DIALOG: Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01844765
• Collaborator: (none)
• Enrollment: 59
• Locations: 36
• Arms: 3
• Actual Duration (Months): 84.3
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To evaluate the safety, efficacy and pharmacokinetics of nilotinib over time in the Ph+ chronic myelogenous leukemia (CML) in pediatric patients (from 1 to <18 years).

Condition or Disease	Intervention/Treatment	Phase
Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia	Drug: nilotinib	Phase 2

Detailed Description

The study was designed as a multi-center, open-label, non-controlled phase II study to assess efficacy, safety and PK parameters of 230 mg/m2 twice daily nilotinib in pediatric patients (1 to <18 years old). The study population consisted of three cohorts of Ph+ CML pediatric patients:

• Cohort 1: Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib

• Cohort 2: Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib

• Cohort 3: Newly-diagnosed Ph+ CML-CP patients in first chronic phase A minimum number of 50 pediatric patients (from 1 to <18 years) were enrolled in the study. Of them, at least 15 patients were Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib, and at least 15 were newly-diagnosed Ph+ CML-CP patients in first chronic phase patients. There was no minimum number of patients required for Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib.

Based on enrollment forecasts as of Jan 2015, and to reflect the agreements with the US FDA and the PDCO, the study remained open for enrollment until the targeted number of 50 patients with at least 15 newly diagnosed Ph+CML patients was achieved or until 31May2015, whichever was later.

Patients who completed the study were treated with nilotinib for a total of 66 cycles of 28 days unless the patient prematurely discontinued study treatment.

The primary analysis cut-off date was the date when all patients enrolled in the trial either completed their visit for treatment cycle 12 or had discontinued study treatment early (EoT/early discontinuation visit). These analyses were reported in the 12-cycle clinical study report (CSR). A 24-cycle analysis was done when all patients had either completed their 24-cycle treatment visit or had discontinued study treatment early.

At trial end, a final comprehensive CSR of all data collected during the trial was produced.

Study Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Open Label, Non-controlled Phase II Study to Evaluate 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
• Actual Study Start Date: Aug 20, 2013
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Aug 28, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Newly diagnosed and untreated Ph+ CML in first CP Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis.	Drug: nilotinib; Nilotinib supplied in 50mg, 150mg, and 200mg capsules. It was administered orally at 230mg/m2, twice daily for up to 66 cycles (1 cycle = 28 days). Dose administration was rounded to the nearest 50mg dose (to a maximum dose of 400mg).; Other Names: AMN107
Experimental: Resistant/intolerant Ph+ CML in CP Resistant or Intolerant to either imatinib or dasatinib	Drug: nilotinib; Nilotinib supplied in 50mg, 150mg, and 200mg capsules. It was administered orally at 230mg/m2, twice daily for up to 66 cycles (1 cycle = 28 days). Dose administration was rounded to the nearest 50mg dose (to a maximum dose of 400mg).; Other Names: AMN107
Experimental: Resistant/intolerant Ph+ CML in AP Resistant or intolerant to either imatinib or dasatinib - at the end no patients were enrolled in this arm.	Drug: nilotinib; Nilotinib supplied in 50mg, 150mg, and 200mg capsules. It was administered orally at 230mg/m2, twice daily for up to 66 cycles (1 cycle = 28 days). Dose administration was rounded to the nearest 50mg dose (to a maximum dose of 400mg).; Other Names: AMN107

Outcome Measures

Primary Outcome Measures

1. Rate of Major Molecular Response (MMR) at 6 Cycles for Ph+ CML CP Patients Resistant or Intolerant to Imatinib or Dasatinib [6 cycles]

   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.

2. MMR Rate by 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients [12 cycles]

   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.

3. Rate of Complete Cytogenic Response (CCyR) at 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients [12 cycles]

   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.

Secondary Outcome Measures

1. MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib [By 3, 6, 9 , 12, 24, 36, 48, 66 cycles ( 1 cycle = 28 days)]

   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.

2. MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients [by 3, 6, 9, 12, 24, 36, 48, 66 cycles (1 cycle = 28 days)]

   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.

3. Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall [up to 66 cycles (1 cycle = 28 days)]

   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)

4. Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall [up to 66 cycles (1 cycle = 28 days)]

   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)

5. Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR [From first dosing to the first MMR within 66 cycles period]

   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.

6. Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR [From first dosing to the first MMR within 66 cycles period]

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

7. Duration of First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib Who Achieved MMR [from MMR until confirmed loss of MMR (Assessed up to 66 cycles)]

   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.

8. Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR [from MMR until confirmed loss of MMR (Assessed up to 66 cycles)es)]

   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.

9. Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall [up to 66 cycles]

   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.

