6	6	6
Best Unconfirmed HR-Unable to Determine	1	0	0	0

No statistical analyses for this end point

Secondary: Time to Major Hematologic Response (MaHR): Stratum 2/3 (PH+ ALL or AP/BP-CML)

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End point title

Time to Major Hematologic Response (MaHR): Stratum 2/3 (PH+ ALL or AP/BP-CML) ^[5]

End point description

Defined as time (in days) from first dose of dasatinib until the first day MaHR criteria were met, provided they were confirmed later (after 28 days) with no concomitant use of anagrelide or hydroxyurea during this interval. MaHR: Defined as participants having as best response a CHR or CHRp. Refer to Outcome Measure 15 for criteria for CHR and CHRp. Estimated by the Kaplan-Meier method and a 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method.

End point type

Secondary

End point timeframe

Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 13, 19, 25, 31, 37; then every 12 weeks upto 24 months; then once/year; until confirmed MaHR (maximum participant time to first MaHR of 44 days).

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose
Number of subjects analysed	8
Units: days
median (confidence interval 95%)	36.0 (29.0 to 42.0)

No statistical analyses for this end point

Secondary: Time to Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)

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End point title

Time to Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML) ^[6]

End point description

Time to CHR is the time (in days) from first dose of dasatinib until the first day CHR criteria were met, provided they were confirmed later after 28 days with no concomitant use of anagrelide or hydroxyurea during this interval. Refer to Outcome Measure 16 for criteria to CHR in Stratum 1 and to Outcome Measure 15 for criteria for CHR in Stratum 2/3. Estimated by the Kaplan-Meier method and a 2-sided 95% CI for median was computed using the Brookmeyer and Crowley method.

End point type

Secondary

End point timeframe

Days 8, 15, 22, 29, 36, 43; Weeks 7, 13, 25, 37; at Week 4, 19, 31 (only stratum 2/3); then every 12 weeks upto 24 months; then once/year; until criteria was first met for CHR (maximum participant time to first CHR of 65 days).

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose
Number of subjects analysed	16	6
Units: days
median (confidence interval 95%)	21.5 (16.0 to 23.0)	39.5 (36.0 to 44.0)

No statistical analyses for this end point

Secondary: Duration of Major Hematologic Response (MaHR): Stratum 2/3 (Ph+ALL or AP/BP-CML)

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End point title

Duration of Major Hematologic Response (MaHR): Stratum 2/3 (Ph+ALL or AP/BP-CML) ^[7]

End point description

Duration of MaHR is the time (in months) from the first day criteria were met for MaHR, provided they were confirmed later at least after 28 days with no concomitant use of anagrelide or hydroxyurea during this interval, until death or progression was first observed. MaHR: Defined as participants having as best response a CHR or CHRp. Refer to outcome measure 20 for criteria for CHR or CHRp. The Kaplan-Meier plot was used. A 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method. Note: 9999 = NA (not available)

End point type

Secondary

End point timeframe

From the date of first confirmed MaHR to date of progression, death, or last tumor assessment (maximum participant duration of response of 37 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: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose
Number of subjects analysed	8
Units: months
median (confidence interval 95%)	4.4 (3.5 to 9999)

No statistical analyses for this end point

Secondary: Duration of Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)

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End point title

Duration of Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML) ^[8]

End point description

Duration of CHR is the time (in months) from the first day criteria were met for CHR, provided they were confirmed later (after 28 days) with no concomitant use of anagrelide or hydroxyurea during this interval until death or progression was first observed. Refer to Outcome Measure 20 for criteria for CHR (Stratum 1) and Outcome Measure 19 for CHR (Stratum 2/3). The Kaplan-Meier plot was used. A 2-sided, 95% CI for the median was computed using the Brookmeyer and Crowley method.

End point type

Secondary

End point timeframe

From the date of first confirmed CHR to date of progression, death, or last tumor assessment (maximum participant duration of response of 50 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: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose
Number of subjects analysed	16	6
Units: months
median (confidence interval 95%)	9999 (14.3 to 9999)	7.3 (3.5 to 9999)

No statistical analyses for this end point

Secondary: Percentage of Participants with Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 1 (Ph+ CP-CML)

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End point title

Percentage of Participants with Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 1 (Ph+ CP-CML)

End point description

A participant was said to have a confirmed HR if all the criteria for HR were fulfilled again at least 28 days after they first met with no concomitant use of anagrelide or hydroxyurea during this interval. HR observed in stratum 1 was CHR. Refer to Outcome Measure 20 for criteria for CHR. The Clopper and Pearson method was used to compute 95% exact CIs.

End point type

Secondary

End point timeframe

Days 8, 15, 22, 29, 36, 43; Weeks 7, 13, 25, 37; then every 12 weeks upto 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63])

End point values	Stratum1 Ph+ CP-CML (Dasatinib 60 mg/m^2)
Number of subjects analysed	11
Units: percentage of participants
number (confidence interval 95%)	90.9 (58.7 to 99.8)

No statistical analyses for this end point

Secondary: Percentage of Participants with Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 2/3 (Ph+ALL or AP/BP-CML)

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End point title

Percentage of Participants with Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 2/3 (Ph+ALL or AP/BP-CML)

End point description

A participant is said to have a confirmed HR if criteria for HR were fulfilled again at least 28 days after they first met with no concomitant use of anagrelide or hydroxyurea during this interval. Confirmed HR observed in stratum 2/3 was either CHR or MaHR or overall hematologic response (OHR). Refer to Outcome Measure 19 for criteria for CHR and MaHR. OHR is defined as MaHR or MiHR. MiHR=CHRp except blasts in BM (≥ 5% and ≤ 15% blasts in BM). The Clopper and Pearson method was used to compute 95% exact CIs.

End point type

Secondary

End point timeframe

Days 8, 15, 22, 29, 36, 43; Weeks 4, 7, 13, 19, 25, 31, 37; then every 12 weeks upto 24 months; then once/year; EOT (Median duration of therapy in months: Stratum 2/3=3.02 [Range: 0.53-37.72])

End point values	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	9
Units: percentage of participants
number (confidence interval 95%)
CHR	55.6 (21.2 to 86.3)
MaHR	66.7 (29.9 to 92.5)
OHR	66.7 (29.9 to 92.5)

No statistical analyses for this end point

Secondary: Number of Participants with Molecular Responses in Stratum 1 (Ph+ CP-CML)

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End point title

Number of Participants with Molecular Responses in Stratum 1 (Ph+ CP-CML)

End point description

Molecular response was calculated by measuring p210 variant of BCR-ABL transcripts in blood during treatment using quantitative polymerase chain reaction (qPCR) assay. Major molecular response (MMR): Ratio of the BCR-ABL to ABL <10^-3 or 0.1% on the international scale. Complete molecular response (CMR): Complete absence of BCR-ABL or the ratio is <10^-4.5 or 0.00316% on the international scale. Confirmed MMR or CMR = Criteria met again >6 weeks. BCR-ABL=the fused gene found in participants with this type of CML.

End point type

Secondary

End point timeframe

At baseline (within 3 weeks before initiation of study therapy), After hematologic response, EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63])

End point values	Stratum 1 Ph+ CP-CML (Dasatinib 60 mg/m^2)	Stratum 1 Ph+ CP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	11	6
Units: participants
MMR (Overall)	6	2
CMR (Unconfirmed)	3	1
CMR (Confirmed)	1	0

No statistical analyses for this end point

Secondary: Number of Participants with Major Molecular Response (MMR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML)

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End point title

Number of Participants with Major Molecular Response (MMR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML)

End point description

Molecular response was calculated by measuring BCR-ABL transcripts in blood during treatment using qPCR assay. MMR: Ratio of the BCR-ABL to ABL <10^-3 or a ≥3 log reduction from baseline in participants with p190 variant; ratio of the BCR-ABL to ABL <10^-3 on the international scale in participants with p210 variant. BCR-ABL=the fused gene found in participants with this type of CML.

