Download PDF

Clinical Trial Results:
A multi-center, open label, non-controlled Phase II study to evaluate the efficacy and safety of oral nilotinib in pediatric patients with newly diagnosed Ph+ chronic myelogenous leukemia (CML) in chronic phase (CP) or with Ph+ CML in CP or accelerated phase (AP) resistant or intolerant to either imatinib or dasatinib. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

Summary
EudraCT number	2013-000200-41
Trial protocol	IT ES HU BE AT GB NL DE FR
Global end of trial date	28 Aug 2020

Results information
Results version number	v2(current)
This version publication date	12 Apr 2021
First version publication date	13 Mar 2021
Other versions	v1
Version creation reason	New data added to full data set Description for endpoint # 28 needs to be updated for clarification.

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CAMN107A2203

ISRCTN number

US NCT number

NCT01844765

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma, AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000290-PIP01-08

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

28 Aug 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Aug 2020

Was the trial ended prematurely?

Main objective of the trial

- To assess efficacy of nilotinib in pediatric patients with Ph+ CMLCPresistant or intolerant to either imatinib or dasatinib - To assess efficacy of nilotinib in pediatric patients with Ph+ CMLAP resistant or intolerant to either imatinib or dasatinib - To assess efficacy of nilotinib in pediatric patients with newly diagnosed Ph+ CML-CP

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Aug 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 5

Country: Number of subjects enrolled

United Kingdom: 2

Country: Number of subjects enrolled

Hungary: 1

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Japan: 9

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Malaysia: 1

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Russian Federation: 4

Country: Number of subjects enrolled

Spain: 2

Country: Number of subjects enrolled

Thailand: 6

Country: Number of subjects enrolled

Turkey: 2

Country: Number of subjects enrolled

United States: 13

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

Top of page

Recruitment details

3 cohorts were planned based on disease classification. In 1 cohort no patients (pts) were enrolled so results presented are based on 2 cohorts. 34 imatinib/dasatinib resistant/intolerant CML-CP pts & 25 newly diagnosed CML-CP pts were enrolled. 1 imatinib/dasatinib resistant/intolerant pt did not receive study drug & was excluded from analysis.

Screening details

Minimum 50 pediatric patients (pts) to be enrolled in the study. At least 15 were to be Ph+ CML-CP pts resistant/intolerant to either imatinib or dasatinib, & at least 15 newly diagnosed Ph+ CML-CP pts. There was no requirement on the minimum number of pts to be enrolled in the Cohort of CML-AP resistant/intolerant to either imatinib or dasatinib.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Resistant/intolerant Ph+ CML in CP

Arm description

Patients resistant or intolerant to either imatinib or dasatinib

Arm type

Experimental

Investigational medicinal product name

Nilotinib 230 mg/m2 bid

Investigational medicinal product code

AMN107

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Nilotinib was administered orally at 230 mg/m2 bid for 28 days (one Cycle) and for a total of up to 66 Cycles (or discontinued early)

Newly diagnosed and untreated Ph+ CML in first CP

Arm description

Patients newly diagnosed in Chronic phase. Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis

Arm type

Experimental

Investigational medicinal product name

Nilotinib 230 mg/m2 bid

Investigational medicinal product code

AMN107

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Nilotinib was administered orally at 230 mg/m2 bid for 28 days (one Cycle) and for a total of up to 66 Cycles (or discontinued early)

Number of subjects in period 1	Resistant/intolerant Ph+ CML in CP	Newly diagnosed and untreated Ph+ CML in first CP
Started	34	25
Treated	33	25
Untreated	1 ^[1]	0 ^[2]
Completed	19	10
Not completed	15	15
Consent withdrawn by subject	2	3
Disease progression	1	-
Adverse event, non-fatal	6	8
Protocol deviation	2	-
Administrative problems	3	4
Untreated	1	-

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: No Statistics were analyzed for this endpoint.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: No Statistics were analyzed for this endpoint.

Baseline characteristics

Top of page

Reporting group title

Resistant/intolerant Ph+ CML in CP

Reporting group description

Patients resistant or intolerant to either imatinib or dasatinib

Reporting group title

Newly diagnosed and untreated Ph+ CML in first CP

Reporting group description

Reporting group values	Resistant/intolerant Ph+ CML in CP	Newly diagnosed and untreated Ph+ CML in first CP	Total
Number of subjects	34	25	59
Age Categorical
Units: Participants
1 to < 12 years	12	6	18
12 to < 18 years	22	19	41
Sex: Female, Male
Units:
Female	13	12	25
Male	21	13	34
Race/Ethnicity, Customized
Units: Subjects
Caucasian	13	18	31
Black	3	0	3
Asian	16	7	23
Native American	1	0	1
Other	1	0	1

End points

Top of page

Reporting group title

Resistant/intolerant Ph+ CML in CP

Reporting group description

Patients resistant or intolerant to either imatinib or dasatinib

Reporting group title

Newly diagnosed and untreated Ph+ CML in first CP

Reporting group description

Subject analysis set title

All patients

Subject analysis set type

Intention-to-treat

Subject analysis set description

All patients enrolled in the study

Primary: Rate of Major Molecular Response (MMR) at 6 cycles for Ph+ CML CP patients resistant or intolerant to imatinib or dasatinib

Top of page

End point title

Rate of Major Molecular Response (MMR) at 6 cycles for Ph+ CML CP patients resistant or intolerant to imatinib or dasatinib ^[1] ^[2]

End point description

MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR at 6 cycles if the patient met the MMR criteria at the Cycle 6 Visit.

End point type

Primary

End point timeframe

6 cycles

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: No Statistics were analyzed for this endpoint.
[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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	33
Units: Percentage of participants
number (confidence interval 95%)	39.4 (22.9 to 57.9)

No statistical analyses for this end point

Primary: MMR rate by 12 cycles in newly diagnosed Ph+ CML-CP patients

Top of page

End point title

MMR rate by 12 cycles in newly diagnosed Ph+ CML-CP patients ^[3] ^[4]

End point description

MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR by 12 cycles if the patient met the MMR criteria at least once at any time between first study drug intake and Cycle 12 visit included.

End point type

Primary

End point timeframe

12 cycles

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistics were analyzed for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: Percentage of participants
number (confidence interval 95%)	64.0 (42.5 to 82.0)

No statistical analyses for this end point

Primary: Rate of complete cytogenic response (CCyR) at 12 cycles in newly diagnosed Ph+ CML-CP patients

Top of page

End point title

Rate of complete cytogenic response (CCyR) at 12 cycles in newly diagnosed Ph+ CML-CP patients ^[5] ^[6]

End point description

Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as CCyR at 12 cycles if the patient met the CCyR criteria at the Cycle 12 Visit.

End point type

Primary

End point timeframe

12 cycles

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistics were analyzed for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: Percentage of participants
number (confidence interval 95%)	64.0 (42.5 to 82.0)

No statistical analyses for this end point

Secondary: MMR rate by time points in Ph+ CML-CP patients resistant or intolerant to imatinib or dasatinib

Top of page

End point title

MMR rate by time points in Ph+ CML-CP patients resistant or intolerant to imatinib or dasatinib ^[7]

End point description

Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample.