10. Best Complete Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients - Overall [up to 66 cycles]

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

11. Summary of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients [From first dosing to the first CCyR up to 66 cycles]

    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.

12. Kaplan-Meier Estimates of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients [From first dosing to the first CCyR up to 66 cycles]

    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.

13. Kaplan-Meier Estimates of Duration of First Complete Cytogenic Response (CCyR) Among Patients Who Achieved CCyR in Newly Diagnosed Ph+ CML-CP Patients [From CCyR to loss of CCyR up to 66 cycles]

    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.

14. Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients [6, 12, 18, 24, 36, 48, 66 cycles]

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

15. Summary of Time to First Major Cytogenetic Response (MCyR) Among Patients Who Achieved MCyR in Newly Diagnosed CML-CP Patients [up to 66 cycles]

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

16. Kaplan-Meier Estimates of Time to First Major Cytogenetic Response (MCyR) in Newly Diagnosed CML-CP Patients [up to 66 cycles]

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

17. Best Complete Hematological Response (CHR) by Time Point [cycle 3, 6, 9, 12, 18, 24, 36, 48, 66]

    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

18. Summary of Time to First Complete Hematological Response (CHR) Among Patients Who Achieved Confirmed CHR in Newly Diagnosed CML-CP Patients [from first dosing to CHR, UP TO 66 CYCLES]

    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

19. Kaplan-Meier Estimates of Time to First Complete Hematological Response (CHR) in Newly Diagnosed CML-CP Patients [from first dosing to CHR, UP TO 66 CYCLES]

    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

20. Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier Estimates [From first dosing to the disease progression within 66 cycles]

    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.

21. Event Free Survival in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients [From first dosing to the disease progression or death up to 66 cycles]

    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)

22. Event Free Survival in Newly Diagnosed CML-CP Patients [From first dosing to the disease progression or death up to 66 cycles]

    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)

23. Overall Survival (OS) in Imatinib/Dasatinib Resistant/Intolerant CML-CP - Kaplan-Meier Estimates [from first dosing to death up to 66 cycles]

    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.

24. Overall Survival (OS) in Newly Diagnosed CML-CP Patients [from first dosing to death up to 66 cycles]

    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.

25. Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle [By 3, 6, 9, 12, 18, 24, 36, 48, 66 cycles]

    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.

26. Pharmacokinetics (PK): Steady State Concentration of Nilotinib in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients [Cycle 1 Day 8]

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

27. Pharmacokinetics: Steady State Concentration of Nilotinib in Newly Diagnosed CML-CP Patients [Cycle 1 Day 8]

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

28. Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort [from first dosing to 66 cycles]

    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.

29. Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation [up to Cycle 12]

    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).

30. Mutational Assessment of BCR-ABL [up to 66 cycles]

    Emerging signs of resistance to nilotinib

Other Outcome Measures

1. Long Term Effect of Nilotinib on Bone Metabolism [Cycle 66]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Newly diagnosed and untreated Ph+ CML CP or Ph+ CML CP or AP resistant or intolerant to either imatinib or dasatinib

• Karnofsky ≥ 50% for patients > 10 years of age and Lansky ≥ 50 for patients ≤ 10 years of age

• Adequate renal, hepatic and pancreatic function

• Potassium, magnesium, phosphorus and total calcium values ≥ LLN (lower limit of normal)

• Written informed consent

Key Exclusion Criteria:

• Treatment with strong CYP3A4 inhibitors or inducers

• Use or planned use of any medications that have a known risk or possible risk to prolong the QT interval

• Acute or chronic liver, pancreatic or severe renal disease

• History of pancreatitis or chronic pancreatitis.

• Impaired cardiac function

• No evidence of active graft vs host and <3mo since Stem Cell Transplant

• Total body irradiation (TBI) or craniospinal radiation therapy <6months

• Hypersensitivity to the active ingredient or any of the excipients including lactose.