End point type

Secondary

End point timeframe

At baseline (within 3 weeks before initiation of study therapy), After hematologic response, EOT (Median duration of therapy in months: Stratum 2/3=3.02 [Range: 0.53-37.72])

End point values	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 60 mg/m^2)	Stratum 2/3 Ph+ ALL or AP/BP-CML (Dasatinib 80 mg/m^2)
Number of subjects analysed	8	9
Units: participants	2	6

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS)

End point description

Time in months from 1st first dose until progression (resistance or refractory disease) or death was first documented by investigator. Progressive disease: Resistant disease for which investigator may electively stop treatment or refractory disease requiring cessation of study treatment. The PFS was estimated using the Kaplan-Meier product-limit method, and a two-sided 95% CI for the median PFS time was computed using the method of Brookmeyer and Crowley.

End point type

Secondary

End point timeframe

From the date of randomization to date of progression, death, last tumor assessment, or 5 years after EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38])

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose
Number of subjects analysed	17	17	24
Units: months
median (confidence interval 95%)	53.6 (11.4 to 9999)	4.9 (0.5 to 8.4)	1.4 (0.4 to 1.6)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Defined as time in months from start of study therapy to death. The OS was estimated using the Kaplan-Meier product-limit method, and a two-sided 95% CI for the median OS time was computed using the Brookmeyer and Crowley method.

End point type

Secondary

End point timeframe

From start of study therapy until death or 5 years after EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72]; Stratum 4=1.14 [Range: 0.03-3.38])

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose
Number of subjects analysed	17	17	24
Units: months
median (confidence interval 95%)	9999 (9999 to 9999)	8.6 (3.2 to 9999)	3.0 (1.7 to 4.4)

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) by Age Group

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End point title

Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) by Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 60 mg/m^2 QD Starting Dose
Number of subjects analysed	53
Units: hours
median (full range (min-max))
Infants and Toddlers (age<2 years old; n=2)	0.5 (0.5 to 0.5)
Children (age>=2 and <12 years old; n=43)	1.1 (0.5 to 4.1)
Adolescents (age>=12 and <18 years old; n=28)	1.0 (0.5 to 6.0)
Above 18 Years (n=1)	0.9 (0.9 to 0.9)
Total (n=74)	1.0 (0.5 to 6.0)

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Age Group

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End point title

Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. T 1/2 is the time required for the concentration of the drug to reach half of its original value in plasma.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 60 mg/m^2 QD Starting Dose
Number of subjects analysed	53
Units: hours
geometric mean (geometric coefficient of variation)
Infants and Toddlers (age<2 years old; n=2)	2.1 ( 24.0 )
Children (age>=2 and <12 years old; n=36)	3.0 ( 62.8 )
Adolescents (age>=12 and <18 years old; n=22)	3.8 ( 43.9 )
Above 18 years (n=1)	7.3 ( 9999 )
Total (n=61)	3.3 ( 55.7 )

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Observed Maximum Plasma Concentration (Cmax) by Age Group

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End point title

Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Observed Maximum Plasma Concentration (Cmax) by Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Dose Normalized Cmax is the maximum observed concentration of drug substance in plasma normalized for different dasatinib dose levels.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 60 mg/m^2 QD Starting Dose
Number of subjects analysed	53
Units: ng/mL/mg/m^2
geometric mean (geometric coefficient of variation)
Infants and Toddlers (age<2 years old; n=2)	1.0 ( 15.2 )
Children (age>=2 and <12 years old; n=43)	1.9 ( 79.9 )
Adolescents (age>=12 and <18 years old; n=28)	1.0 ( 69.7 )
Above 18 Years (n=1)	0.9 ( 9999 )
Total (n=74)	1.5 ( 86.9 )

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time 0 to the time of the last quantifiable concentration (AUC[0-T]) by Age Group

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End point title

Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time 0 to the time of the last quantifiable concentration (AUC[0-T]) by Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC[0-T] is the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration, normalized by dasatinib dose level.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 60 mg/m^2 QD Starting Dose
Number of subjects analysed	53
Units: ng.h/mL/mg/m^2
geometric mean (geometric coefficient of variation)
Infants and Toddlers (age<2 years old; n=2)	2.8 ( 4.6 )
Children (age>=2 and <12 years old; n=40)	6.1 ( 95.7 )
Adolescents (age>=12 and <18 years old; n=28)	3.8 ( 66.8 )
Above 18 Years (n=1)	2.2 ( 9999 )
Total (n=71)	4.9 ( 98.1 )

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) by Age Group

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End point title

Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) by Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time, normalized by dasatinib dose level.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 60 mg/m^2 QD Starting Dose
Number of subjects analysed	53
Units: ng.h/mL/mg/m^2
geometric mean (geometric coefficient of variation)
Infants and Toddlers (age<2 years old; n=2)	3.2 ( 17.7 )
Children (age>=2 and <12 years old; n=36)	6.7 ( 95.0 )
Adolescents (age>=12 and <18 years old; n=22)	4.2 ( 67.6 )
Above 18 Years (n=1)	2.4 ( 9999 )
Total (n=61)	5.4 ( 97.1 )

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group

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End point title

Dasatinib Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2
Number of subjects analysed	20	25	19	10
Units: ng/mL
geometric mean (geometric coefficient of variation)
Infants and Toddlers (age>2yr; n=0; n=0; n=1; n=1)	9999 ( 9999 )	9999 ( 9999 )	30.6 ( 9999 )	53.8 ( 9999 )
Children (age>=2 and <12yr; n=11; n=16; n=9; n=7)	110.6 ( 61.8 )	142.5 ( 80.2 )	111.2 ( 82.6 )	208.4 ( 78.5 )
Adolescents (age>=12; n=9; n=8; n=9; n=2)	92.6 ( 50.6 )	116.5 ( 73.0 )	235.1 ( 59.0 )	123.3 ( 68.3 )
Above 18 years (n=0; n=1; n=0; n=0)	9999 ( 9999 )	143.2 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
Total	102.1 ( 58.0 )	133.6 ( 77.6 )	148.1 ( 75.0 )	163.9 ( 87.6 )

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group

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End point title

Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2
Number of subjects analysed	20	25	19	10
Units: hour
median (full range (min-max))
Infants and Toddlers (age<2yr; n=0; n=0; n=1; n=1)	9999 (9999 to 9999)	9999 (9999 to 9999)	0.5 (0.5 to 0.5)	0.5 (0.5 to 0.5)
Children (age>=2 and <12yr; n=11; n=16; n=9; n=7)	1.1 (0.5 to 2.1)	1.5 (0.5 to 3.2)	1.1 (0.6 to 4.1)	1.0 (0.9 to 2.2)
Adolescents(age>=12 and <12yr; n=9; n=8; n=9; n=2)	1.0 (0.5 to 4.0)	1.1 (0.5 to 4.0)	1.0 (0.5 to 6.0)	1.6 (1.0 to 2.1)
Above 18 years (n=0; n=1; n=0; n=0)	9999 (9999 to 9999)	0.9 (0.9 to 0.9)	9999 (9999 to 9999)	9999 (9999 to 9999)
Total	1.0 (0.5 to 4.0)	1.1 (0.5 to 4.0)	1.0 (0.5 to 6.0)	1.0 (0.5 to 2.2)

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-T]) by Dose Level and Age Group

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End point title

Dasatinib Plasma Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-T]) by Dose Level and Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC(0-T) is the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 80 mg/m^2	Dasatinib 60 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2
Number of subjects analysed	25	19	18	9
Units: ng.h/mL
geometric mean (geometric coefficient of variation)
Infants and Toddlers (age<2yr; n=0; n=0; n=1; n=1)	9999 ( 9999 )	9999 ( 9999 )	100.8 ( 9999 )	134.9 ( 9999 )
Children (age>=2 and <12yr; n=10; n=16; n=8; n=6)	490.8 ( 96.7 )	295.0 ( 63.5 )	373.5 ( 82.0 )	676.7 ( 99.9 )
Adolescents(age>=12 and <18yr; n=9; n=8; n=9; n=2)	488.1 ( 35.0 )	320.8 ( 59.1 )	787.0 ( 76.2 )	526.1 ( 56.6 )
Above 18 years (n=0; n=1; n=0; n=0)	367.2 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
Total	484.3 ( 88.9 )	307.0 ( 60.2 )	504.1 ( 89.6 )	534.9 ( 103.9 )

