A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Myelogenous Leukemia, Chronic Clinical Trial

— ENESTnd  

Official title:

A Phase III Multi-center, Open-label, Randomized Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00471497
• Other study ID #: CAMN107A2303
• Secondary ID: 2007-000208-34
• Status: Completed
• Phase: Phase 3
• Start date: July 31, 2007
• Est. completion date: August 21, 2019

Study information

• Verified date: October 2020
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In this study, the efficacy and safety of two nilotinib doses, 300 mg twice daily and 400 mg twice daily, were compared with imatinib 400 mg once daily in newly diagnosed patients with Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia in the chronic phase (CML-CP). An extension protocol was included in this study design to allow patients who did not show sufficient response to their assigned treatments the opportunity to receive imatinib 400 mg BID (option available until protocol amendment 7) or nilotinib 400 mg BID, using an abbreviated safety and efficacy assessment schedule.

Description:

Primary objectives of this study: - Compared the efficacy (major molecular response (MMR) rate at 12 months) of nilotinib at 400 mg bid with that of imatinib 400 mg qd in newly diagnosed, previously untreated Ph+ CML-CP patients. - Compared the efficacy (MMR rate at 12 months) of nilotinib at 300 mg bid with that of imatinib 400 mg qd in newly diagnosed, previously untreated Ph+ CML-CP patients. The Primary objectives of Extension Phase of the study: - Characterized the safety and tolerability profile of nilotinib 400 mg BID after failure of imatinib or insufficiently responded to nilotinib 300 mg BID therapy and the safety and tolerability profile of imatinib therapy after failure of nilotinib therapy. The study was designed to determine whether the treatment of newly diagnosed, previously untreated Ph+ CML-CP patients with either nilotinib 300 mg bid or 400 mg bid demonstrated improved efficacy compared to imatinib 400 mg qd. The primary efficacy endpoint was the rate of MMR defined as the proportion of patients who achieved ≥ 3 log reduction in BCR-ABL transcripts compared to either the standardized Baseline established in the IRIS trial (International Randomized Interferon versus STI571) (Cortes et al 2005) or to the BCR-ABL ratio ≤ 0.1% by International Scale, as detected by real-time quantitative polymerase chain reaction (RQ-PCR) at 12 months. The key secondary endpoint was to compare the rate of durable MMR between nilotinib 300 mg bid with that of imatinib, and of nilotinib 400 mg bid with that of imatinib at 24 months. This report presents the final results of efficacy and safety at the LPLV (21-Aug-2019). The main data analysis was done at the time when all patients completed 12 cycles of treatment (or discontinued earlier). There were two primary comparisons at this time point: the MMR rate of nilotinib 400 mg versus the MMR rate of imatinib 400 mg, and the MMR rate of the nilotinib 300 mg versus the MMR rate of the imatinib 400 mg. Comparisons were done sequentially, i.e. the MMR rate of nilotinib 400 mg versus the MMR rate of imatinib 400 mg was to be compared first; if it was significant at 5% level, the MMR rate of the nilotinib 300 mg versus the MMR rate of the imatinib 400 mg was to be compared. The study had a 90% power to detect a 15% difference between the nilotinib 400 mg arm versus imatinib 400 mg arm assuming that the MMR rate of imatinib is 40% and the MMR rate of nilotinib is 55%. The study also had a 90% power to detect a 15% difference between the nilotinib 300 mg and the imatinib 400 mg arms, if the comparison between the nilotinib 400 mg and the imatinib 400 mg was significant. The second main data analysis was done at the time when all patients completed 24 cycles of treatment (or discontinued earlier). There were two key comparisons at this time point: the rate of durable MMR at 24 months of the nilotinib 400 mg versus the imatinib 400 mg, and the rate of durable MMR at 24 months of the nilotinib 300 mg versus the imatinib 400 mg. In order to control the overall type I error rate at or below 5%, only when the corresponding comparison on the primary efficacy endpoint(s) was (were) significant, the key secondary comparison(s) of the respective nilotinib doses (400 mg bid and/or 300 mg bid) versus imatinib 400 mg qd were tested at two-sided 5% significance level. Patients participating after demonstrating suboptimal response/treatment failure to their assigned study treatment in the core study were offered the option to continue in the extension study and to receive imatinib 400 mg bid (option available only until protocol amendment 7) or nilotinib therapy at a dose of 400 mg bid.