• the criteria regarding pregnancy and contraception

• Active or systemic bacterial, fungal, or viral infection

• known Hepatitis B, Hepatitis C, or HIV infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University Cancer Center	Loma Linda	California	United States	92350
2	Lucile Salter Packard Children's Hospital at Stanford	Palo Alto	California	United States	94304
3	Nemours Childrens Hospital	Orlando	Florida	United States	32827
4	St. Mary's Hospital	West Palm Beach	Florida	United States	33407
5	Johns Hopkins Oncology Center ORA	Baltimore	Maryland	United States	21231
6	UNC Chapel Hill	Chapel Hill	North Carolina	United States	27599
7	Nationwide Childrens Hospital	Columbus	Ohio	United States	43205
8	University of Texas Southwestern Medical Center Oncology	Dallas	Texas	United States	75235
9	Cook Children's Medical Center Oncology	Fort Worth	Texas	United States	76104
10	Seattle Childrens Hospital	Seattle	Washington	United States	98105
11	Novartis Investigative Site	Bordeaux	Aquitaine	France	33076
12	Novartis Investigative Site	Lille		France	59000
13	Novartis Investigative Site	Paris Cedex		France	75019
14	Novartis Investigative Site	Poitiers		France	86021
15	Novartis Investigative Site	Budapest		Hungary	1094
16	Novartis Investigative Site	Genova	GE	Italy	16147
17	Novartis Investigative Site	Monza	MB	Italy	20900
18	Novartis Investigative Site	Padova	PD	Italy	35128
19	Novartis Investigative Site	Torino	TO	Italy	10126
20	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	232-8555
21	Novartis Investigative Site	Sakyo Ku	Kyoto	Japan	606 8507
22	Novartis Investigative Site	Shinjuku-ku	Tokyo	Japan	160 8582
23	Novartis Investigative Site	Saitama		Japan	330 8777
24	Novartis Investigative Site	Shizuoka		Japan	420 8660
25	Novartis Investigative Site	Seoul		Korea, Republic of	03080
26	Novartis Investigative Site	Seoul		Korea, Republic of	06351
27	Novartis Investigative Site	Kuala Lumpur		Malaysia	50589
28	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
29	Novartis Investigative Site	Moscow		Russian Federation	117198
30	Novartis Investigative Site	Madrid		Spain	28009
31	Novartis Investigative Site	Muang	Chiangmai	Thailand	50200
32	Novartis Investigative Site	Bangkok		Thailand	10330
33	Novartis Investigative Site	Bangkok		Thailand	10700
34	Novartis Investigative Site	Istanbul		Turkey	34093
35	Novartis Investigative Site	Sutton	Surrey	United Kingdom	SM2 5PT
36	Novartis Investigative Site	Bristol		United Kingdom	BS2 8BJ

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01844765
• Other Study ID Numbers: CAMN107A2203; 2013-000200-41
• First Posted: May 1, 2013
• Last Update Posted: Apr 22, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Tasigna; nilotinib treatment; chronic phase; Ph+ CML; accelerated phase; newly diagnosed Ph+ CML; pediatric; leukemia; leukemia, pediatric; leukemia, myleiod; leukemia, mylegenous, chronic; leukemia, mylegenous, accelerated; BCR-ABL positive; myeloproliferative disorder; bone marrow disease; hematologic diseases; neoplastic processes; imatinib; dasatinib; enzyme inhibitor; protein kinase inhibitor
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Study Results

Participant Flow

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.
Pre-assignment Detail	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.

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib	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
Period Title: Overall Study
STARTED	34	25
Treated	33	25
Untreated	1	0
COMPLETED	19	10
NOT COMPLETED	15	15

Baseline Characteristics

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP	Newly Diagnosed and Untreated Ph+ CML in First CP	Total
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib	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	Total of all reporting groups
Overall Participants	33	25	58
Age, Customized (Number) [Number]
1 to < 12 years	12 36.4%	6 24%	18 31%
12 to < 18 years	21 63.6%	19 76%	40 69%
Sex: Female, Male (Count of Participants)
Female	12 36.4%	12 48%	24 41.4%
Male	21 63.6%	13 52%	34 58.6%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	12 36.4%	18 72%	30 51.7%
Black	3 9.1%	0 0%	3 5.2%
Asian	16 48.5%	7 28%	23 39.7%
Native American	1 3%	0 0%	1 1.7%
Other	1 3%	0 0%	1 1.7%

Outcome Measures

1. Primary Outcome

Title	Rate of Major Molecular Response (MMR) at 6 Cycles for Ph+ CML CP Patients Resistant or Intolerant to Imatinib or Dasatinib
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.
Time Frame	6 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	33
Number (95% Confidence Interval) [Percentage of participants]	39.4 119.4%

2. Primary Outcome

Title	MMR Rate by 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients
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.
Time Frame	12 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Number (95% Confidence Interval) [Percentage of participants]	64.0 193.9%

3. Primary Outcome

Title	Rate of Complete Cytogenic Response (CCyR) at 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients
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.
Time Frame	12 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Number (95% Confidence Interval) [Percentage of participants]	64.0 193.9%

4. Secondary Outcome

Title	MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib
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.
Time Frame	By 3, 6, 9 , 12, 24, 36, 48, 66 cycles ( 1 cycle = 28 days)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	33
By cycle 3	36.4 110.3%
By cycle 6	45.5 137.9%
By cycle 9	51.5 156.1%
By cycle 12	57.6 174.5%
By cycle 18	57.6 174.5%
By cycle 24	57.6 174.5%
By cycle 36	57.6 174.5%
By cycle 48	60.6 183.6%
By cycle 66	60.6 183.6%