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) by Dose Level and Age Group

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End point title

Dasatinib Plasma Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) by Dose Level and Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC(INF) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2
Number of subjects analysed	18	20	15	8
Units: ng.h/mL
geometric mean (geometric coefficient of variation)
Infants and Toddlers (age<2yr; n=0; n=0; n=1; n=1)	0 ( 0 )	0 ( 0 )	127.7 ( 9999 )	142.1 ( 9999 )
Children (age>=2 and <12yr; n=10; n=14; n=7; n=5)	313.9 ( 59.8 )	513.6 ( 99.2 )	429.1 ( 76.8 )	817.6 ( 93.7 )
Adolescents(age>=12 and <18yr; n=8; n=5; n=7; n=2)	305.8 ( 60.9 )	605.1 ( 25.3 )	1008.9 ( 69.4 )	547.8 ( 58.2 )
Above 18 years (n=0; n=1; n=0; n=0)	0 ( 0 )	390.0 ( 9999 )	0 ( 0 )	0 ( 0 )
Total	310.3 ( 58.6 )	527.8 ( 90.4 )	589.8 ( 86.2 )	594.4 ( 101.5 )

No statistical analyses for this end point

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Dose Level and Age Group

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End point title

Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Dose Level and Age Group

End point description

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2
Number of subjects analysed	18	20	15	8
Units: hour
arithmetic mean (standard deviation)
Infants and Toddlers (age<2yr; n=0; n=0; n=1; n=1)	9999 ( 9999 )	9999 ( 9999 )	2.5 ( 9999 )	1.8 ( 9999 )
Children (age>=2 and <12yr; n=10; n=14; n=7; n=5)	2.4 ( 1.0 )	3.9 ( 1.9 )	4.6 ( 3.5 )	3.2 ( 1.9 )
Adolescents(age>=12 and <18yr; n=8; n=5; n=7; n=2)	3.7 ( 1.6 )	5.1 ( 0.5 )	4.5 ( 2.5 )	3.5 ( 2.9 )
Above 18 years (n=0; n=1; n=0; n=0)	9999 ( 9999 )	7.3 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
Total	3.0 ( 1.4 )	4.4 ( 1.8 )	4.4 ( 2.9 )	3.1 ( 1.9 )

No statistical analyses for this end point

Secondary: Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group

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End point title

Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 80 mg/m^2	Dasatinib 120 mg/m^2	Dasatinib 60 mg/m^2	Dasatinib 100 mg/m^2
Number of subjects analysed	25	10	18	16
Units: ng/mL
geometric mean (geometric coefficient of variation)
Infants and Toddlers (age<2yr; n=0; n=0; n=0; n=1)	9999 ( 9999 )	1.2 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
Children (age>=2 and <12yr; n=10; n=16; n=7; n=7)	3.4 ( 82.0 )	4.8 ( 65.3 )	3.6 ( 46.4 )	6.0 ( 69.3 )
Adolescents(age>=12 and <18yr; n=8; n=8; n=9; n=2)	3.6 ( 56.7 )	4.3 ( 77.9 )	3.1 ( 40.3 )	6.9 ( 75.0 )
Above 18 years (n=0; n=1; n=0; n=0)	2.2 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
Total	3.4 ( 74.4 )	4.1 ( 70.8 )	3.4 ( 43.7 )	6.5 ( 72.0 )

No statistical analyses for this end point

Secondary: Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group

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End point title

Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group

End point description

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 80 mg/m^2	Dasatinib 120 mg/m^2	Dasatinib 60 mg/m^2	Dasatinib 100 mg/m^2
Number of subjects analysed	25	10	18	16
Units: hour
median (full range (min-max))
Infants and Toddlers (age<2yr; n=0; n=0; n=0; n=1)	9999 (9999 to 9999)	0.9 (0.9 to 0.9)	9999 (9999 to 9999)	9999 (9999 to 9999)
Children (age>=2 and <12yr; n=10; n=16; n=7; n=7)	2.0 (0.5 to 6.0)	2.0 (1.0 to 2.2)	2.0 (1.0 to 4.5)	2.1 (1.0 to 4.1)
Adolescents(age>=12 and <18yr; n=8; n=8; n=9; n=2)	2.0 (1.0 to 4.0)	2.1 (2.0 to 2.1)	2.0 (1.0 to 4.0)	2.0 (1.0 to 8.1)
Above 18 years (n=0; n=1; n=0; n=0)	0.9 (0.9 to 0.9)	9999 (9999 to 9999)	9999 (9999 to 9999)	9999 (9999 to 9999)
Total	2.0 (0.5 to 6.0)	2.0 (0.9 to 2.2)	2.0 (1.0 to 4.5)	2.0 (1.0 to 8.1)

No statistical analyses for this end point

Secondary: Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-T]) by Dose Level and Age Group

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End point title

Dasatinib Metabolite (BMS-582691) Plasma Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-T]) by Dose Level and Age Group

End point description

End point type

Secondary

End point timeframe

During Week 1 of Course 1, and any course in which dose escalation was performed (at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hours).

End point values	Dasatinib 120 mg/m^2	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2
Number of subjects analysed	9	13	21	14
Units: ng.h/mL
geometric mean (geometric coefficient of variation)
Infants and Toddlers (age<2yr; n=0; n=0; n=0; n=1)	1.9 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )	9999 ( 9999 )
Children (age>=2 and <12yr; n=7; n=12; n=5; n=6)	23.6 ( 102.2 )	8.8 ( 50.4 )	16.6 ( 145.2 )	25.4 ( 71.1 )
Adolescents(age>=12 and <12yr; n=6; n=8; n=9; n=2)	15.8 ( 105.5 )	12.3 ( 38.4 )	13.5 ( 54.4 )	20.0 ( 112.3 )
Above 18 years (n=0; n=1; n=0; n=0)	9999 ( 9999 )	9999 ( 9999 )	6.6 ( 9999 )	9999 ( 9999 )
Total	16.3 ( 110.3 )	10.3 ( 44.9 )	14.7 ( 141.1 )	21.8 ( 100.1 )

No statistical analyses for this end point

Secondary: Concentration of Dasatinib in Cerebrospinal Fluid (CSF) by Dose Level and Age Group

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End point title

Concentration of Dasatinib in Cerebrospinal Fluid (CSF) by Dose Level and Age Group

End point description

Concentration of dasatinib in CSF was assessed only in participants who had lumbar puncture during the treatment. y=years

End point type

Secondary

End point timeframe

4 hours after oral dose

End point values	Dasatinib 60 mg/m^2	Dasatinib 80 mg/m^2	Dasatinib 100 mg/m^2	Dasatinib 120 mg/m^2
Number of subjects analysed	4	10	6	1
Units: ng/mL
arithmetic mean (standard deviation)
Children (age>=2 and <12 y; n=3, n=9, n=3, n=1)	1.1 ( 0.2 )	1.5 ( 0.6 )	1.7 ( 0.4 )	3.8 ( 9999 )
Adolescents(age>=12 and <18 y; n=1; n=1; n=3; n=0)	1.1 ( 9999 )	1.0 ( 9999 )	2.6 ( 0.6 )	9999 ( 9999 )
Total (Children + Adolescents;n=4; n=10; n=6; n=1)	1.1 ( 0.1 )	1.4 ( 0.6 )	2.1 ( 0.7 )	3.8 ( 9999 )

No statistical analyses for this end point

Secondary: Number of Participants with BCR-ABL Mutations at Baseline: Stratum1 Ph+ CP-CML and Stratum 2/3 Ph+ALL or AP/BP-CML

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End point title

Number of Participants with BCR-ABL Mutations at Baseline: Stratum1 Ph+ CP-CML and Stratum 2/3 Ph+ALL or AP/BP-CML ^[9]

End point description

BCR-ABL, also referred to as the Philadelphia chromosome, is formed from the fusion of the BCR gene on chromosome 22 with the ABL gene on chromosome 9.