End point type

Secondary

End point timeframe

By 3, 6, 9 , 12, 24, 36, 48, 66 cycles ( 1 cycle = 28 days)

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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	33
Units: Percentage of participants
number (confidence interval 95%)
By cycle 3	36.4 (20.4 to 54.9)
By cycle 6	45.5 (28.1 to 63.6)
By cycle 9	51.5 (33.5 to 69.2)
By cycle 12	57.6 (39.2 to 74.5)
By cycle 18	57.6 (39.2 to 74.5)
By cycle 24	57.6 (39.2 to 74.5)
By cycle 36	57.6 (39.2 to 74.5)
By cycle 48	60.6 (42.1 to 77.1)
By cycle 66	60.6 (42.1 to 77.1)

No statistical analyses for this end point

Secondary: MMR rate by time points in newly diagnosed Ph+ CML-CP patients

Top of page

End point title

MMR rate by time points in newly diagnosed Ph+ CML-CP patients ^[8]

End point description

Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample.

End point type

Secondary

End point timeframe

by 3, 6, 9, 12, 24, 36, 48, 66 cycles (1 cycle = 28 days)

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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: Percentage of participants
number (confidence interval 95%)
By cycle 3	12.0 (2.5 to 31.2)
By cycle 6	52.0 (31.3 to 72.2)
By cycle 9	56.0 (34.9 to 75.6)
By cycle 12	64.0 (42.5 to 82.0)
By cycle 18	68.0 (46.5 to 85.1)
By cycle 24	68.0 (46.5 to 85.1)
By cycle 36	76.0 (54.9 to 90.6)
By cycle 48	76.0 (54.9 to 90.6)
By cycle 66	76.0 (54.9 to 90.6)

No statistical analyses for this end point

Secondary: Best BCR-ABL ratio categories for resistant/intolerant Ph+ CML - overall

Top of page

End point title

Best BCR-ABL ratio categories for resistant/intolerant Ph+ CML - overall ^[9]

End point description

MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL ratio by percentage: > 0.0032 to ≤ 0.01% is equal to a log reduction category of >= 4 to <4.5 -log reduction (MR4); BCR-ABL ratio by percentage: <=0.0032% is equal to a log reduction category of >= 4.5-log reduction (MMR4.5)

End point type

Secondary

End point timeframe

up to 66 cycles (1 cycle = 28 days)

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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	33
Units: Percentage of participants
number (not applicable)
<=0.0032%	12.1
> 0.0032% - ≤ 0.01%	15.2
>0.01% - ≤ 0.1%	33.3
>0.1% - ≤ 1%	21.2
>1% - ≤ 10%	9.1
> 10%	6.1
Atypical transcripts at baseline	3.0

No statistical analyses for this end point

Secondary: Best BCR-ABL ratio categories for newly diagnosed Ph+ CML-CP - Overall

Top of page

End point title

Best BCR-ABL ratio categories for newly diagnosed Ph+ CML-CP - Overall ^[10]

End point description

MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL ratio by percentage: > 0.0032 to ≤ 0.01% is equal to a log reduction category of >= 4 to <4.5 -log reduction (MR4); BCR-ABL ratio by percentage: <=0.0032% is equal to a log reduction category of >= 4.5-log reduction (MMR4.5)

End point type

Secondary

End point timeframe

up to 66 cycles (1 cycle = 28 days)

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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: Percentage of participants
number (not applicable)
≤ 0.0032%	44.0
>0.0032% - ≤ 0.01%	12.0
>0.01% - ≤ 0.1%	20.0
>0.1% - ≤ 1%	8.0
>1% - ≤ 10%	8.0
>10%	8.0

No statistical analyses for this end point

Secondary: Time to first MMR among imatinib or dasatinib resistant or intolerant CML-CP patients who achieved MMR

Top of page

End point title

Time to first MMR among imatinib or dasatinib resistant or intolerant CML-CP patients who achieved MMR ^[11]

End point description

Time from first study drug intake to first MMR amongst imatinib or dasatinib resistant or intolerant patients with CML-CP computed only for patients who achieved MMR.

End point type

Secondary

End point timeframe

From first dosing to the first MMR within 66 cycles period

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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	20
Units: months
median (confidence interval 95%)	2.79 (0.03 to 5.75)

No statistical analyses for this end point

Secondary: Time to first MMR among newly diagnosed Ph+ CML-CP patients who achieved MMR

Top of page

End point title

Time to first MMR among newly diagnosed Ph+ CML-CP patients who achieved MMR ^[12]

End point description

Time to MMR is the time from first study drug intake to first major molecular response computed only for participants who achieved MMR.

End point type

Secondary

End point timeframe

From first dosing to the first MMR within 66 cycles period

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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	19
Units: Months
median (confidence interval 95%)	5.59 (5.52 to 10.84)

No statistical analyses for this end point

Secondary: Duration of first MMR among patients who were resistant or intolerant to either imatinib or dasatinib who achieved MMR

Top of page

End point title

Duration of first MMR among patients who were resistant or intolerant to either imatinib or dasatinib who achieved MMR ^[13]

End point description

Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date.

End point type

Secondary

End point timeframe

from MMR until confirmed loss of MMR (Assessed up to 66 cycles)

Notes
[13] - 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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	20
Units: months
median (confidence interval 95%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Duration of first MMR among newly diagnosed patients who achieved MMR

Top of page

End point title

Duration of first MMR among newly diagnosed patients who achieved MMR ^[14]

End point description

End point type

Secondary

End point timeframe

from MMR until confirmed loss of MMR (Assessed up to 66 cycles)es)

Notes
[14] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	19
Units: months
median (confidence interval 95%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Best Complete Cytogenetic Response (CCyR) categories in Ph+ CML-CP patients resistant or intolerant to imatinib or dasatinib - overall

Top of page

End point title

Best Complete Cytogenetic Response (CCyR) categories in Ph+ CML-CP patients resistant or intolerant to imatinib or dasatinib - overall ^[15]

End point description

• Complete cytogenetic response (CCyR) - 0% Ph+ metaphases • Partial cytogenetic response (PCyR) - >0 to 35% Ph+ metaphases • Minor cytogenetic response (mCyR) - >35 to 65% Ph+ metaphases • Minimal - >65 to 95% Ph+ metaphases • None - >95 to 100% Ph+ metaphases • Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

End point type

Secondary

End point timeframe

up to 66 cycles

Notes
[15] - 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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	33
Units: Percentage of participants
number (not applicable)
Major cytogenetic response: Complete	81.1
Major cytogenetic response: Partial	3.0
Minimal	3.0
None	3.0
Missing	9.1

No statistical analyses for this end point

Secondary: Best Complete Cytogenetic Response (CCyR) in newly diagnosed Ph+ CML-CP patients - Overall

Top of page

End point title

Best Complete Cytogenetic Response (CCyR) in newly diagnosed Ph+ CML-CP patients - Overall ^[16]

End point description

Complete cytogenetic response (CCyR) - 0% Ph+ metaphases No response - >95 to 100% Ph+ metaphases