5. Secondary Outcome

Title	MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients
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.
Time Frame	by 3, 6, 9, 12, 24, 36, 48, 66 cycles (1 cycle = 28 days)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
By cycle 3	12.0 36.4%
By cycle 6	52.0 157.6%
By cycle 9	56.0 169.7%
By cycle 12	64.0 193.9%
By cycle 18	68.0 206.1%
By cycle 24	68.0 206.1%
By cycle 36	76.0 230.3%
By cycle 48	76.0 230.3%
By cycle 66	76.0 230.3%

6. Secondary Outcome

Title	Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall
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)
Time Frame	up to 66 cycles (1 cycle = 28 days)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	33
<=0.0032%	12.1 36.7%
> 0.0032% - ≤ 0.01%	15.2 46.1%
>0.01% - ≤ 0.1%	33.3 100.9%
>0.1% - ≤ 1%	21.2 64.2%
>1% - ≤ 10%	9.1 27.6%
> 10%	6.1 18.5%
Atypical transcripts at baseline	3.0 9.1%

7. Secondary Outcome

Title	Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall
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)
Time Frame	up to 66 cycles (1 cycle = 28 days)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
≤ 0.0032%	44.0 133.3%
>0.0032% - ≤ 0.01%	12.0 36.4%
>0.01% - ≤ 0.1%	20.0 60.6%
>0.1% - ≤ 1%	8.0 24.2%
>1% - ≤ 10%	8.0 24.2%
>10%	8.0 24.2%

8. Secondary Outcome

Title	Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR
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.
Time Frame	From first dosing to the first MMR within 66 cycles period

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication.

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	20
Median (95% Confidence Interval) [months]	2.79

9. Secondary Outcome

Title	Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR
Description	Time to MMR is the time from first study drug intake to first major molecular response computed only for participants who achieved MMR.
Time Frame	From first dosing to the first MMR within 66 cycles period

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication.

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	19
Median (95% Confidence Interval) [Months]	5.59

10. Secondary Outcome

Title	Duration of First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib Who Achieved MMR
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.
Time Frame	from MMR until confirmed loss of MMR (Assessed up to 66 cycles)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication.

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	20
Median (95% Confidence Interval) [months]	NA

11. Secondary Outcome

Title	Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR
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.
Time Frame	from MMR until confirmed loss of MMR (Assessed up to 66 cycles)es)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication.

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	19
Median (95% Confidence Interval) [months]	NA

12. Secondary Outcome

Title	Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall
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.
Time Frame	up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication.

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	33
Major cytogenetic response: Complete	81.1 245.8%
Major cytogenetic response: Partial	3.0 9.1%
Minimal	3.0 9.1%
None	3.0 9.1%
Missing	9.1 27.6%

13. Secondary Outcome

Title	Best Complete Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients - Overall
Description	Complete cytogenetic response (CCyR) - 0% Ph+ metaphases No response - >95 to 100% Ph+ metaphases
Time Frame	up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication.

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Number (95% Confidence Interval) [Percentage of participants]	84.0 254.5%

14. Secondary Outcome

Title	Summary of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients
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.
Time Frame	From first dosing to the first CCyR up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Median (95% Confidence Interval) [months]	5.55

15. Secondary Outcome

Title	Kaplan-Meier Estimates of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients
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.
Time Frame	From first dosing to the first CCyR up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Median (95% Confidence Interval) [months]	5.6

16. Secondary Outcome

Title	Kaplan-Meier Estimates of Duration of First Complete Cytogenic Response (CCyR) Among Patients Who Achieved CCyR in Newly Diagnosed Ph+ CML-CP Patients
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.
Time Frame	From CCyR to loss of CCyR up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	21
Median (95% Confidence Interval) [months]	NA

17. Secondary Outcome

Title	Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients
Description	Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.
Time Frame	6, 12, 18, 24, 36, 48, 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
by cycle 6	88.0 266.7%
by cycle 12	88.0 266.7%
by cycle 18	88.0 266.7%
by cycle 24	88.0 266.7%
by cycle 36	88.0 266.7%
by cycle 48	88.0 266.7%
by cycle 66	88.0 266.7%

18. Secondary Outcome

Title	Summary of Time to First Major Cytogenetic Response (MCyR) Among Patients Who Achieved MCyR in Newly Diagnosed CML-CP Patients
Description	Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.
Time Frame	up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	22
Median (95% Confidence Interval) [months]	5.55

19. Secondary Outcome

Title	Kaplan-Meier Estimates of Time to First Major Cytogenetic Response (MCyR) in Newly Diagnosed CML-CP Patients
Description	Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.
Time Frame	up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Median (95% Confidence Interval) [months]	5.55