Other known NCT identifiers

• NCT00718263

Recruitment information / eligibility

• Status: Completed
• Enrollment: 846
• Est. completion date: August 21, 2019
• Est. primary completion date: September 2, 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion criteria:

• Chronic myelogenous leukemia in chronic phase patients within the first 6 months of diagnosis.
• Diagnosis of chronic myelogenous leukemia in chronic phase with confirmation of Philadelphia chromosome of (9:22) translocations

Key Exclusion criteria:

• Previously documented T315I mutation
• Treatment with a tyrosine kinase inhibitor prior to study entry is not allowed except for no more than 2 weeks in duration of imatinib
• Any medical treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide
• Impaired cardiac function.
• Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection).
• Use of therapeutic coumarin derivatives (i.e., warfarin, acenocoumarol, phenprocoumon)
• Currently receiving treatment with any medications that have the potential to prolong the QT interval.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Myelogenous Leukemia, Chronic
• Philadelphia Chromosome

Intervention

Drug:
• nilotinib
Nilotinib was supplied as 50 mg, 150 mg and 200 mg hard gelatin capsules and administered orally at 300 mg BID (twice a day) or 400 mg BID (twice a day)depending on the randomized dose.
• imatinib
Imatinib was supplied as 100 mg and 400 mg tablets and administered orally at 400 mg QD (once a day).