End point type

Secondary

End point timeframe

up to 66 cycles

Notes
[16] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: Percentage of participants
number (confidence interval 95%)	84.0 (63.9 to 95.5)

No statistical analyses for this end point

Secondary: Summary of time to first complete cytogenic response (CCyR) in newly diagnosed Ph+ CML-CP patients

Top of page

End point title

Summary of time to first complete cytogenic response (CCyR) in newly diagnosed Ph+ CML-CP patients ^[17]

End point description

Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

End point type

Secondary

End point timeframe

From first dosing to the first CCyR up to 66 cycles

Notes
[17] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: months
median (confidence interval 95%)	5.55 (5.49 to 5.59)

No statistical analyses for this end point

Secondary: Kaplan-Meier estimates of time to first complete cytogenic response (CCyR) in newly diagnosed Ph+ CML-CP patients

Top of page

End point title

Kaplan-Meier estimates of time to first complete cytogenic response (CCyR) in newly diagnosed Ph+ CML-CP patients ^[18]

End point description

Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

End point type

Secondary

End point timeframe

From first dosing to the first CCyR up to 66 cycles

Notes
[18] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: months
median (confidence interval 95%)	5.6 (5.5 to 5.6)

No statistical analyses for this end point

Secondary: Kaplan-Meier estimates of duration of first complete cytogenic response (CCyR) among patients who achieved CCyR in newly diagnosed Ph+ CML-CP patients

Top of page

End point title

Kaplan-Meier estimates of duration of first complete cytogenic response (CCyR) among patients who achieved CCyR in newly diagnosed Ph+ CML-CP patients ^[19]

End point description

Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

End point type

Secondary

End point timeframe

From CCyR to loss of CCyR up to 66 cycles

Notes
[19] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	21
Units: months
median (confidence interval 95%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Best major cytogenetic response (MCyR) rate by time point in Newly diagnosed Ph+ CML patients

Top of page

End point title

Best major cytogenetic response (MCyR) rate by time point in Newly diagnosed Ph+ CML patients ^[20]

End point description

Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

End point type

Secondary

End point timeframe

6, 12, 18, 24, 36, 48, 66 cycles

Notes
[20] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: Percentage of participants
number (confidence interval 95%)
by cycle 6	88.0 (68.8 to 97.5)
by cycle 12	88.0 (68.8 to 97.5)
by cycle 18	88.0 (68.8 to 97.5)
by cycle 24	88.0 (68.8 to 97.5)
by cycle 36	88.0 (68.8 to 97.5)
by cycle 48	88.0 (68.8 to 97.5)
by cycle 66	88.0 (68.8 to 97.5)

No statistical analyses for this end point

Secondary: Summary of time to first major cytogenetic response (MCyR) among patients who achieved MCyR in newly diagnosed CML-CP patients

Top of page

End point title

Summary of time to first major cytogenetic response (MCyR) among patients who achieved MCyR in newly diagnosed CML-CP patients ^[21]

End point description

Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

End point type

Secondary

End point timeframe

up to 66 cycles

Notes
[21] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	22
Units: months
median (confidence interval 95%)	5.55 (5.52 to 5.59)

No statistical analyses for this end point

Secondary: Kaplan-Meier estimates of time to first major cytogenetic response (MCyR) in newly diagnosed CML-CP patients

Top of page

End point title

Kaplan-Meier estimates of time to first major cytogenetic response (MCyR) in newly diagnosed CML-CP patients ^[22]

End point description

Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

End point type

Secondary

End point timeframe

up to 66 cycles

Notes
[22] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: months
median (confidence interval 95%)	5.55 (5.52 to 5.59)

No statistical analyses for this end point

Secondary: Best Complete Hematological Response (CHR) by time point

Top of page

End point title

Best Complete Hematological Response (CHR) by time point ^[23]

End point description

Complete Hematological Response (CHR) was defined as • WBC count <10×109/L • platelet count <450×109/L • basophils <5% • no blasts and promyelocytes in peripheral blood • myelocytes+metamyelocytes <5% in peripheral blood • no evidence of extramedullary disease, including spleen and liver • Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP

End point type

Secondary

End point timeframe

cycle 3, 6, 9, 12, 18, 24, 36, 48, 66

Notes
[23] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: Percentage of participants
number (confidence interval 95%)
by cycle 3	76.0 (54.9 to 90.6)
by cycle 6	84.0 (63.9 to 95.5)
by cycle 9	88.0 (68.8 to 97.5)
by cycle 12	92.0 (74.0 to 99.0)
by cycle 18	92.0 (74.0 to 99.0)
by cycle 24	92.0 (74.0 to 99.0)
by cycle 36	92.0 (74.0 to 99.0)
by cycle 48	92.0 (74.0 to 99.0)
by cycle 66	92.0 (74.0 to 99.0)

No statistical analyses for this end point

Secondary: Summary of time to first Complete Hematological Response (CHR) among patients who achieved confirmed CHR in newly diagnosed CML-CP patients

Top of page

End point title

Summary of time to first Complete Hematological Response (CHR) among patients who achieved confirmed CHR in newly diagnosed CML-CP patients ^[24]

End point description

End point type

Secondary

End point timeframe

from first dosing to CHR, UP TO 66 CYCLES

Notes
[24] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	23
Units: months
median (confidence interval 95%)	0.95 (0.72 to 2.76)

No statistical analyses for this end point

Secondary: Kaplan-Meier estimates of time to first Complete Hematological Response (CHR) in newly diagnosed CML-CP patients

Top of page

End point title

Kaplan-Meier estimates of time to first Complete Hematological Response (CHR) in newly diagnosed CML-CP patients ^[25]

End point description

End point type

Secondary

End point timeframe

from first dosing to CHR, UP TO 66 CYCLES

Notes
[25] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: months
median (confidence interval 95%)	1.0 (1.0 to 2.8)

No statistical analyses for this end point

Secondary: Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier estimates

Top of page

End point title

Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier estimates ^[26]

End point description

Time to disease progression is the time from the date of first study drug intake to the date of event defined as the first progression to AP or BC (from CP) or to BC (from AP) or the date of CML-related death occurring on treatment, whichever was earlier.

End point type

Secondary

End point timeframe

From first dosing to the disease progression within 66 cycles

Notes
[26] - 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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	33
Units: months
median (confidence interval 95%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Event Free Survival in imatinib/dasatinib resistant/intolerant CML-CP patients

Top of page

End point title

Event Free Survival in imatinib/dasatinib resistant/intolerant CML-CP patients ^[27]

End point description

Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment)

End point type

Secondary

End point timeframe

From first dosing to the disease progression or death up to 66 cycles

Notes
[27] - 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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	33
Units: months
median (confidence interval 95%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Event Free Survival in newly diagnosed CML-CP patients

Top of page

End point title

Event Free Survival in newly diagnosed CML-CP patients ^[28]

End point description

End point type

Secondary

End point timeframe

From first dosing to the disease progression or death up to 66 cycles

Notes
[28] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: months
median (confidence interval 95%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Overall survival (OS) in Imatinib/dasatinib resistant/intolerant CML-CP - Kaplan-Meier estimates

Top of page

End point title

Overall survival (OS) in Imatinib/dasatinib resistant/intolerant CML-CP - Kaplan-Meier estimates ^[29]

End point description

Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up.