End point type

Secondary

End point timeframe

At baseline (within 3 weeks before initiation of study therapy)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose
Number of subjects analysed	17	17
Units: participants
L384M	1	0
G250E	1	0
T315I	0	1
Y253H	0	1
Y253F	0	1
No Mutation	15	11
No Data	0	3

No statistical analyses for this end point

Secondary: Number of Participants with BCR-ABL Mutations at End-of-Treatment: Stratum1 Ph+ CP-CML and Stratum2/3 Ph+ ALL or AP/BP-CML

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End point title

Number of Participants with BCR-ABL Mutations at End-of-Treatment: Stratum1 Ph+ CP-CML and Stratum2/3 Ph+ ALL or AP/BP-CML ^[10]

End point description

BCR-ABL = These are fused genes found in participants with this type of leukemia.

End point type

Secondary

End point timeframe

At EOT (Median duration of therapy in months: Stratum 1=24.11 [Range: 2.27-50.63]; Stratum 2/3=3.02 [Range: 0.53-37.72])

Notes
[10] - 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: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose
Number of subjects analysed	17	17
Units: participants
T315I	0	4
No Mutation	8	9
No Data	9	4

No statistical analyses for this end point

Secondary: Number of Participants with FLT3 and KIT Mutations in Stratum4 Ph- ALL/AML at Baseline

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End point title

Number of Participants with FLT3 and KIT Mutations in Stratum4 Ph- ALL/AML at Baseline ^[11]

End point description

FLT3 and KIT = These are fused genes found in participants with this type of leukemia.

End point type

Secondary

End point timeframe

At baseline (within 3 weeks before initiation of study therapy)

Notes
[11] - 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: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose
Number of subjects analysed	24
Units: participants
FLT3 Absent	20
FLT3 Present	1
FLT3 No Data	3
KIT Absent	21
KIT Present	0
KIT No Data	3

No statistical analyses for this end point

Secondary: Number of Participants with FLT3 and KIT Mutations in Stratum4 Ph- ALL/AML at End-Of-Treatment

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End point title

Number of Participants with FLT3 and KIT Mutations in Stratum4 Ph- ALL/AML at End-Of-Treatment ^[12]

End point description

FLT3 and KIT = These are fused genes found in participants with this type of leukemia.

End point type

Secondary

End point timeframe

At EOT (Median duration of therapy in months: Stratum 4=1.14 [Range: 0.03-3.38])

Notes
[12] - 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: Endpoint is specific to Stratum 1 and Stratum 2/3 arms only

End point values	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose
Number of subjects analysed	24
Units: participants
FLT3 Absent	6
FLT3 Present	0
FLT3 No Data	18
KIT Absent	6
KIT Present	0
KIT No Data	18

No statistical analyses for this end point

Other pre-specified: Number of Participants With Hematologic Toxicity at Baseline by NCI CTCAE Version 3.0

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End point title

Number of Participants With Hematologic Toxicity at Baseline by NCI CTCAE Version 3.0

End point description

GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. White Blood Cell (WBC):GR1=<LLN-3.0*10^9/L; GR2=<3.0-2.0*10^9/L; GR3=<2.0-1.0*10^9/L; GR4=<1.0*10^9/L. Absolute Neutrophil Count (ANC): GR1=<LLN-1.5*10^9 /L; GR2=<1.5-1.0*10^9/L; GR3=<1.0-0.5*10^9/L; GR4=<0.5*10^9/L. Hemoglobin: GR1=<LLN-10.0g/dL; GR2=<10.0-8.0g/dL; GR3=<8.0-6.5g/dL; GR4=<6.5g/dL. Platelets: GR1=<LLN-75.0*10^9/L; GR2=<75.0-50.0*10^9/L; GR3=<50.0-25.0*10^9/L; GR4=<25.0*10^9/L. LLN=lower limit of normal.

End point type

Other pre-specified

End point timeframe

At baseline (within 1 week before initiation of study therapy)

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose
Number of subjects analysed	17	17	24
Units: participants
WBC GR1	1	2	3
WBC GR2	0	2	2
WBC GR3	0	0	6
WBC GR4	0	1	4
ANC GR1	1	2	3
ANC GR2	1	1	0
ANC GR3	0	2	3
ANC GR4	0	2	13
Platelet GR1	1	5	5
Platelet GR2	0	2	3
Platelet GR3	0	3	8
Platelet GR4	0	2	6
Hemoglobin GR1	7	7	7
Hemoglobin GR2	1	7	7
Hemoglobin GR3	0	1	3
Hemoglobin GR4	0	0	0

No statistical analyses for this end point

Other pre-specified: Number of Participants With Serum Chemistry Abnormalities (Liver and Renal Function) at Baseline by NCI CTCAE Version 3.0

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End point title

Number of Participants With Serum Chemistry Abnormalities (Liver and Renal Function) at Baseline by NCI CTCAE Version 3.0

End point description

GR1=Mild; GR2=Moderate; GR3=Severe; GR4=Life-threatening or disabling. Normal ranges provided by local laboratory and may also vary from site to site. Aspartate aminotransferase (AST) and alanine aminotransferase(ALT): GR1=>ULN-2.5*ULN; GR2=>2.5-5.0*ULN; GR3=>5.0-20.0*ULN; GR4=>20.0*ULN. Total bilirubin:GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3-10*ULN, GR4=>10*ULN. Creatinine: GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3.0-6.0*ULN, GR4=>6.0*ULN. ULN=upper limit of normal.

End point type

Other pre-specified

End point timeframe

At baseline (within 1 week before initiation of study therapy)

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose
Number of subjects analysed	17	17	24
Units: participants
AST GR1	1	3	8
AST GR2	0	2	1
AST GR3	0	1	0
AST GR4	0	0	0
AST GR Not Reported	1	3	2
High ALT GR1	2	6	6
High ALT GR2	0	2	5
High ALT GR3	0	0	0
High ALT GR4	0	0	0
High ALT GR Not Reported	0	0	0
High Total Bilirubin GR1	3	0	1
High Total Bilirubin GR2	0	1	0
High Total Bilirubin GR3	0	0	0
High Total Bilirubin G4	0	0	0
High Total Bilirubin GR Not Reported	0	0	1
High Serum Creatinine GR1	2	0	4
High Serum Creatinine GR2	0	1	0
High Serum Creatinine GR3	0	0	0
High Serum Creatinine GR4	0	0	0
High Serum Creatinine GR Not Reported	0	0	1

No statistical analyses for this end point

Other pre-specified: Number of Participants With Serum Chemistry Abnormalities (Calcium, Magnesium, and Phosphate) at Baseline by NCI CTCAE Version 3.0

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End point title

Number of Participants With Serum Chemistry Abnormalities (Calcium, Magnesium, and Phosphate) at Baseline by NCI CTCAE Version 3.0

End point description

End point type

Other pre-specified

End point timeframe

At baseline (within 1 week before initiation of study therapy)

End point values	Stratum1 Ph+ CP-CML; Dasatinib 60 mg/m^2 Starting Dose	Stratum2/3 Ph+ALL or AP/BP-CML;Dasatinib60mg/m^2 Starting Dose	Stratum4 Ph- ALL/AML; Dasatinib 60 mg/m^2 Starting Dose
Number of subjects analysed	17	17	24
Units: participants
Low Calcium GR1	0	0	1
Low Calcium GR2	0	0	0
Low Calcium GR3	0	0	0
Low Calcium GR4	0	0	0
Low Calcium GR Not Reported	0	0	2
Low Magnesium GR1	0	6	0
Low Magnesium GR2	0	0	0
Low Magnesium GR3	0	0	0
Low Magnesium GR4	0	0	0
Low Magnesium GR Not Reported	0	0	2
Low Phosphate GR1	0	1	0
Low Phosphate GR2	0	0	0
Low Phosphate GR3	0	1	0
Low Phosphate GR4	0	0	0
Low Phosphate GR Not Reported	2	0	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Time frame for AE reporting