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	La Plata	Buenos Aires
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Charleroi
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Yvoir
Brazil	Novartis Investigative Site	Brasilia	DF
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Curitiba	PR
Brazil	Novartis Investigative Site	Jau	SP
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
Canada	Novartis Investigative Site	Vancouver	British Columbia
Colombia	Novartis Investigative Site	Bogota	Cundinamarca
Colombia	Novartis Investigative Site	Bogota
Czechia	Novartis Investigative Site	Olomouc	CZE
Czechia	Novartis Investigative Site	Praha 2	Czech Republic
Denmark	Novartis Investigative Site	Copenhagen
Denmark	Novartis Investigative Site	Vejle
Egypt	Novartis Investigative Site	Cairo
Finland	Novartis Investigative Site	HUS Helsinki
Finland	Novartis Investigative Site	Turku
France	Novartis Investigative Site	Angers Cedex 1
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Caen	Cedex
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Grenoble
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Nantes
France	Novartis Investigative Site	Nice Cedex
France	Novartis Investigative Site	Paris Cedex 10	Cedex 10
France	Novartis Investigative Site	Pierre Benite Cedex
France	Novartis Investigative Site	Poitiers
France	Novartis Investigative Site	Rennes
France	Novartis Investigative Site	Saint Priest en Jarez	Loire
France	Novartis Investigative Site	Toulouse
France	Novartis Investigative Site	Vandoeuvre les Nancy
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Eisenach
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mannheim	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Ulm
Hong Kong	Novartis Investigative Site	Hong Kong
Hungary	Novartis Investigative Site	Budapest
Italy	Novartis Investigative Site	Alessandria	AL
Italy	Novartis Investigative Site	Ancona	AN
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Pavia	PV
Italy	Novartis Investigative Site	Perugia
Italy	Novartis Investigative Site	Pescara	PE
Italy	Novartis Investigative Site	Pisa	PI
Italy	Novartis Investigative Site	Reggio Calabria	RC
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Siena	SI
Italy	Novartis Investigative Site	Udine	UD
Japan	Novartis Investigative Site	Akita
Japan	Novartis Investigative Site	Bunkyo ku	Tokyo
Japan	Novartis Investigative Site	Bunkyo-ku	Tokyo
Japan	Novartis Investigative Site	Chiba
Japan	Novartis Investigative Site	Chuo ku	Tokyo
Japan	Novartis Investigative Site	Hamamatsu-city	Shizuoka
Japan	Novartis Investigative Site	Hidaka-city	Saitama
Japan	Novartis Investigative Site	Hiroshima
Japan	Novartis Investigative Site	Kanazawa-city	Ishikawa
Japan	Novartis Investigative Site	Kumamoto City	Kumamoto
Japan	Novartis Investigative Site	Maebashi	Gunma
Japan	Novartis Investigative Site	Maebashi city	Gunma
Japan	Novartis Investigative Site	Nagasaki-city	Nagasaki
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Niigata
Japan	Novartis Investigative Site	Nishinomiya	Hyogo
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka Sayama	Osaka
Japan	Novartis Investigative Site	Saitama
Japan	Novartis Investigative Site	Sapporo	Hokkaido
Japan	Novartis Investigative Site	Sapporo city	Hokkaido
Japan	Novartis Investigative Site	Shimotsuke	Tochigi
Japan	Novartis Investigative Site	Shinagawa ku	Tokyo
Japan	Novartis Investigative Site	Shinjuku-ku	Tokyo
Japan	Novartis Investigative Site	Shinjuku-ku	Tokyo
Japan	Novartis Investigative Site	Suita city	Osaka
Japan	Novartis Investigative Site	Tsu-city	Mie
Japan	Novartis Investigative Site	Tsukuba city	Ibaraki
Korea, Republic of	Novartis Investigative Site	Jeollanam-do
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Seocho Gu
Korea, Republic of	Novartis Investigative Site	Taegu
Malaysia	Novartis Investigative Site	Selangor
Mexico	Novartis Investigative Site	Mexico	Distrito Federal
Mexico	Novartis Investigative Site	Monterrey	Nuevo Leon
Netherlands	Novartis Investigative Site	Amsterdam
Norway	Novartis Investigative Site	Oslo
Norway	Novartis Investigative Site	Trondheim
Poland	Novartis Investigative Site	Katowice
Poland	Novartis Investigative Site	Lublin
Poland	Novartis Investigative Site	Rzeszow
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Wroclaw
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Novosibirsk
Russian Federation	Novartis Investigative Site	Saint Petersburg