End point type

Secondary

End point timeframe

from first dosing to death up to 66 cycles

Notes
[29] - 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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	33
Units: months
median (confidence interval 95%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Overall survival (OS) in newly diagnosed CML-CP patients

Top of page

End point title

Overall survival (OS) in newly diagnosed CML-CP patients ^[30]

End point description

End point type

Secondary

End point timeframe

from first dosing to death up to 66 cycles

Notes
[30] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: months
median (confidence interval 95%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Pharmacodynamics (BCR-ABL transcript levels determined with standard protocols in peripheral blood): best MMR status by cycle

Top of page

End point title

Pharmacodynamics (BCR-ABL transcript levels determined with standard protocols in peripheral blood): best MMR status by cycle

End point description

BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL transcript levels were summarized by cohort and time point. MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR.

End point type

Secondary

End point timeframe

By 3, 6, 9, 12, 18, 24, 36, 48, 66 cycles

End point values	Resistant/intolerant Ph+ CML in CP	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	33	25
Units: Percentage of participants
number (confidence interval 95%)
By Cycle 3	36.4 (20.4 to 54.9)	12.0 (2.5 to 31.2)
By Cycle 6	45.5 (28.1 to 63.6)	52.0 (31.3 to 72.2)
By Cycle 9	51.5 (33.5 to 69.2)	56.0 (34.9 to 75.6)
By Cycle 12	57.6 (39.2 to 74.5)	64.0 (42.5 to 82.0)
By Cycle 18	57.6 (39.2 to 74.5)	68.0 (46.5 to 85.1)
By Cycle 24	57.6 (39.2 to 74.5)	68.0 (46.5 to 85.1)
By Cycle 36	57.6 (39.2 to 74.5)	76.0 (54.9 to 90.6)
By Cycle 48	60.6 (42.1 to 77.1)	76.0 (54.9 to 90.6)
By Cycle 66	60.6 (42.1 to 77.1)	76.0 (54.9 to 90.6)

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK): Steady state concentration of nilotinib in Imatinib/dasatinib resistant/intolerant CML-CP patients

Top of page

End point title

Pharmacokinetics (PK): Steady state concentration of nilotinib in Imatinib/dasatinib resistant/intolerant CML-CP patients ^[31]

End point description

PK was analyzed only when all patients has completed 12 cycles on treatment or discontinued the study treatment early.

End point type

Secondary

End point timeframe

Cycle 1 Day 8

Notes
[31] - 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: No Statistics were analyzed for this endpoint.

End point values	Resistant/intolerant Ph+ CML in CP
Number of subjects analysed	30
Units: ng/mL
geometric mean (geometric coefficient of variation)	1407.89 ( 41.67 )

No statistical analyses for this end point

Secondary: Pharmacokinetics: Steady state concentration of nilotinib in newly diagnosed CML-CP patients

Top of page

End point title

Pharmacokinetics: Steady state concentration of nilotinib in newly diagnosed CML-CP patients ^[32]

End point description

PK was analyzed only when all patients has completed 12 cycles of treatment or discontinued the study treatment early.

End point type

Secondary

End point timeframe

Cycle 1 Day 8

Notes
[32] - 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: No Statistics were analyzed for this endpoint.

End point values	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	25
Units: ng/mL
geometric mean (geometric coefficient of variation)	1274.30 ( 46.21 )

No statistical analyses for this end point

Secondary: Growth Data: Abnormal height Standard deviation scores (SDS) changes by cohort

Top of page

End point title

Growth Data: Abnormal height Standard deviation scores (SDS) changes by cohort

End point description

To assess long term effect on growth, development and maturation of nilotinib treatment in pediatric patients with Ph+ CML in participants with both a baseline and post-baseline value.

End point type

Secondary

End point timeframe

from first dosing to 66 cycles

End point values	Resistant/intolerant Ph+ CML in CP	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	32	24
Units: Percentage of participants
number (not applicable)
Decrease from baseline of 1 SDS category	27.3	32.0
Decrease from baseline of 2 SDS categories	3.0	16.0
Decrease from baseline of 3 SDS categories	6.1	4.0

No statistical analyses for this end point

Secondary: Acceptability (including palatability) of dose forms used after first dose, cycle 1 and cycle 12 study drug formulation

Top of page

End point title

Acceptability (including palatability) of dose forms used after first dose, cycle 1 and cycle 12 study drug formulation

End point description

Acceptability of the study drug was evaluated from a questionnaire completed by patients, with the help from parents or caregivers at visits. The Questionnaire to capture patient assessment of palatability (very good to very bad) and acceptability of taking the medication (very easy to very hard to administration).

End point type

Secondary

End point timeframe

up to Cycle 12

End point values	All patients
Number of subjects analysed	58
Units: Percentage of participants
number (not applicable)
Cycle(C)1 Day(D)1:Completed questionnaire-Patients	75.9
C1D1:Completed questionnaire -Parents/Caregivers	22.4
C1D1: Patients who swallowed capsule whole	91.4
C1D1: Patients had capsule mixed with apple sauce	6.9
C1D1:Pts reported no taste/unable to answer quest.	43.1
C1D1:Patients reported taste as good/very good	12.1
C1D1:Patients reported taste as not good/not bad	34.5
C1D1:Reported capsule to be v. easy/easy to admin	79.3
C1D28: Completed questionnaire - Patients	55.2
C1D28:Completed questionnaire-Parents/Caregivers	22.4
C12D28: Completed questionnaire - Patients	55.2
C12D28:Completed questionnaire-Parents/Caregivers	22.4

No statistical analyses for this end point

Secondary: Mutational assessment of BCR-ABL

Top of page

End point title

Mutational assessment of BCR-ABL

End point description

Emerging signs of resistance to nilotinib

End point type

Secondary

End point timeframe

up to 66 cycles

End point values	Resistant/intolerant Ph+ CML in CP	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	33	25
Units: Percentage of participants
number (not applicable)
Pts. with >=1 eval. post-BL mutational analysis	39.4	32.0
Patients with any emergent mutation on treatment	0.0	0.0
Pts with multiple emergent mutations on treatment	0.0	0.0

No statistical analyses for this end point

Other pre-specified: Long term effect of nilotinib on bone metabolism

Top of page

End point title

Long term effect of nilotinib on bone metabolism

End point description

The summary of bone age and Dual-energy X-ray absorptiometry (DEXA) by cohort. Alteration of bone biochemical markers of hand and wrist X-Ray evaluation was observed in bone age standard deviation scores (SDS) and for bone mineral density for DEXA before and after treatment with nilotinib.