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

CP-CML

Reporting group description

CP-CML

Reporting group title

Ph-ALL/AML

Reporting group description

Ph-ALL/AML

Reporting group title

Ph+ALL or AP/BP-CML

Reporting group description

Ph+ALL or AP/BP-CML

Serious adverse events	CP-CML	Ph-ALL/AML	Ph+ALL or AP/BP-CML
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 17 (47.06%)	22 / 24 (91.67%)	14 / 17 (82.35%)
number of deaths (all causes)	3	23	12
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	0 / 17 (0.00%)	7 / 24 (29.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 6	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	2 / 17 (11.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Vascular disorders
Hypertension
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pain
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 17 (5.88%)	4 / 24 (16.67%)	3 / 17 (17.65%)
occurrences causally related to treatment / all	1 / 1	1 / 8	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Graft versus host disease
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Respiratory failure
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Product issues
Thrombosis in device
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Ammonia increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
White blood cell count increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Coma
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial nerve disorder
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 17 (0.00%)	5 / 24 (20.83%)	3 / 17 (17.65%)
occurrences causally related to treatment / all	0 / 0	2 / 5	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	2 / 17 (11.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 17 (5.88%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Vomiting
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Exfoliative rash
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash macular
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 17 (5.88%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Anal infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 17 (5.88%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 17 (5.88%)	2 / 24 (8.33%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Sepsis
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Varicella zoster virus infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	CP-CML	Ph-ALL/AML	Ph+ALL or AP/BP-CML
Total subjects affected by non serious adverse events
subjects affected / exposed	16 / 17 (94.12%)	24 / 24 (100.00%)	16 / 17 (94.12%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chloroma
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Skin papilloma
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Vascular disorders
Flushing
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Hot flush
subjects affected / exposed	1 / 17 (5.88%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences all number	1	1	0
Hypertension
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Thrombosis
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Catheter site erythema
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Catheter site haemorrhage
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Catheter site pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Chest pain
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	2 / 17 (11.76%)
occurrences all number	2	0	2
Chills
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Face oedema
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Fatigue
subjects affected / exposed	7 / 17 (41.18%)	4 / 24 (16.67%)	4 / 17 (23.53%)
occurrences all number	15	5	5
Influenza like illness
subjects affected / exposed	2 / 17 (11.76%)	1 / 24 (4.17%)	2 / 17 (11.76%)
occurrences all number	10	1	10
Injection site pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Injection site reaction
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	2
Malaise
subjects affected / exposed	3 / 17 (17.65%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	4	0	0
Mucosal inflammation
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	0	1
Oedema
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Oedema peripheral
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	3	0	1
Pain
subjects affected / exposed	3 / 17 (17.65%)	0 / 24 (0.00%)	3 / 17 (17.65%)
occurrences all number	3	0	4
Peripheral swelling
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Pyrexia
subjects affected / exposed	5 / 17 (29.41%)	8 / 24 (33.33%)	8 / 17 (47.06%)
occurrences all number	13	10	9
Swelling
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Swelling face
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Hypersensitivity
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Reproductive system and breast disorders
Ovarian failure
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	11 / 17 (64.71%)	2 / 24 (8.33%)	5 / 17 (29.41%)
occurrences all number	30	3	16
Dry throat
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Dyspnoea
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Epistaxis
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	3 / 17 (17.65%)
occurrences all number	3	0	3
Nasal congestion
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Oropharyngeal pain
subjects affected / exposed	5 / 17 (29.41%)	1 / 24 (4.17%)	2 / 17 (11.76%)
occurrences all number	18	1	20
Pleural effusion
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	1 / 17 (5.88%)
occurrences all number	0	2	1
Pulmonary oedema
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Rhinorrhoea
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Wheezing
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	1
Anxiety
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	2
Depressed mood
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Enuresis
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Insomnia
subjects affected / exposed	1 / 17 (5.88%)	1 / 24 (4.17%)	1 / 17 (5.88%)
occurrences all number	1	1	1
Sleep disorder
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Suicidal ideation
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Investigations
Body temperature
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	2 / 17 (11.76%)
occurrences all number	0	3	2
Heart rate increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Hepatic enzyme increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	3
Neutrophil count decreased
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Weight decreased
subjects affected / exposed	1 / 17 (5.88%)	4 / 24 (16.67%)	0 / 17 (0.00%)
occurrences all number	1	5	0
Weight increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
White blood cell count decreased
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Clavicle fracture
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Contusion
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	3 / 17 (17.65%)
occurrences all number	3	0	3
Fall
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Head injury
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Joint injury
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Ligament sprain
subjects affected / exposed	3 / 17 (17.65%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Mouth injury
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Post lumbar puncture syndrome
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Skin abrasion
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Skin laceration
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Sunburn
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Wound
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Post-Traumatic pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	3 / 17 (17.65%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	5	0	1
Nervous system disorders
Disturbance in attention
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Dizziness
subjects affected / exposed	3 / 17 (17.65%)	1 / 24 (4.17%)	1 / 17 (5.88%)
occurrences all number	5	1	1
Facial paralysis
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Headache
subjects affected / exposed	11 / 17 (64.71%)	6 / 24 (25.00%)	5 / 17 (29.41%)
occurrences all number	83	10	6
Intracranial pressure increased
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Neuralgia
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Post-Traumatic headache
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	2	0	1
Pancytopenia
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Splenomegaly
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	0 / 17 (0.00%)
occurrences all number	0	2	0
Thrombocytopenia
subjects affected / exposed	1 / 17 (5.88%)	3 / 24 (12.50%)	3 / 17 (17.65%)
occurrences all number	1	4	4
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Ear pain
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	3 / 17 (17.65%)
occurrences all number	6	0	4
Middle ear effusion
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	4	0	0
Eye disorders
Chalazion
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Dacryoadenitis acquired
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Dry eye
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Erythema of eyelid
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Eye discharge
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Eye pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	2 / 17 (11.76%)
occurrences all number	1	0	2
Eye pruritus
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Eye swelling
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Eyelid oedema
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	1 / 17 (5.88%)
occurrences all number	0	3	1
Eyelid ptosis
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Orbital oedema
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Periorbital oedema
subjects affected / exposed	1 / 17 (5.88%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences all number	3	1	0
Swelling of eyelid
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Abdominal distension
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Abdominal pain
subjects affected / exposed	9 / 17 (52.94%)	3 / 24 (12.50%)	2 / 17 (11.76%)
occurrences all number	33	3	8
Abdominal pain lower
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Abdominal pain upper
subjects affected / exposed	3 / 17 (17.65%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	7	0	4
Aphthous ulcer
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Colitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Constipation
subjects affected / exposed	3 / 17 (17.65%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences all number	3	1	0
Dental caries
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Diarrhoea
subjects affected / exposed	11 / 17 (64.71%)	6 / 24 (25.00%)	7 / 17 (41.18%)
occurrences all number	28	7	18
Dyspepsia
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Flatulence
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Gingival bleeding
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	1 / 17 (5.88%)
occurrences all number	0	2	1
Irritable bowel syndrome
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Mouth ulceration
subjects affected / exposed	3 / 17 (17.65%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	11	0	0
Nausea
subjects affected / exposed	7 / 17 (41.18%)	13 / 24 (54.17%)	6 / 17 (35.29%)
occurrences all number	18	15	10
Oral mucosal blistering
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Oral pain
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	3
Periodontal disease
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Tongue disorder
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Tongue ulceration
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Tooth loss
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Toothache
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	5	0	0
Vomiting
subjects affected / exposed	9 / 17 (52.94%)	11 / 24 (45.83%)	7 / 17 (41.18%)
occurrences all number	25	12	19
Hepatobiliary disorders
Hepatomegaly
subjects affected / exposed	0 / 17 (0.00%)	2 / 24 (8.33%)	0 / 17 (0.00%)
occurrences all number	0	3	0
Hepatotoxicity
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Hyperbilirubinaemia
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	2 / 17 (11.76%)
occurrences all number	2	0	3
Alopecia
subjects affected / exposed	1 / 17 (5.88%)	1 / 24 (4.17%)	2 / 17 (11.76%)
occurrences all number	1	1	3
Dermatitis
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Dermatitis acneiform
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Dermatitis contact
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Dry skin
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	3	0	1
Erythema
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Hair colour changes
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	1
Hyperhidrosis
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	1 / 17 (5.88%)
occurrences all number	0	1	2
Miliaria
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Nail disorder
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Night sweats
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Petechiae
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	3 / 17 (17.65%)
occurrences all number	0	1	3
Pigmentation disorder
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Pruritus
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Rash
subjects affected / exposed	7 / 17 (41.18%)	3 / 24 (12.50%)	6 / 17 (35.29%)
occurrences all number	9	4	9
Rash macular
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	3
Skin disorder
subjects affected / exposed	1 / 17 (5.88%)	1 / 24 (4.17%)	0 / 17 (0.00%)
occurrences all number	1	1	0
Urticaria
subjects affected / exposed	3 / 17 (17.65%)	2 / 24 (8.33%)	1 / 17 (5.88%)
occurrences all number	5	2	1
Musculoskeletal and connective tissue disorders
Aneurysmal bone cyst
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Arthralgia
subjects affected / exposed	6 / 17 (35.29%)	4 / 24 (16.67%)	3 / 17 (17.65%)
occurrences all number	21	6	4
Back pain
subjects affected / exposed	5 / 17 (29.41%)	1 / 24 (4.17%)	4 / 17 (23.53%)
occurrences all number	11	1	6
Bone pain
subjects affected / exposed	1 / 17 (5.88%)	4 / 24 (16.67%)	1 / 17 (5.88%)
occurrences all number	2	4	1
Epiphyses delayed fusion
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Growth retardation
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Hypermobility syndrome
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Muscle spasms
subjects affected / exposed	4 / 17 (23.53%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	7	0	1
Muscle tightness
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Muscular weakness
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Musculoskeletal chest pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	1
Musculoskeletal disorder
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Musculoskeletal pain
subjects affected / exposed	2 / 17 (11.76%)	2 / 24 (8.33%)	1 / 17 (5.88%)
occurrences all number	3	2	1
Myalgia
subjects affected / exposed	4 / 17 (23.53%)	1 / 24 (4.17%)	1 / 17 (5.88%)
occurrences all number	5	1	2
Neck pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	1	0	1
Osteoporosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Pain in extremity
subjects affected / exposed	9 / 17 (52.94%)	2 / 24 (8.33%)	5 / 17 (29.41%)
occurrences all number	25	2	9
Infections and infestations
Conjunctivitis
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	3	0	1
Conjunctivitis bacterial
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Cystitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Device related infection
subjects affected / exposed	0 / 17 (0.00%)	1 / 24 (4.17%)	1 / 17 (5.88%)
occurrences all number	0	1	1
Epididymitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Eye infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Folliculitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Fungal skin infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Gastrointestinal infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Herpes simplex
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Herpes zoster
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	2 / 17 (11.76%)
occurrences all number	0	0	2
Infection
subjects affected / exposed	2 / 17 (11.76%)	2 / 24 (8.33%)	1 / 17 (5.88%)
occurrences all number	3	2	1
Lice infestation
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Molluscum contagiosum
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Nasopharyngitis
subjects affected / exposed	8 / 17 (47.06%)	0 / 24 (0.00%)	2 / 17 (11.76%)
occurrences all number	21	0	14
Oral fungal infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Oral herpes
subjects affected / exposed	1 / 17 (5.88%)	1 / 24 (4.17%)	2 / 17 (11.76%)
occurrences all number	1	1	2
Otitis externa
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Otitis media
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	3	0	1
Pharyngitis
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	3	0	0
Rhinitis
subjects affected / exposed	3 / 17 (17.65%)	1 / 24 (4.17%)	1 / 17 (5.88%)
occurrences all number	4	2	1
Sinusitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Skin infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Tinea cruris
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Upper respiratory tract infection
subjects affected / exposed	3 / 17 (17.65%)	0 / 24 (0.00%)	3 / 17 (17.65%)
occurrences all number	7	0	4
Urinary tract infection
subjects affected / exposed	2 / 17 (11.76%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Varicella
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Viral infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0
Viral rhinitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	0 / 17 (0.00%)
occurrences all number	2	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 17 (5.88%)	0 / 24 (0.00%)	2 / 17 (11.76%)
occurrences all number	2	0	2
Hyperglycaemia
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1
Hypokalaemia
subjects affected / exposed	0 / 17 (0.00%)	3 / 24 (12.50%)	0 / 17 (0.00%)
occurrences all number	0	5	0
Tumour lysis syndrome
subjects affected / exposed	0 / 17 (0.00%)	0 / 24 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