20. Secondary Outcome

Title	Best Complete Hematological Response (CHR) by Time 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
Time Frame	cycle 3, 6, 9, 12, 18, 24, 36, 48, 66

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
by cycle 3	76.0 230.3%
by cycle 6	84.0 254.5%
by cycle 9	88.0 266.7%
by cycle 12	92.0 278.8%
by cycle 18	92.0 278.8%
by cycle 24	92.0 278.8%
by cycle 36	92.0 278.8%
by cycle 48	92.0 278.8%
by cycle 66	92.0 278.8%

21. Secondary Outcome

Title	Summary of Time to First Complete Hematological Response (CHR) Among Patients Who Achieved Confirmed CHR in Newly Diagnosed CML-CP Patients
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
Time Frame	from first dosing to CHR, UP TO 66 CYCLES

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	23
Median (95% Confidence Interval) [months]	0.95

22. Secondary Outcome

Title	Kaplan-Meier Estimates of Time to First Complete Hematological Response (CHR) in Newly Diagnosed CML-CP Patients
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
Time Frame	from first dosing to CHR, UP TO 66 CYCLES

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Median (95% Confidence Interval) [months]	1.0

23. Secondary Outcome

Title	Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier Estimates
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.
Time Frame	From first dosing to the disease progression within 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	33
Median (95% Confidence Interval) [months]	NA

24. Secondary Outcome

Title	Event Free Survival in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients
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)
Time Frame	From first dosing to the disease progression or death up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	33
Median (95% Confidence Interval) [months]	NA

25. Secondary Outcome

Title	Event Free Survival in Newly Diagnosed CML-CP Patients
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)
Time Frame	From first dosing to the disease progression or death up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Median (95% Confidence Interval) [months]	NA

26. Secondary Outcome

Title	Overall Survival (OS) in Imatinib/Dasatinib Resistant/Intolerant CML-CP - Kaplan-Meier Estimates
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.
Time Frame	from first dosing to death up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	33
Median (95% Confidence Interval) [months]	NA

27. Secondary Outcome

Title	Overall Survival (OS) in Newly Diagnosed CML-CP Patients
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.
Time Frame	from first dosing to death up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Median (95% Confidence Interval) [months]	NA

28. Secondary Outcome

Title	Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle
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.
Time Frame	By 3, 6, 9, 12, 18, 24, 36, 48, 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication.

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib	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.
Measure Participants	33	25
By Cycle 3	36.4 110.3%	12.0 48%
By Cycle 6	45.5 137.9%	52.0 208%
By Cycle 9	51.5 156.1%	56.0 224%
By Cycle 12	57.6 174.5%	64.0 256%
By Cycle 18	57.6 174.5%	68.0 272%
By Cycle 24	57.6 174.5%	68.0 272%
By Cycle 36	57.6 174.5%	76.0 304%
By Cycle 48	60.6 183.6%	76.0 304%
By Cycle 66	60.6 183.6%	76.0 304%

29. Secondary Outcome

Title	Pharmacokinetics (PK): Steady State Concentration of Nilotinib in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients
Description	PK was analyzed only when all patients has completed 12 cycles on treatment or discontinued the study treatment early.
Time Frame	Cycle 1 Day 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetics Analysis Set (PAS): All patients with at least one evaluable PK blood sample. Of the 32 patients included in the PAS, only 30 had evaluable Ctrough.

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib
Measure Participants	30
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1407.89 (41.67)

30. Secondary Outcome

Title	Pharmacokinetics: Steady State Concentration of Nilotinib in Newly Diagnosed CML-CP Patients
Description	PK was analyzed only when all patients has completed 12 cycles of treatment or discontinued the study treatment early.
Time Frame	Cycle 1 Day 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetics Analysis Set (PAS): All patients with at least one evaluable PK blood sample.

Arm/Group Title	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group 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.
Measure Participants	25
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1274.30 (46.21)

31. Secondary Outcome

Title	Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort
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.
Time Frame	from first dosing to 66 cycles

Outcome Measure Data

Analysis Population Description

Safety Set (SAF): All patients who received at least one dose of study medication in participants with both a baseline and post-baseline value.

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib	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
Measure Participants	33	25
Decrease from baseline of 1 SDS category (n=32,24)	27.3 82.7%	32.0 128%
Decrease from baseline of 2 SDS categories (n=32, 24)	3.0 9.1%	16.0 64%
Decrease from baseline of 3 SDS categories(n= 32, 24)	6.1 18.5%	4.0 16%

32. Secondary Outcome

Title	Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation
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).
Time Frame	up to Cycle 12

Outcome Measure Data

Analysis Population Description

Safety Set (SAF): All patients who received at least one dose of study medication.