End point type

Other pre-specified

End point timeframe

Cycle 66

End point values	Resistant/intolerant Ph+ CML in CP	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	33	25
Units: Percentage of participants
arithmetic mean (standard deviation)
X-ray	-0.61 ( 1.703 )	999 ( 999 )
DEXA	-0.35 ( 1.243 )	-0.70 ( 1.043 )

No statistical analyses for this end point

Post-hoc: All Collected Deaths

Top of page

End point title

All Collected Deaths

End point description

On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 64.5 months (treatment duration ranged from 0.7 to 63.5 months). Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 7 years.

End point type

Post-hoc

End point timeframe

approx. 64.5 month, approx. 7 years

End point values	Resistant/intolerant Ph+ CML in CP	Newly diagnosed and untreated Ph+ CML in first CP
Number of subjects analysed	33	25
Units: Participants
On-treatment deaths	0	0
Total Deaths	1	3

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 64.5 months. Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 7 years.

Adverse event reporting additional description

Adverse Event: Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Resistant/intolerant Ph+ CML in CP

Reporting group description

Patients resistant or intolerant to either imatinib or dasatinib

Reporting group title

Newly diagnosed and untreated Ph+ CML in first CP

Reporting group description

Reporting group title

All Patients

Reporting group description

All of the patients enrolled in the study.