06 Jul 2006

The purpose of this amendment is to make numerous corrections which arose during review process: 1) Delete references throughout protocol to Pharmacodynamic assays and to central morphology review of BM smears, which will not be performed in this trial. Reason: Analysis will not be performed. 2) Correct primary efficacy endpoint from CHR to MaHR in Strata 2- 4. 3) Specify that Mutation analysis will be done in all Strata (mutations of Abl in Strata 1 - 3 and of Flt3 & Kit in Stratum 4). 4) Add moderate neutropenia (i.e. ANC 500 - 1,000) to the definition of CHRp Reason: bring definition into consistency with previous dasatinib studies. 5) Specify definitions of imatinib-resistance and imatinib-intolerance by stratum. Reason: Definitions were unclear in previous protocols. 6) Removed requirement for baseline lumbar puncture (LP) in Stratum 1 (chronic phase). Reason: Not considered indicated in chronic phase population. 7) Modifications in eligibility criteria a. Clearly state that search for an identical HLA donor must be ongoing for subjects included in Stratum 1. Reason: French regulatory request. b. Permit Grade 1 electrolyte abnormalities and Grade 2 renal insufficiency. Reason: Numerous exceptions have been issued for Grade 1 electrolyte abnormalities of no clinical significance (note: serum Ca will still be required to e ≥LLN). Moderate renal insufficiency (Grade 2) emitted because drug is not excreted significantly via urine. 8) Changed certain anticoagulants from prohibited to “used as indicated” in absence of hrombopenia. Reason: Hemorrhage is typically associated with thrombopenia and numerous exceptions have been issued for concomitant anticoagulants in absence of thrombopenia. 9) Moved strong CYP3A4 inhibitors from restricted to prohibited Reason: Data are available showing 5 - 6 fold increase in dasatinib exposure in presence of strong 3A4 inhibitor, consistent with safety risk.

06 Jul 2006

10) Changed on-treatment CXR to “at Investigator discretion” Reason: German regulatory request. 11) Allowed multiple-gated acquisition scan (MUGA) or echocardiogram for cardiac assessment to be consistent with prior evaluations per institutional choice. Reason: Many subjects will have had prior cardiac evaluation; the same method should be used for accuracy. 12) Echocardiograms (or MUGA scans) will be performed within the first month, after course 4, and then every 8 courses (6 months) while on study, and in case of heart failure. Additionally added echocardiogram or MUGA at end of treatment visit. Reason: French regulatory request. 13) Added that BM aspirates are NOT required to document progressive disease IF there is an increase in the white blood cell with blasts in the peripheral blood. Reason: flow cytometry can be performed on peripheral blood, so BM is unnecessary.