Arm/Group Title	All Patients
Arm/Group Description	All patients enrolled in the study
Measure Participants	58
Cycle (C) 1 Day (D) 1: Completed questionnaire - Patients	75.9 230%
C1D1: Completed questionnaire - Parents/Caregivers	22.4 67.9%
C1D1: Patients who swallowed capsule whole	91.4 277%
C1D1: Patients had capsule mixed with apple sauce	6.9 20.9%
C1D1: Patients who reported no taste/unable to answer question	43.1 130.6%
C1D1: Patients who reported taste as good/very good	12.1 36.7%
C1D1: Patients who reported taste as not good/not bad	34.5 104.5%
C1D1: Reported capsule to be very easy/easy to administer	79.3 240.3%
C1D28: Completed questionnaire - Patients	55.2 167.3%
C1D28: Completed questionnaire - Parents/Caregivers	22.4 67.9%
C12D28: Completed questionnaire - Patients	55.2 167.3%
C12D28: Completed questionnaire - Parents/Caregivers	22.4 67.9%

33. Secondary Outcome

Title	Mutational Assessment of BCR-ABL
Description	Emerging signs of resistance to nilotinib
Time Frame	up to 66 cycles

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Arm/Group Title	Resistant/i Ntolerant Ph+ CML in CP	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib	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.
Measure Participants	33	25
Patients with >=1 evaluable post-baseline mutational analysis	39.4 119.4%	32.0 128%
Patients with any emergent mutation on treatment	0.0 0%	0.0 0%
Patients with multiple emergent mutations on treatment	0.0 0%	0.0 0%

34. Other Pre-specified Outcome

Title	Long Term Effect of Nilotinib on Bone Metabolism
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.
Time Frame	Cycle 66

Outcome Measure Data

Analysis Population Description

Safety Set (SAF): All patients who received at least one dose of study medication.

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib	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
Measure Participants	33	25
X-ray (n= 6, 0)	-0.61 (1.703) -1.8%
DEXA (n = 14, 10)	-0.35 (1.243) -1.1%	-0.70 (1.043) -2.8%

35. Post-Hoc Outcome

Title	All Collected Deaths
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.
Time Frame	approx. 64.5 months, approx. 7 years

Outcome Measure Data

Analysis Population Description

Clinical Database Population: All treated participants.

Arm/Group Title	Resistant/Intolerant Ph+ CML in CP	Newly Diagnosed and Untreated Ph+ CML in First CP
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib	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.
Measure Participants	33	25
On-treatment deaths	0 0%	0 0%
Total Deaths	1 3%	3 12%