Serious adverse events	Resistant/intolerant Ph+ CML in CP	Newly diagnosed and untreated Ph+ CML in first CP	All Patients
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 33 (33.33%)	4 / 25 (16.00%)	15 / 58 (25.86%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Vascular disorders
Hyperaemia
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	2 / 33 (6.06%)	0 / 25 (0.00%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 33 (0.00%)	1 / 25 (4.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 33 (0.00%)	1 / 25 (4.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Muscle strain
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Facial paralysis
subjects affected / exposed	0 / 33 (0.00%)	1 / 25 (4.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 33 (0.00%)	1 / 25 (4.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 33 (0.00%)	1 / 25 (4.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 33 (0.00%)	1 / 25 (4.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 33 (0.00%)	1 / 25 (4.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoids thrombosed
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toothache
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatomegaly
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 33 (0.00%)	1 / 25 (4.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 33 (0.00%)	1 / 25 (4.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Growth hormone deficiency
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone swelling
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaw cyst
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 33 (3.03%)	1 / 25 (4.00%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaria
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 33 (3.03%)	1 / 25 (4.00%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 33 (3.03%)	0 / 25 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
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	Resistant/intolerant Ph+ CML in CP	Newly diagnosed and untreated Ph+ CML in first CP	All Patients
Total subjects affected by non serious adverse events
subjects affected / exposed	33 / 33 (100.00%)	25 / 25 (100.00%)	58 / 58 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	3 / 33 (9.09%)	2 / 25 (8.00%)	5 / 58 (8.62%)
occurrences all number	4	2	6
Hypotension
subjects affected / exposed	3 / 33 (9.09%)	1 / 25 (4.00%)	4 / 58 (6.90%)
occurrences all number	5	1	6
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 33 (3.03%)	2 / 25 (8.00%)	3 / 58 (5.17%)
occurrences all number	2	3	5
Fatigue
subjects affected / exposed	0 / 33 (0.00%)	6 / 25 (24.00%)	6 / 58 (10.34%)
occurrences all number	0	11	11
Malaise
subjects affected / exposed	2 / 33 (6.06%)	1 / 25 (4.00%)	3 / 58 (5.17%)
occurrences all number	2	2	4
Non-cardiac chest pain
subjects affected / exposed	1 / 33 (3.03%)	3 / 25 (12.00%)	4 / 58 (6.90%)
occurrences all number	1	4	5
Pyrexia
subjects affected / exposed	11 / 33 (33.33%)	9 / 25 (36.00%)	20 / 58 (34.48%)
occurrences all number	18	13	31
Immune system disorders
Seasonal allergy
subjects affected / exposed	2 / 33 (6.06%)	1 / 25 (4.00%)	3 / 58 (5.17%)
occurrences all number	3	1	4
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	1 / 33 (3.03%)	3 / 25 (12.00%)	4 / 58 (6.90%)
occurrences all number	2	3	5
Gynaecomastia
subjects affected / exposed	2 / 33 (6.06%)	2 / 25 (8.00%)	4 / 58 (6.90%)
occurrences all number	2	2	4
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 33 (9.09%)	7 / 25 (28.00%)	10 / 58 (17.24%)
occurrences all number	5	10	15
Dyspnoea
subjects affected / exposed	1 / 33 (3.03%)	3 / 25 (12.00%)	4 / 58 (6.90%)
occurrences all number	1	3	4
Nasal congestion
subjects affected / exposed	3 / 33 (9.09%)	1 / 25 (4.00%)	4 / 58 (6.90%)
occurrences all number	7	2	9
Oropharyngeal pain
subjects affected / exposed	7 / 33 (21.21%)	2 / 25 (8.00%)	9 / 58 (15.52%)
occurrences all number	8	3	11
Rhinitis allergic
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	3	3
Rhinorrhoea
subjects affected / exposed	2 / 33 (6.06%)	3 / 25 (12.00%)	5 / 58 (8.62%)
occurrences all number	2	4	6
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 33 (3.03%)	2 / 25 (8.00%)	3 / 58 (5.17%)
occurrences all number	1	2	3
Investigations
Alanine aminotransferase increased
subjects affected / exposed	10 / 33 (30.30%)	11 / 25 (44.00%)	21 / 58 (36.21%)
occurrences all number	18	22	40
Amylase increased
subjects affected / exposed	3 / 33 (9.09%)	0 / 25 (0.00%)	3 / 58 (5.17%)
occurrences all number	5	0	5
Aspartate aminotransferase increased
subjects affected / exposed	8 / 33 (24.24%)	9 / 25 (36.00%)	17 / 58 (29.31%)
occurrences all number	11	20	31
Blood bilirubin increased
subjects affected / exposed	12 / 33 (36.36%)	10 / 25 (40.00%)	22 / 58 (37.93%)
occurrences all number	24	17	41
Blood cholesterol increased
subjects affected / exposed	2 / 33 (6.06%)	2 / 25 (8.00%)	4 / 58 (6.90%)
occurrences all number	2	3	5
Blood creatine phosphokinase increased
subjects affected / exposed	3 / 33 (9.09%)	0 / 25 (0.00%)	3 / 58 (5.17%)
occurrences all number	5	0	5
Blood creatinine increased
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Blood glucose increased
subjects affected / exposed	2 / 33 (6.06%)	1 / 25 (4.00%)	3 / 58 (5.17%)
occurrences all number	2	2	4
Blood triglycerides increased
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Electrocardiogram QT prolonged
subjects affected / exposed	5 / 33 (15.15%)	1 / 25 (4.00%)	6 / 58 (10.34%)
occurrences all number	6	1	7
Gamma-glutamyltransferase increased
subjects affected / exposed	4 / 33 (12.12%)	1 / 25 (4.00%)	5 / 58 (8.62%)
occurrences all number	5	2	7
Lipase increased
subjects affected / exposed	3 / 33 (9.09%)	1 / 25 (4.00%)	4 / 58 (6.90%)
occurrences all number	6	1	7
Neutrophil count decreased
subjects affected / exposed	2 / 33 (6.06%)	3 / 25 (12.00%)	5 / 58 (8.62%)
occurrences all number	2	4	6
Platelet count decreased
subjects affected / exposed	0 / 33 (0.00%)	5 / 25 (20.00%)	5 / 58 (8.62%)
occurrences all number	0	10	10
Weight decreased
subjects affected / exposed	2 / 33 (6.06%)	3 / 25 (12.00%)	5 / 58 (8.62%)
occurrences all number	2	3	5
Weight increased
subjects affected / exposed	1 / 33 (3.03%)	3 / 25 (12.00%)	4 / 58 (6.90%)
occurrences all number	1	3	4
Injury, poisoning and procedural complications
Arthropod sting
subjects affected / exposed	2 / 33 (6.06%)	0 / 25 (0.00%)	2 / 58 (3.45%)
occurrences all number	2	0	2
Fall
subjects affected / exposed	2 / 33 (6.06%)	0 / 25 (0.00%)	2 / 58 (3.45%)
occurrences all number	3	0	3
Joint injury
subjects affected / exposed	2 / 33 (6.06%)	0 / 25 (0.00%)	2 / 58 (3.45%)
occurrences all number	2	0	2
Ligament sprain
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Procedural pain
subjects affected / exposed	3 / 33 (9.09%)	1 / 25 (4.00%)	4 / 58 (6.90%)
occurrences all number	3	1	4
Congenital, familial and genetic disorders
Gilbert's syndrome
subjects affected / exposed	1 / 33 (3.03%)	2 / 25 (8.00%)	3 / 58 (5.17%)
occurrences all number	1	2	3
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 33 (3.03%)	3 / 25 (12.00%)	4 / 58 (6.90%)
occurrences all number	1	4	5
Headache
subjects affected / exposed	13 / 33 (39.39%)	14 / 25 (56.00%)	27 / 58 (46.55%)
occurrences all number	20	57	77
Hypoaesthesia
subjects affected / exposed	2 / 33 (6.06%)	0 / 25 (0.00%)	2 / 58 (3.45%)
occurrences all number	2	0	2
Paraesthesia
subjects affected / exposed	2 / 33 (6.06%)	2 / 25 (8.00%)	4 / 58 (6.90%)
occurrences all number	4	3	7
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 33 (12.12%)	3 / 25 (12.00%)	7 / 58 (12.07%)
occurrences all number	5	4	9
Leukopenia
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Neutropenia
subjects affected / exposed	1 / 33 (3.03%)	2 / 25 (8.00%)	3 / 58 (5.17%)
occurrences all number	1	9	10
Thrombocytopenia
subjects affected / exposed	1 / 33 (3.03%)	3 / 25 (12.00%)	4 / 58 (6.90%)
occurrences all number	1	6	7
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 33 (3.03%)	2 / 25 (8.00%)	3 / 58 (5.17%)
occurrences all number	1	2	3
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Ocular hyperaemia
subjects affected / exposed	1 / 33 (3.03%)	3 / 25 (12.00%)	4 / 58 (6.90%)
occurrences all number	1	4	5
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 33 (9.09%)	6 / 25 (24.00%)	9 / 58 (15.52%)
occurrences all number	3	7	10
Abdominal pain upper
subjects affected / exposed	1 / 33 (3.03%)	3 / 25 (12.00%)	4 / 58 (6.90%)
occurrences all number	1	4	5
Constipation
subjects affected / exposed	1 / 33 (3.03%)	2 / 25 (8.00%)	3 / 58 (5.17%)
occurrences all number	1	4	5
Dental caries
subjects affected / exposed	3 / 33 (9.09%)	0 / 25 (0.00%)	3 / 58 (5.17%)
occurrences all number	4	0	4
Diarrhoea
subjects affected / exposed	7 / 33 (21.21%)	4 / 25 (16.00%)	11 / 58 (18.97%)
occurrences all number	7	4	11
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	3	3
Nausea
subjects affected / exposed	8 / 33 (24.24%)	10 / 25 (40.00%)	18 / 58 (31.03%)
occurrences all number	8	13	21
Odynophagia
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Vomiting
subjects affected / exposed	7 / 33 (21.21%)	8 / 25 (32.00%)	15 / 58 (25.86%)
occurrences all number	8	12	20
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	4 / 33 (12.12%)	8 / 25 (32.00%)	12 / 58 (20.69%)
occurrences all number	14	26	40
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	4 / 33 (12.12%)	4 / 25 (16.00%)	8 / 58 (13.79%)
occurrences all number	5	4	9
Alopecia
subjects affected / exposed	4 / 33 (12.12%)	2 / 25 (8.00%)	6 / 58 (10.34%)
occurrences all number	4	3	7
Dermatitis
subjects affected / exposed	4 / 33 (12.12%)	2 / 25 (8.00%)	6 / 58 (10.34%)
occurrences all number	4	4	8
Dry skin
subjects affected / exposed	3 / 33 (9.09%)	0 / 25 (0.00%)	3 / 58 (5.17%)
occurrences all number	3	0	3
Erythema
subjects affected / exposed	4 / 33 (12.12%)	4 / 25 (16.00%)	8 / 58 (13.79%)
occurrences all number	4	5	9
Keratosis pilaris
subjects affected / exposed	2 / 33 (6.06%)	0 / 25 (0.00%)	2 / 58 (3.45%)
occurrences all number	2	0	2
Madarosis
subjects affected / exposed	2 / 33 (6.06%)	0 / 25 (0.00%)	2 / 58 (3.45%)
occurrences all number	2	0	2
Pruritus
subjects affected / exposed	0 / 33 (0.00%)	3 / 25 (12.00%)	3 / 58 (5.17%)
occurrences all number	0	10	10
Rash
subjects affected / exposed	7 / 33 (21.21%)	11 / 25 (44.00%)	18 / 58 (31.03%)
occurrences all number	12	16	28
Rash maculo-papular
subjects affected / exposed	5 / 33 (15.15%)	3 / 25 (12.00%)	8 / 58 (13.79%)
occurrences all number	16	5	21
Rash papular
subjects affected / exposed	2 / 33 (6.06%)	1 / 25 (4.00%)	3 / 58 (5.17%)
occurrences all number	8	1	9
Urticaria
subjects affected / exposed	3 / 33 (9.09%)	1 / 25 (4.00%)	4 / 58 (6.90%)
occurrences all number	3	2	5
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	5 / 33 (15.15%)	4 / 25 (16.00%)	9 / 58 (15.52%)
occurrences all number	7	5	12
Back pain
subjects affected / exposed	3 / 33 (9.09%)	2 / 25 (8.00%)	5 / 58 (8.62%)
occurrences all number	3	2	5
Bone pain
subjects affected / exposed	1 / 33 (3.03%)	2 / 25 (8.00%)	3 / 58 (5.17%)
occurrences all number	2	2	4
Muscular weakness
subjects affected / exposed	1 / 33 (3.03%)	2 / 25 (8.00%)	3 / 58 (5.17%)
occurrences all number	1	2	3
Musculoskeletal pain
subjects affected / exposed	2 / 33 (6.06%)	1 / 25 (4.00%)	3 / 58 (5.17%)
occurrences all number	2	2	4
Myalgia
subjects affected / exposed	3 / 33 (9.09%)	4 / 25 (16.00%)	7 / 58 (12.07%)
occurrences all number	4	12	16
Pain in extremity
subjects affected / exposed	9 / 33 (27.27%)	7 / 25 (28.00%)	16 / 58 (27.59%)
occurrences all number	9	9	18
Infections and infestations
Conjunctivitis
subjects affected / exposed	3 / 33 (9.09%)	0 / 25 (0.00%)	3 / 58 (5.17%)
occurrences all number	3	0	3
Cystitis
subjects affected / exposed	2 / 33 (6.06%)	0 / 25 (0.00%)	2 / 58 (3.45%)
occurrences all number	2	0	2
Ear infection
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Gastroenteritis
subjects affected / exposed	0 / 33 (0.00%)	6 / 25 (24.00%)	6 / 58 (10.34%)
occurrences all number	0	11	11
Influenza
subjects affected / exposed	4 / 33 (12.12%)	2 / 25 (8.00%)	6 / 58 (10.34%)
occurrences all number	7	2	9
Nasopharyngitis
subjects affected / exposed	5 / 33 (15.15%)	7 / 25 (28.00%)	12 / 58 (20.69%)
occurrences all number	15	15	30
Otitis media acute
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Parotitis
subjects affected / exposed	2 / 33 (6.06%)	1 / 25 (4.00%)	3 / 58 (5.17%)
occurrences all number	2	1	3
Pharyngitis
subjects affected / exposed	3 / 33 (9.09%)	3 / 25 (12.00%)	6 / 58 (10.34%)
occurrences all number	4	4	8
Rhinitis
subjects affected / exposed	4 / 33 (12.12%)	4 / 25 (16.00%)	8 / 58 (13.79%)
occurrences all number	9	4	13
Upper respiratory tract infection
subjects affected / exposed	10 / 33 (30.30%)	7 / 25 (28.00%)	17 / 58 (29.31%)
occurrences all number	18	9	27
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	5 / 33 (15.15%)	1 / 25 (4.00%)	6 / 58 (10.34%)
occurrences all number	5	1	6
Hyperuricaemia
subjects affected / exposed	0 / 33 (0.00%)	2 / 25 (8.00%)	2 / 58 (3.45%)
occurrences all number	0	2	2
Vitamin D deficiency
subjects affected / exposed	2 / 33 (6.06%)	1 / 25 (4.00%)	3 / 58 (5.17%)
occurrences all number	2	1	3