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Bratislava	Slovak Republic
Slovakia	Novartis Investigative Site	Bratislava
South Africa	Novartis Investigative Site	Bloemfontein
South Africa	Novartis Investigative Site	Cape Town
South Africa	Novartis Investigative Site	Parktown
South Africa	Novartis Investigative Site	Pretoria
South Africa	Novartis Investigative Site	Pretoria
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Bilbao	Pais Vasco
Spain	Novartis Investigative Site	Elche	Alicante
Spain	Novartis Investigative Site	Granada	Andalucia
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	La Laguna	Santa Cruz De Tenerife
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Spain	Novartis Investigative Site	San Sebastian	Pais Vasco
Spain	Novartis Investigative Site	Santander	Cantabria
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Zaragoza
Sweden	Novartis Investigative Site	Göteborg
Sweden	Novartis Investigative Site	Huddinge
Sweden	Novartis Investigative Site	Lulea
Sweden	Novartis Investigative Site	Lund
Sweden	Novartis Investigative Site	Orebro
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Sundsvall
Sweden	Novartis Investigative Site	Umeå
Sweden	Novartis Investigative Site	Uppsala
Switzerland	Novartis Investigative Site	Geneve
Taiwan	Novartis Investigative Site	Kaohsiung City
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Istanbul	TUR
Turkey	Novartis Investigative Site	Izmir
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Leeds
United Kingdom	Novartis Investigative Site	Liverpool
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Nottingham
United States	Indiana Blood and Marrow Institute Dept. of Indiana Blood&Marrow	Beech Grove	Indiana
United States	University of North Carolina UNC Lineberger Cancer Center	Chapel Hill	North Carolina
United States	Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology	Chattanooga	Tennessee
United States	University of Chicago Section of Hematology/Oncology	Chicago	Illinois
United States	University of Cincinnati / Barrett Cancer Center Dept.of Internal Med.	Cincinnati	Ohio
United States	Cleveland Clinic Foundation CCF	Cleveland	Ohio
United States	Missouri Cancer Associates Dept. of Boone Hospital Center	Columbia	Missouri
United States	Texas Cancer Center ( Medical City Dallas Hospital)	Dallas	Texas
United States	Florida Cancer Specialists Dept. FloridaCancerSpecialists	Fort Myers	Florida
United States	Cancer Centers of the Carolinas CC of C -Eastside	Greenville	South Carolina
United States	Rocky Mountain Cancer Centers RMCC - Colorado Springs	Greenwood Village	Colorado
United States	Hackensack University Medical Center Department of Research	Hackensack	New Jersey
United States	University of Iowa Hospitals and Clinics Dept.of U of Iowa Hosp&Clinics	Iowa City	Iowa
United States	Michigan State University / Breslin Cancer Center Breslin Cancer Center	Lansing	Michigan
United States	University of California at Los Angeles Dept. of Hematology Clinic	Los Angeles	California
United States	Advanced Medical Specialties Research Dept.	Miami	Florida
United States	Tennessee Oncology Dept. of Centennial Medical	Nashville	Tennessee
United States	LSU HEALTH SCIENCES CENTER/ LSU SCHOOL OF MEDICINE Feist-Weiller Cancer Center	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center Clinical Trials Office	New York	New York
United States	Cancer Centers of Florida PA Cancer Centers of FL	Ocoee	Florida
United States	Florida Retina Institute Flordia Cancer Affilates	Orlando	Florida
United States	Kansas City Cancer Center KCCC Business Office	Overland Park	Kansas
United States	Northwest Cancer Specialists Compass Oncology -BKM	Portland	Oregon
United States	Hematology Oncology Consultants, Inc. Deptof Hem. Onc.Consunsultants	Saint Louis	Missouri
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	Cancer Care Centers of South Texas HOAST CCC of So.TX- Medical Center	San Antonio	Texas
United States	Kaiser Permanente - California Southern Dept of Kaiser South 3	San Diego	California
United States	Tyler Cancer Center	Tyler	Texas
United States	Kaiser Permanente - California Northern Kaiser Med	Vallejo	California
United States	Kaiser Permanente - California Northern Vallejo Med Center/Med Offices	Vallejo	California
United States	Wake Forest University Health Sciences Dept. of Industry Research	Winston-Salem	North Carolina
Venezuela	Novartis Investigative Site	Caracas	Distrito Capital