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	Adverse Event: Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Arm/Group Title	Resistant/Intolerant Ph+ CML in CP		Newly Diagnosed and Untreated Ph+ CML in First CP		All Patients
Arm/Group Description	Patients resistant or intolerant to either imatinib or dasatinib		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		All of the patients enrolled in the study.
All Cause Mortality
	Resistant/Intolerant Ph+ CML in CP		Newly Diagnosed and Untreated Ph+ CML in First CP		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/25 (0%)		0/58 (0%)
Serious Adverse Events
	Resistant/Intolerant Ph+ CML in CP		Newly Diagnosed and Untreated Ph+ CML in First CP		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/33 (33.3%)		4/25 (16%)		15/58 (25.9%)
Blood and lymphatic system disorders
Leukocytosis	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Lymphadenitis	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Endocrine disorders
Growth hormone deficiency	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Gastrointestinal disorders
Abdominal pain	0/33 (0%)		1/25 (4%)		1/58 (1.7%)
Diarrhoea	0/33 (0%)		1/25 (4%)		1/58 (1.7%)
Haemorrhoids thrombosed	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Toothache	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
General disorders
Pyrexia	2/33 (6.1%)		0/25 (0%)		2/58 (3.4%)
Hepatobiliary disorders
Hepatomegaly	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Hyperbilirubinaemia	0/33 (0%)		1/25 (4%)		1/58 (1.7%)
Infections and infestations
Appendicitis	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Bronchitis	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Gastroenteritis	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Gastroenteritis viral	1/33 (3%)		1/25 (4%)		2/58 (3.4%)
Malaria	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Tonsillitis	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Tooth infection	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Viral infection	1/33 (3%)		1/25 (4%)		2/58 (3.4%)
Injury, poisoning and procedural complications
Muscle strain	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Investigations
Electrocardiogram QT prolonged	0/33 (0%)		1/25 (4%)		1/58 (1.7%)
Weight decreased	0/33 (0%)		1/25 (4%)		1/58 (1.7%)
Metabolism and nutrition disorders
Dehydration	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Musculoskeletal and connective tissue disorders
Bone swelling	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Jaw cyst	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Nervous system disorders
Facial paralysis	0/33 (0%)		1/25 (4%)		1/58 (1.7%)
Headache	0/33 (0%)		1/25 (4%)		1/58 (1.7%)
Syncope	0/33 (0%)		1/25 (4%)		1/58 (1.7%)
Skin and subcutaneous tissue disorders
Rash	0/33 (0%)		1/25 (4%)		1/58 (1.7%)
Vascular disorders
Hyperaemia	1/33 (3%)		0/25 (0%)		1/58 (1.7%)
Other (Not Including Serious) Adverse Events
	Resistant/Intolerant Ph+ CML in CP		Newly Diagnosed and Untreated Ph+ CML in First CP		All Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/33 (100%)		25/25 (100%)		58/58 (100%)
Blood and lymphatic system disorders
Anaemia	4/33 (12.1%)		3/25 (12%)		7/58 (12.1%)
Leukopenia	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Neutropenia	1/33 (3%)		2/25 (8%)		3/58 (5.2%)
Thrombocytopenia	1/33 (3%)		3/25 (12%)		4/58 (6.9%)
Cardiac disorders
Palpitations	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Congenital, familial and genetic disorders
Gilbert's syndrome	1/33 (3%)		2/25 (8%)		3/58 (5.2%)
Ear and labyrinth disorders
Ear pain	1/33 (3%)		2/25 (8%)		3/58 (5.2%)
Eye disorders
Conjunctival haemorrhage	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Ocular hyperaemia	1/33 (3%)		3/25 (12%)		4/58 (6.9%)
Gastrointestinal disorders
Abdominal pain	3/33 (9.1%)		6/25 (24%)		9/58 (15.5%)
Abdominal pain upper	1/33 (3%)		3/25 (12%)		4/58 (6.9%)
Constipation	1/33 (3%)		2/25 (8%)		3/58 (5.2%)
Dental caries	3/33 (9.1%)		0/25 (0%)		3/58 (5.2%)
Diarrhoea	7/33 (21.2%)		4/25 (16%)		11/58 (19%)
Gastrooesophageal reflux disease	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Nausea	8/33 (24.2%)		10/25 (40%)		18/58 (31%)
Odynophagia	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Vomiting	7/33 (21.2%)		8/25 (32%)		15/58 (25.9%)
General disorders
Asthenia	1/33 (3%)		2/25 (8%)		3/58 (5.2%)
Fatigue	0/33 (0%)		6/25 (24%)		6/58 (10.3%)
Malaise	2/33 (6.1%)		1/25 (4%)		3/58 (5.2%)