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

15 Sep 2014

To fulfill the EMA PDCO agreement for the assessment of potential long-term safety & efficacy issues in relation to pediatric nilotinib use, the study duration was extended from 24 to 66 Cycles. To revise the primary efficacy endpoint as recommended by the FDA. For Cohort 1, “Rate of major cytogenetic response (MCyR) by 12 months” was revised to “Rate of MCyR at 6 Cycles” & for Cohort 3, “Rate of MCyR by 12 months” was revised to “Rate of complete cytogenetic response (CCyR) at 12 cycles”. To add event free survival as a new secondary endpoint, 2 sensitivity analyses for disease progression, collection of additional bio pecimens from patients participating on the clinical study for future research studies (Children’s Oncology Group’s sites only), pre- & post-dose ECG measurements throughout the study in order to provide additional safety information in regards to nilotinib’s effect on QT prolongation. To describe in more detail the censoring method for K-M analyses of duration of response, time to progression, overall survival & event free survival. To clarify cholesterol testing during the conduct of the study, assessment of blood glucose at baseline & during the conduct of this study, patient inclusion/exclusion criteria, study treatment dosing & pregnancy testing; to incorporate feedback received from Investigators during study start-up; to harmonize dose reductions guidelines of nilotinib across Novartis-sponsored Tasigna study protocols & to update dose reduction guidelines for cardiac QT, ischemic vascular or cardiovascular events. To incorporate precautions on the use for antacid drugs in alignment with the Tasigna Prescribing Information & EU SmPC & to incorporate guidance for the management of increases of serum cholesterol & blood glucose, as well as other cardiac risk factors, ischemic vascular or ischemic cardiovascular events and also to further define ischemic vascular and ischemic cardiovascular events as AESI, including their reporting modalities.

04 May 2015

The main purpose of this amendment was to adjust the minimum total sample size, as well as the minimum sample size of the newly diagnosed Ph+ CML-CP (Cohort 3), to reflect the agreements with the US FDA and the EMA PDCO and the updated feasibility assessment in view of the very low incidence of Ph+ CML in the pediatric population and the actual study accrual rates, and to enable timely availability of information in this population. The original study enrollment target was planned for a minimum of 65 total patients of which at least 50 would be Ph+CML newly diagnosed. Based on enrollment forecasts at the time of amendment and regulatory requirements, a reduction in the sample size to at least 50 patients in total with at least 15 newly diagnosed Ph+ CML-CP patients would support a timely completion of the study and timely access of the available information to the medical community. Additional changes in this amendment included confirmation of the dose in the patients aged 1 to <10 for this study as a result of the second interim analysis of study CAMN107A2120 and administrative changes.

08 Feb 2016

The primary endpoint for Cohort 1 was revised to enable an assessment of the impact of therapy in patients with Ph+ CML-CP resistant or intolerant to either imatinib or dasatinib. The rationale for this change was that as part of routine study monitoring, it was observed that a significant number of patients enrolling in this Cohort were already in MCyR or CCyR at baseline. This finding was also consistent with findings from a recently published study (Zwaan et al 2013). The protocol was additionally amended, to remove the binary endpoints related to CHR, MCyR and CCyR which were no longer appropriate measures to evaluate the therapeutic effect of nilotinib in this patient population. The determination of BCR-ABL molecular response was also clarified.

18 Apr 2016

The primary purpose for the amendment was to include hepatitis B virus testing as one of the study procedures and to identify study patients who might be at risk of hepatitis B virus reactivation.

05 May 2017

The primary purposes for this amendment were to define the discontinuation of development and growth assessments (X-ray of hand and wrist) in the study once skeletal maturity of a patient in post-puberty stage was confirmed by last x-ray and to include HbA1c in the clinical chemistry assessment. The guidance on co-administration of drugs with a “known”, “possible” or “conditional” risk of Torsades de Pointes was updated, and additional discontinuation criteria were added based on the update in Novartis Safety guidance. The definitions for loss of CHR, loss of MMR and disease progression, as well as description of methods for growth and development analyses were clarified. In addition, description of analysis for exploratory objectives were clarified to be based on standard deviation scores (SDS).

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.