06 Jul 2006

14) Increased ‘window’ for baseline BM and LP to 3 weeks prior to treatment. Reason: It proved to be impractical to require that baseline procedures be within 1 week. 15) Increased ‘window’ for initiation of treatment after enrollment for Stratum 1 from 3 to 10 days and for Strata 2 - 4 from 3 to 5 days. Reason: It proved to be impractical to require that treatment start within 3 days. 16) Added orange or apple juice as vehicles for dispersion of tablets if necessary, including revised Appendix 3: Reason: Apple and orange juices were shown to be adequate vehicles for dasatinib tablet dispersion. 17) Correct inconsistencies in eligibility criteria, specifically in definition of primary cytogenetic resistance, minimum accepted age, Karnofsky/Lansky score. Reason: Typographical inconsistencies were found between Synopsis and Protocol text. 18) State that effect of dasatinib on spermatogenesis and fertility have not been studied. Reason: German regulatory request. 19) Reduce the washout period of imatinib before treatment start. Reason: Specifically in advanced stages of disease, patients can progress very rapidly, and remain on imatinib until alternative therapies are available, therefore a 2 week washout was impractical.

06 Dec 2007

Amendment Rationale: The purpose of this amendment is to make changes to the protocol based on slower than excepted accrual rates and recent findings in the ongoing adult Phase II program. 1) Update the Study Medical Monitor and Director. 2) Elimination of the previous stratum 3 (accelerated or myeloid blast phase CML, or Ph+ AML in ≥ 2nd relapse), and incorporate previous strata 2 and 3 into a newly called stratum “2/3”. Reason: (a) the accelerated or myeloid blast phase CML or Ph+AML in ≥ 2nd relapse are rare which resulted in too slow an enrollment. Consolidating the strata will allow for faster enrollment within one group (stratum “2/3”) and diseases are very similar based on adult CML data; (b) the name stratum “2/3” is chosen for it accurately indicates the ‘historical’ composition of this stratum. 3) The stratum 4 remains and keeps its original name. Reason: despite that there will only be 3 separate strata, it was felt to be less confusing going forward to keep the name for Stratum 4. 4) Hence, upon implementation of this amendment the 3 strata will be as follows: Stratum 1: unchanged, i.e., Ph+ CML in chronic phase with resistant or progressive disease during, or intolerance to, imatinib; Stratum 2/3: consolidation of old stratum 2 and 3 into a single stratum, i.e., Ph+ leukemia (ALL, AML) in first or subsequent relapse [≥ 25% blasts in bone marrow] after prior imatinib and/or Ph+ CML in accelerated, myeloid or lymphoid blast phase with resistant or progressive disease during, or intolerance to, imatinib; Stratum 4: unchanged Ph-negative acute leukemia, any cytopathologic subtype, in second or subsequent relapse [≥ 25% blasts in bone marrow] or refractory after 2 or more induction regimens and for whom no therapy of greater curative potential is available

06 Dec 2007

5) Add additional data from an ongoing phase I study in pedatric patients with refractory/relapsed solid tumors or imatinib resistant Ph+ leukemias and an adult Phase II breast cancer trial to provide an update when using dasatinib doses at or above 120 mg/m2 QD. Given our limited pediatric data we will accrue a total of 6 patients at the 120 mg/m2 starting dose level if the first 3 patients at the 120 starting mg/m2 QD dose level do not show excessive toxicity. Based on the safety data obtained in these 6 patients enrolled at 120 mg/m2 QD starting dose level decisions will be made regarding future enrollment of patients at the 150 mg/m2 QD starting dose levels. 6) In accordance with the above, in each of strata 2/3 and 4, a maximum of 6 subjects will be accrued per dose level in the Phase I portion of the study. Intra-patient dose escalation for lack of efficacy in case of proven safety in a subject will be allowed and will be based on the tolerability and the clinical efficacy at any given dose. Regardless of efficacy data, no patients will be treated at a dose higher than 150 mg/m2.

06 Dec 2007

7) Additional enrollment at the recommended Phase II dose for strata 1, 2/3, and 4, (i.e., ‘expansion of the cohorts at the recommended Phase II dose’) will be discussed at a later stage when the ‘expansion’ cohorts will be discussed. The final recommended Phase II dose level and the numbers of patients to enroll in the expansion phase for each cohort will be decided based on the forthcoming safety and observed efficacy data for each stratum. Reason: based on ongoing discussions with worldwide regulatory authorities regarding the use of dasatinib in a pediatric population. 8) Allow extramedullary disease. Reason: stratum 2 currently has allowed patients with isolated asymptomatic CNS disease (with previous enrollment exceptions) and the patients have responded well without toxicity. 9) Clarify the pharmacodynamic secondary objectives. 10) Clarify that confirmation of hematologic response must occur at least 4 weeks after it is first documented and clarify complete hematological response. 11) Since interphase FISH will be used in subjects with unsuccessful cytogenetic analysis, it is recommended that FISH analysis is systematically conducted when a cytogenetic analysis is performed 12) Clarification of the preparation of an oral solution of dasatinib. 13) Clarification of the “Handling and Dispensing of Investigational Product”

24 Jun 2008

Amendment Rationale: The purpose of this amendment is to open the study to participation of clinical sites outside of the ITCC consortium. This revision will not impact study conduct or data analysis, it applies to all future enrolled patients. Other changes incorporated in this amendment are: 1) Updated Medical Monitor. 2) Updated contact details of coordinating investigator. 3) Updated description of investigational product. 4) Removed inconsistencies in description of duration of treatment. 5) Added additional detail regarding collection of peripheral blood and bone marrow aspirate samples. 6) Inserted a new mandatory paragraph pertaining to serious breaches of GCP. 7) Removed typographical errors and any references to pharmacodynamic tests. 8) Added clarification regarding collection of samples for mutation analysis. 9) Updated protocol language to comply with current model document

18 Nov 2008

Amendment 4 will clarify that study CA 180018 will not proceed to its phase II component. It will also lead to the timely completion of CA180018 and transitioning to the phase II trial. Other changes incorporated in this amendment are: 1) Clarification of per-stratum use of dose levels both for starting doses and for intra-patient dose escalations. 2) Adjustment of patient numbers that will be accrued per stratum. 3) Change of study phase from Phase I/II to Phase I. 4) Change in duration and content of follow-up period. 5) Added precision to requirements for SAE collection post study drug treatment period. 6) Removal of typos.

08 Dec 2009

Amendment 05 will add tests to monitor growth & development and bone metabolism both during the treatment period and also for up to 5 years of follow-up after study drug administration. Amendment 05 will also implement a modified visit schedule for study participants who are on treatment for more than 12 months. Other changes incorporated in this amendment are:  Update of Central Medical Monitor and emergency telephone number  Updated maximum treatment duration  Amended visit schedule for study subjects after 12 months of treatment  Included language to expand on regulation of access to study drug after the end of the study  Updated tables in the section “Flow Chart/Time and Events Schedules”  Added paragraph, providing rationale for radiograph and DXAscan.  Handling of Serious Adverse Events: updated standard language to describe change in the SAE submission process (hardcopies no longer required); updated SAE telephone contacts.  References: added references 56 and 57  Appendix 3: added a new version; clarified that only glass containers can be used for preparation of oral drug solution; added safety recommendations and clean-up instructions; added precision to the language throughout the document.  Appendix 4: newly added appendix (The Tanner Stages). Change of emergency telephone number. Change of SAE submission process (mailing of hardcopies is no longer a requirement).