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Venezuela,  Argentina,  Austria,  Belgium,  Brazil,  Canada,  Colombia,  Czechia,  Denmark,  Egypt,  Finland,  France,  Germany,  Hong Kong,  Hungary,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Mexico,  Netherlands,  Norway,  Poland,  Russian Federation,  Singapore,  Slovakia,  South Africa,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation	MMR is defined as the percentage of participants in MMR (reduction of = 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or = 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.	Baseline, 12 months
Primary	Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation	MMR is defined as the percentage of participants in MMR (reduction of = 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or = 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.	12 months
Secondary	Rates of Durable MMR at 24 Months Between All 3 Arms	Durable MMR at 24 months is defined as having MMR both at 12 months and at 24 months, and with no documented loss of MMR between these 12 month and 24 month time points.	24 months
Secondary	Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months	CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. Patients with no CCyR as the best response by any specific time point, all missing cytogenetic evaluations by that time point or Ph- at baseline are combined as "Nocomplete cytogenetic response".	12, 24, 36, 48, 60, 72 months (M)
Secondary	Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms	MMR is defined as the percentage of participants in MMR (reduction of = 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or = 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months based on 12-month cut-off interim data.	12 months
Secondary	Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms	MMR is defined as the percentage of participants in MMR (reduction of = 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or = 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 6 months and beyond up to 120 months based on final data.	6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months
Secondary	Rate of a = 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib	Molecular response of <=0.01% is defined as BCR-ABL ratio (%) on IS <= 0.01% (corresponds to >=4 log reduction of BCR-ABL transcripts from standardized baseline value)	at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months
Secondary	Rate of a = 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib	This is the molecular response of <=0.0032% is defined as BCR-ABL ratio (%) on IS <= 0.0032% (corresponds to >=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)	at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months
Secondary	Time to First MMR	Time to MMR is defined as time from date of randomization to the date of the first documented MMR in nilotinib treatment arms, compared to imatinib in adult patients with Ph+ CML in CP.	up to 84 months
Secondary	Duration of MMR	Duration of MMR for patients with MMR is defined as the time between date of MMR and the earliest of the following: loss of MMR, CML-related death or progression to AP/BC during study treatment The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.	approx. 11 years
Secondary	Time to Both a = 4 and = 4.5 Log Reduction in BCR-ABL Transcripts	Time to BCR-ABL ratio of = 0.01% and = 0.0032% is defined as: date of first BCR-ABL ratio of = 0.01% and = 0.0032% - date of randomization +1.	up to 84 months
Secondary	Duration of Both a = 4 and = 4.5 Log Reduction in BCR-ABL Transcripts	It is defined as the time from the date of first documented BCR-ABL ratio of = 0.01% and = 0.0032% to the earliest of the following: Loss of BCR-ABL ratio of = 0.01% and = 0.0032%, respectively, CML-related death or progression to AP/BC during study treatment. The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.	approx. 11 years
Secondary	Rate of Hematologic Response	Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count <10 x 109/L, Platelet count <450 x 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).	12 months, 24 months, Overall on Core study (approx. 11 years)
Secondary	Time to Complete Cytogenic Response (CCyR)	Time to CCyR is defined as the time from the date of randomization to the date of first documented CCyR	24 months
Secondary	Duration of CCyR	Duration of CCyR is defined as the time from date of first documented CCyR to the earliest date of loss of CCyR.	up to 72 months
Secondary	Progression-free Survival (PFS)	Progression-free survival is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring in the core or extension study, or during the follow-up period after discontinuation of core or extension study	approx. 11 years
Secondary	Event-free Survival (EFS)	Event-free survival is defined as the time from the date of randomization to the date of first occurrence of any of the following: death due to any cause (if death is the primary reason for discontinuation), progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR	approx. 11 years
Secondary	Overall Survival (OS)	OS is defined as the time from the date of randomization to the date death. Up to 10 calendar years of follow up from the date when the last patient randomized received the first dose of study drug in all active treatment arms of adult patients with Ph+ CML CP.	approx. 11 years
Secondary	Actual Dose-intensity	Actual dose intensity is defined as total dose over time on treatment	approx. 11 years
Secondary	Time to Progression to AP/BC	Time to progression to AP/BC is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of CML related death.	approx. 11 years
Secondary	Pharmacokinetics: Cmax	Cmax is defined as the maximum serum concentration after dose	any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
Secondary	Pharmacokinetics: Cmin	Cmin is defined as the minimum serum concentration after dose	any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
Secondary	Pharmacokinetics: Tmax	Tmax is defined as the sampling time when maximum measured serum concentration occurs	any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
Secondary	Pharmacokinetics: AUC0-last	AUC0-last is defined as area under concentration-time curve from time zero to the last measurable sample, calculated by log-linear trapezoidal method	any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration
Secondary	Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count <10 x 109/L, Platelet count <450 x 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).	Overall for Extension study for approx. 10 years
Secondary	Rate of Complete Cytogenetic Response (CCyR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	Rate of CCyR is defined as the percentage of participants in complete cytogenetic response (CCyR). CcyR is defined as 0% of Ph+ metaphases in the bone marrow.	Overall for Extension study for approx. 10 years
Secondary	Rate of Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	Rate of MMR is defined as the percentage pf participants in MMR (reduction of = 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or = 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR))	Overall for Extension study for approx. 10 years
Secondary	Rate of a = 4 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	Molecular response of <=0.01% is defined as BCR-ABL ratio (%) on IS <= 0.01% (corresponds to >=4 log reduction of BCR-ABL transcripts from standardized baseline value)	Overall for Extension study for approx. 10 years
Secondary	Rate of = 4.5 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	Molecular response of <=0.0032% is defined as BCR-ABL ratio (%) on IS <= 0.0032% (corresponds to >=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)	Overall for Extension study for approx. 10 years
Secondary	Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension)	This is the percentage of patients with any emergent mutation on extension treatment. The mutation comprised of T315T, less sensitive to nilotinib, unknown and sensitive to nilotinib.	Overall for Extension study for approx. 10 years