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Rate of Major Molecular Response (MMR) at 6 cycles for Ph+ CML CP patients resistant or intolerant to imatinib or dasatinib

Primary: Rate of Major Molecular Response (MMR) at 6 cycles for Ph+ CML CP patients resistant or intolerant to imatinib or dasatinib

Primary: MMR rate by 12 cycles in newly diagnosed Ph+ CML-CP patients

Primary: MMR rate by 12 cycles in newly diagnosed Ph+ CML-CP patients

Primary: Rate of complete cytogenic response (CCyR) at 12 cycles in newly diagnosed Ph+ CML-CP patients

Primary: Rate of complete cytogenic response (CCyR) at 12 cycles in newly diagnosed Ph+ CML-CP patients

Secondary: MMR rate by time points in Ph+ CML-CP patients resistant or intolerant to imatinib or dasatinib

Secondary: MMR rate by time points in Ph+ CML-CP patients resistant or intolerant to imatinib or dasatinib

Secondary: MMR rate by time points in newly diagnosed Ph+ CML-CP patients

Secondary: MMR rate by time points in newly diagnosed Ph+ CML-CP patients

Secondary: Best BCR-ABL ratio categories for resistant/intolerant Ph+ CML - overall

Secondary: Best BCR-ABL ratio categories for resistant/intolerant Ph+ CML - overall

Secondary: Best BCR-ABL ratio categories for newly diagnosed Ph+ CML-CP - Overall

Secondary: Best BCR-ABL ratio categories for newly diagnosed Ph+ CML-CP - Overall

Secondary: Time to first MMR among imatinib or dasatinib resistant or intolerant CML-CP patients who achieved MMR

Secondary: Time to first MMR among imatinib or dasatinib resistant or intolerant CML-CP patients who achieved MMR

Secondary: Time to first MMR among newly diagnosed Ph+ CML-CP patients who achieved MMR

Secondary: Time to first MMR among newly diagnosed Ph+ CML-CP patients who achieved MMR

Secondary: Duration of first MMR among patients who were resistant or intolerant to either imatinib or dasatinib who achieved MMR

Secondary: Duration of first MMR among patients who were resistant or intolerant to either imatinib or dasatinib who achieved MMR

Secondary: Duration of first MMR among newly diagnosed patients who achieved MMR

Secondary: Duration of first MMR among newly diagnosed patients who achieved MMR

Secondary: Best Complete Cytogenetic Response (CCyR) categories in Ph+ CML-CP patients resistant or intolerant to imatinib or dasatinib - overall

Secondary: Best Complete Cytogenetic Response (CCyR) categories in Ph+ CML-CP patients resistant or intolerant to imatinib or dasatinib - overall

Secondary: Best Complete Cytogenetic Response (CCyR) in newly diagnosed Ph+ CML-CP patients - Overall

Secondary: Best Complete Cytogenetic Response (CCyR) in newly diagnosed Ph+ CML-CP patients - Overall

Secondary: Summary of time to first complete cytogenic response (CCyR) in newly diagnosed Ph+ CML-CP patients

Secondary: Summary of time to first complete cytogenic response (CCyR) in newly diagnosed Ph+ CML-CP patients

Secondary: Kaplan-Meier estimates of time to first complete cytogenic response (CCyR) in newly diagnosed Ph+ CML-CP patients

Secondary: Kaplan-Meier estimates of time to first complete cytogenic response (CCyR) in newly diagnosed Ph+ CML-CP patients

Secondary: Kaplan-Meier estimates of duration of first complete cytogenic response (CCyR) among patients who achieved CCyR in newly diagnosed Ph+ CML-CP patients

Secondary: Kaplan-Meier estimates of duration of first complete cytogenic response (CCyR) among patients who achieved CCyR in newly diagnosed Ph+ CML-CP patients

Secondary: Best major cytogenetic response (MCyR) rate by time point in Newly diagnosed Ph+ CML patients

Secondary: Best major cytogenetic response (MCyR) rate by time point in Newly diagnosed Ph+ CML patients

Secondary: Summary of time to first major cytogenetic response (MCyR) among patients who achieved MCyR in newly diagnosed CML-CP patients

Secondary: Summary of time to first major cytogenetic response (MCyR) among patients who achieved MCyR in newly diagnosed CML-CP patients

Secondary: Kaplan-Meier estimates of time to first major cytogenetic response (MCyR) in newly diagnosed CML-CP patients

Secondary: Kaplan-Meier estimates of time to first major cytogenetic response (MCyR) in newly diagnosed CML-CP patients

Secondary: Best Complete Hematological Response (CHR) by time point

Secondary: Best Complete Hematological Response (CHR) by time point

Secondary: Summary of time to first Complete Hematological Response (CHR) among patients who achieved confirmed CHR in newly diagnosed CML-CP patients

Secondary: Summary of time to first Complete Hematological Response (CHR) among patients who achieved confirmed CHR in newly diagnosed CML-CP patients

Secondary: Kaplan-Meier estimates of time to first Complete Hematological Response (CHR) in newly diagnosed CML-CP patients

Secondary: Kaplan-Meier estimates of time to first Complete Hematological Response (CHR) in newly diagnosed CML-CP patients

Secondary: Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier estimates

Secondary: Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier estimates

Secondary: Event Free Survival in imatinib/dasatinib resistant/intolerant CML-CP patients

Secondary: Event Free Survival in imatinib/dasatinib resistant/intolerant CML-CP patients

Secondary: Event Free Survival in newly diagnosed CML-CP patients

Secondary: Event Free Survival in newly diagnosed CML-CP patients

Secondary: Overall survival (OS) in Imatinib/dasatinib resistant/intolerant CML-CP - Kaplan-Meier estimates

Secondary: Overall survival (OS) in Imatinib/dasatinib resistant/intolerant CML-CP - Kaplan-Meier estimates

Secondary: Overall survival (OS) in newly diagnosed CML-CP patients

Secondary: Overall survival (OS) in newly diagnosed CML-CP patients

Secondary: Pharmacodynamics (BCR-ABL transcript levels determined with standard protocols in peripheral blood): best MMR status by cycle

Secondary: Pharmacodynamics (BCR-ABL transcript levels determined with standard protocols in peripheral blood): best MMR status by cycle

Secondary: Pharmacokinetics (PK): Steady state concentration of nilotinib in Imatinib/dasatinib resistant/intolerant CML-CP patients

Secondary: Pharmacokinetics (PK): Steady state concentration of nilotinib in Imatinib/dasatinib resistant/intolerant CML-CP patients

Secondary: Pharmacokinetics: Steady state concentration of nilotinib in newly diagnosed CML-CP patients

Secondary: Pharmacokinetics: Steady state concentration of nilotinib in newly diagnosed CML-CP patients

Secondary: Growth Data: Abnormal height Standard deviation scores (SDS) changes by cohort

Secondary: Growth Data: Abnormal height Standard deviation scores (SDS) changes by cohort

Secondary: Acceptability (including palatability) of dose forms used after first dose, cycle 1 and cycle 12 study drug formulation

Secondary: Acceptability (including palatability) of dose forms used after first dose, cycle 1 and cycle 12 study drug formulation

Secondary: Mutational assessment of BCR-ABL

Secondary: Mutational assessment of BCR-ABL

Other pre-specified: Long term effect of nilotinib on bone metabolism

Other pre-specified: Long term effect of nilotinib on bone metabolism

Post-hoc: All Collected Deaths

Post-hoc: All Collected Deaths

Adverse events