02 Dec 2011

The purpose of the amendment is to modify the frequency of the follow-up visits from quarterly visits to annual visits, as the conduct of quarterly follow-up visit is no longer required to meet the study objectives. In addition, the conduct of procedures to monitor growth and development will be requested for all study subjects, the current limitation for some procedures to only “subjects with a significant growth deceleration” will be removed to ensure complete alignment with Pediatric Investigational Plan. Change in the assignment of the Central Medical Monitor and an update of the SAE contact details. PK sample collection for study participants that are on treatment and may have dose escalations in the future is no longer a protocol requirement and such samples should neither be collected nor shipped

06 Feb 2014

The main purpose of this amendment is to extend the maximum treatment duration from 6 years to 10 years to allow participants who are still on treatment and benefitting continued access to the study drug. Dasatinib has not been formally studied in pregnant women. However, the dasatinib team has recently completed a comprehensive review of the BMS Dasatinib safety database (CARES) for all pregnancies in female patients or female partners of male patients in order to reassess the risk of use of dasatinib during pregnancy. Pregnancies in female patients on dasatinib sometimes resulted in spontaneous abortions or infant and fetal anomalies. Based on this analysis and a revision to an internal BMS directive related to “Women of Childbearing Potential (WOCBP) in clinical trials”, protocols in the dasatinib program are being amended to: 1) update language related to WOCBP to harmonize with the new BMS directive including requiring 2 highly effective forms of birth control 2) define highly effective forms of birth control 3) adjust language related to sexually active fertile men with WOCBP partners and adapt the length of birth control to be used after the last dose of investigational product (90 days). In the study under discussion only male subjects were on treatment when the amendment was authored. The amendment will hence implement changes to the rules governing pregnancy prevention for sexually active fertile men and their partners, as referenced in items 2 and 3 above.

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: Phase 1 Study of SRC, ABL Tyrosine Kinase Inhibitor Dasatinib (BMS-354825) in Children and Adolescents with Relapsed or Refractory Leukemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Recommended Phase II Dose of Dasatinib in Children and Adolescents with Relapsed or Refractory Leukemia

Primary: Recommended Phase II Dose of Dasatinib in Children and Adolescents with Relapsed or Refractory Leukemia

Secondary: Number of Participants with Related Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Secondary: Number of Participants with Related Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Secondary: Number of Participants with Dose-limiting Toxicity (DLT)

Secondary: Number of Participants with Dose-limiting Toxicity (DLT)

Secondary: Number of Participants with Hematology Abnormalities by NCI CTCAE Version 3.0

Secondary: Number of Participants with Hematology Abnormalities by NCI CTCAE Version 3.0

Secondary: Number of Participants with Serum Chemistry Abnormalities (calcium, magnesium, and phosphate) by NCI CTCAE Version 3.0

Secondary: Number of Participants with Serum Chemistry Abnormalities (calcium, magnesium, and phosphate) by NCI CTCAE Version 3.0

Secondary: Number of Participants with Serum Chemistry Abnormalities (Liver and Renal Function) by NCI CTCAE Version 3.0

Secondary: Number of Participants with Serum Chemistry Abnormalities (Liver and Renal Function) by NCI CTCAE Version 3.0

Secondary: Number of Participants with Major Cytogenetic Response (MCyR) at Any Time in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Number of Participants with Major Cytogenetic Response (MCyR) at Any Time in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Number of Participants with Major Cytogenetic Response (MCyR) in Stratum 1 (Ph+ CP-CML) Within First 12 and 24 Weeks

Secondary: Number of Participants with Major Cytogenetic Response (MCyR) in Stratum 1 (Ph+ CP-CML) Within First 12 and 24 Weeks

Secondary: Best Cytogenetic Response (CyR) in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Best Cytogenetic Response (CyR) in Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Percentage of Participants with Complete Cytogenetic Response (CCyR) or Major Cytogenetic Response (MCyR) at Recommended Phase II Dose

Secondary: Percentage of Participants with Complete Cytogenetic Response (CCyR) or Major Cytogenetic Response (MCyR) at Recommended Phase II Dose

Secondary: Time to Major Cytogenetic Response (MCyR) in Responders: Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Time to Major Cytogenetic Response (MCyR) in Responders: Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Duration of Major Cytogenetic Response (MCyR) in Responders (Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML])

Secondary: Duration of Major Cytogenetic Response (MCyR) in Responders (Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML])

Secondary: Duration of Complete Cytogenetic Response (CCyR) in Responders: Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML]

Secondary: Duration of Complete Cytogenetic Response (CCyR) in Responders: Stratum 1 [Ph+ CP-CML] and Stratum 2/3 [Ph+ ALL or AP/BP-CML]

Secondary: Number of Participants with Major Hematologic Response (MaHR) at Any Time in Stratum 2/3 (Ph+ ALL or AP/BP-CML) and Stratum 4 (Ph- ALL/AML)

Secondary: Number of Participants with Major Hematologic Response (MaHR) at Any Time in Stratum 2/3 (Ph+ ALL or AP/BP-CML) and Stratum 4 (Ph- ALL/AML)

Secondary: Number of Participants with Major Hematologic Response (MaHR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML) Within First 6 and 24 Weeks

Secondary: Number of Participants with Major Hematologic Response (MaHR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML) Within First 6 and 24 Weeks

Secondary: Best Hematologic Response (HR) At Any Time: Stratum 1 (Ph+ CP-CML)

Secondary: Best Hematologic Response (HR) At Any Time: Stratum 1 (Ph+ CP-CML)

Secondary: Best Hematologic Response (HR) At Any Time: Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Best Hematologic Response (HR) At Any Time: Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Best Hematologic Response (HR) At Any Time: Stratum 4 (Ph- ALL/AML)

Secondary: Best Hematologic Response (HR) At Any Time: Stratum 4 (Ph- ALL/AML)

Secondary: Time to Major Hematologic Response (MaHR): Stratum 2/3 (PH+ ALL or AP/BP-CML)

Secondary: Time to Major Hematologic Response (MaHR): Stratum 2/3 (PH+ ALL or AP/BP-CML)

Secondary: Time to Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)

Secondary: Time to Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)

Secondary: Duration of Major Hematologic Response (MaHR): Stratum 2/3 (Ph+ALL or AP/BP-CML)

Secondary: Duration of Major Hematologic Response (MaHR): Stratum 2/3 (Ph+ALL or AP/BP-CML)

Secondary: Duration of Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)

Secondary: Duration of Complete Hematologic Response (CHR): Stratum 1 (Ph+ CP-CML) and Stratum 2/3 (Ph+ALL or AP/BP-CML)

Secondary: Percentage of Participants with Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 1 (Ph+ CP-CML)

Secondary: Percentage of Participants with Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 1 (Ph+ CP-CML)

Secondary: Percentage of Participants with Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 2/3 (Ph+ALL or AP/BP-CML)

Secondary: Percentage of Participants with Confirmed Hematologic Response (HR) at Recommended Phase II Dose: Stratum 2/3 (Ph+ALL or AP/BP-CML)

Secondary: Number of Participants with Molecular Responses in Stratum 1 (Ph+ CP-CML)

Secondary: Number of Participants with Molecular Responses in Stratum 1 (Ph+ CP-CML)

Secondary: Number of Participants with Major Molecular Response (MMR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Number of Participants with Major Molecular Response (MMR) in Stratum 2/3 (Ph+ ALL or AP/BP-CML)

Secondary: Progression Free Survival (PFS)

Secondary: Progression Free Survival (PFS)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Terminal Half-life (T 1/2) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Observed Maximum Plasma Concentration (Cmax) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Observed Maximum Plasma Concentration (Cmax) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time 0 to the time of the last quantifiable concentration (AUC[0-T]) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time 0 to the time of the last quantifiable concentration (AUC[0-T]) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Dose Normalized Area Under the Plasma Concentration Versus Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) by Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group

Secondary: Dasatinib Plasma Pharmacokinetic Parameter: Observed Maximum Plasma Concentration (Cmax) by Dose Level and Age Group

Secondary: Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group

Secondary: Dasatinib Plasma Pharmacokinetic (PK) Parameter: Time to Achieve the Observed Maximum Plasma Concentration (Tmax) By Dose Level and Age Group

Clinical Trial Results:
Phase 1 Study of SRC, ABL Tyrosine Kinase Inhibitor Dasatinib (BMS-354825) in Children and Adolescents with Relapsed or Refractory Leukemia