Non-cardiac chest pain	1/33 (3%)		3/25 (12%)		4/58 (6.9%)
Pyrexia	11/33 (33.3%)		9/25 (36%)		20/58 (34.5%)
Hepatobiliary disorders
Hyperbilirubinaemia	4/33 (12.1%)		8/25 (32%)		12/58 (20.7%)
Immune system disorders
Seasonal allergy	2/33 (6.1%)		1/25 (4%)		3/58 (5.2%)
Infections and infestations
Conjunctivitis	3/33 (9.1%)		0/25 (0%)		3/58 (5.2%)
Cystitis	2/33 (6.1%)		0/25 (0%)		2/58 (3.4%)
Ear infection	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Gastroenteritis	0/33 (0%)		6/25 (24%)		6/58 (10.3%)
Influenza	4/33 (12.1%)		2/25 (8%)		6/58 (10.3%)
Nasopharyngitis	5/33 (15.2%)		7/25 (28%)		12/58 (20.7%)
Otitis media acute	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Parotitis	2/33 (6.1%)		1/25 (4%)		3/58 (5.2%)
Pharyngitis	3/33 (9.1%)		3/25 (12%)		6/58 (10.3%)
Rhinitis	4/33 (12.1%)		4/25 (16%)		8/58 (13.8%)
Upper respiratory tract infection	10/33 (30.3%)		7/25 (28%)		17/58 (29.3%)
Injury, poisoning and procedural complications
Arthropod sting	2/33 (6.1%)		0/25 (0%)		2/58 (3.4%)
Fall	2/33 (6.1%)		0/25 (0%)		2/58 (3.4%)
Joint injury	2/33 (6.1%)		0/25 (0%)		2/58 (3.4%)
Ligament sprain	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Procedural pain	3/33 (9.1%)		1/25 (4%)		4/58 (6.9%)
Investigations
Alanine aminotransferase increased	10/33 (30.3%)		11/25 (44%)		21/58 (36.2%)
Amylase increased	3/33 (9.1%)		0/25 (0%)		3/58 (5.2%)
Aspartate aminotransferase increased	8/33 (24.2%)		9/25 (36%)		17/58 (29.3%)
Blood bilirubin increased	12/33 (36.4%)		10/25 (40%)		22/58 (37.9%)
Blood cholesterol increased	2/33 (6.1%)		2/25 (8%)		4/58 (6.9%)
Blood creatine phosphokinase increased	3/33 (9.1%)		0/25 (0%)		3/58 (5.2%)
Blood creatinine increased	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Blood glucose increased	2/33 (6.1%)		1/25 (4%)		3/58 (5.2%)
Blood triglycerides increased	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Electrocardiogram QT prolonged	5/33 (15.2%)		1/25 (4%)		6/58 (10.3%)
Gamma-glutamyltransferase increased	4/33 (12.1%)		1/25 (4%)		5/58 (8.6%)
Lipase increased	3/33 (9.1%)		1/25 (4%)		4/58 (6.9%)
Neutrophil count decreased	2/33 (6.1%)		3/25 (12%)		5/58 (8.6%)
Platelet count decreased	0/33 (0%)		5/25 (20%)		5/58 (8.6%)
Weight decreased	2/33 (6.1%)		3/25 (12%)		5/58 (8.6%)
Weight increased	1/33 (3%)		3/25 (12%)		4/58 (6.9%)
Metabolism and nutrition disorders
Decreased appetite	5/33 (15.2%)		1/25 (4%)		6/58 (10.3%)
Hyperuricaemia	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Vitamin D deficiency	2/33 (6.1%)		1/25 (4%)		3/58 (5.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/33 (15.2%)		4/25 (16%)		9/58 (15.5%)
Back pain	3/33 (9.1%)		2/25 (8%)		5/58 (8.6%)
Bone pain	1/33 (3%)		2/25 (8%)		3/58 (5.2%)
Muscular weakness	1/33 (3%)		2/25 (8%)		3/58 (5.2%)
Musculoskeletal pain	2/33 (6.1%)		1/25 (4%)		3/58 (5.2%)
Myalgia	3/33 (9.1%)		4/25 (16%)		7/58 (12.1%)
Pain in extremity	9/33 (27.3%)		7/25 (28%)		16/58 (27.6%)
Nervous system disorders
Dizziness	1/33 (3%)		3/25 (12%)		4/58 (6.9%)
Headache	13/33 (39.4%)		14/25 (56%)		27/58 (46.6%)
Hypoaesthesia	2/33 (6.1%)		0/25 (0%)		2/58 (3.4%)
Paraesthesia	2/33 (6.1%)		2/25 (8%)		4/58 (6.9%)
Psychiatric disorders
Anxiety	1/33 (3%)		2/25 (8%)		3/58 (5.2%)
Reproductive system and breast disorders
Dysmenorrhoea	1/33 (3%)		3/25 (12%)		4/58 (6.9%)
Gynaecomastia	2/33 (6.1%)		2/25 (8%)		4/58 (6.9%)
Respiratory, thoracic and mediastinal disorders
Cough	3/33 (9.1%)		7/25 (28%)		10/58 (17.2%)
Dyspnoea	1/33 (3%)		3/25 (12%)		4/58 (6.9%)
Nasal congestion	3/33 (9.1%)		1/25 (4%)		4/58 (6.9%)
Oropharyngeal pain	7/33 (21.2%)		2/25 (8%)		9/58 (15.5%)
Rhinitis allergic	0/33 (0%)		2/25 (8%)		2/58 (3.4%)
Rhinorrhoea	2/33 (6.1%)		3/25 (12%)		5/58 (8.6%)
Skin and subcutaneous tissue disorders
Acne	4/33 (12.1%)		4/25 (16%)		8/58 (13.8%)
Alopecia	4/33 (12.1%)		2/25 (8%)		6/58 (10.3%)
Dermatitis	4/33 (12.1%)		2/25 (8%)		6/58 (10.3%)
Dry skin	3/33 (9.1%)		0/25 (0%)		3/58 (5.2%)
Erythema	4/33 (12.1%)		4/25 (16%)		8/58 (13.8%)
Keratosis pilaris	2/33 (6.1%)		0/25 (0%)		2/58 (3.4%)
Madarosis	2/33 (6.1%)		0/25 (0%)		2/58 (3.4%)
Pruritus	0/33 (0%)		3/25 (12%)		3/58 (5.2%)
Rash	7/33 (21.2%)		11/25 (44%)		18/58 (31%)
Rash maculo-papular	5/33 (15.2%)		3/25 (12%)		8/58 (13.8%)
Rash papular	2/33 (6.1%)		1/25 (4%)		3/58 (5.2%)
Urticaria	3/33 (9.1%)		1/25 (4%)		4/58 (6.9%)
Vascular disorders
Hypertension	3/33 (9.1%)		2/25 (8%)		5/58 (8.6%)
Hypotension	3/33 (9.1%)		1/25 (4%)		4/58 (6.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.