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Myeloid Leukemia

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Nilotinib

Imatinib Mesylate

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Tyrosine

Imatinib

Novartis Pharmaceuticals

The study will compare the efficacy and safety of Nilotinib versus Imatinib in newly diagnosed Chinese patients with CML-CP.

Safety and Efficacy of Nilotinib vs. Imatinib in the Treatment of Newly Diagnosed Chinese Ph+ CML-CP Patients

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

Major molecular response (MMR) was defined as a value of ≤ 0.1% of BCR-ABL ratio on the IS. The minimum number of control genes for a sample to be valid was 3000. For statistical comparison purpose, MMR was considered as a binary variable with patients achieving MMR grouped as 'responders' and patients not achieving MMR, patients with missing PCR evaluations or patients with atypical transcripts at baseline grouped as 'non-responders'. This endpoint was calculated based on the 12 month analysis.

Major molecular response (MMR) was defined as a value of ≤ 0.1% of BCR-ABL ratio on the IS. The minimum number of control genes for a sample to be valid was 3000. For statistical comparison purpose, MMR was considered as a binary variable with patients achieving MMR grouped as 'responders' and patients not achieving MMR, patients with missing PCR evaluations or patients with atypical transcripts at baseline grouped as 'non-responders'. These time points including the 12 month data were calculated based on the final analysis after the end of the study.

Best MMR rates by scheduled time point are cumulative response rates up to that time point. In this analysis, patients who had achieved MMR at or before the time point were counted as responders, no matter if they lost the response/discontinued or not. Therefore, this response rate represented the best observed response rate up to that specific time point.

Time to first MMR (months) = (date of first MMR or censoring - date of randomization + 1) / 30.4375.

The rate of durable MMR at 24 months, defined as the proportion of patients who have achieved MMR at 12 months, and also maintain continuous MMR until the 24 month time point (1 month = 28 days) without intervening loss of MMR in between 12 and 24 months

Duration of first MMR (months) = (date of loss of MMR or censoring-date of first MMR + 1)/30.4375.

CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics.

Time to first CCyR (months) = (date of first CCyR - date of randomization + 1) / 30.4375.

Duration of CCyR (months) = (date of CCyR loss or censoring-date of first CCyR + 1)/30.4375

Time to progression to AP/BC was defined as the time from the date of randomization to the date of event defined as the first disease progression to AP/BC or the date of CML-related death, whichever is earlier. This variable was analyzed in 2 ways:

* On-treatment: included progressions to AP/BC or CML-related deaths occurring on treatment in the study as events. The time was censored at the date of last on-treatment assessment (hematology, extramedullary disease, or cytogenetic evaluation) in the study for patients without event.
* On-study: included progressions to AP/BC or CML-related deaths occurring in the study or during the follow-up period after discontinuation of treatment as events. The time was censored at the last assessment date in the study for patients who were still being treated and at the date of last contact for patients who discontinued treatment

Event-free survival was 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, - Progression to AP or BC, Loss of partial cytogenetic response (PCyR), - Loss of CCyR, - Loss of CHR

Progression-free survival was defined as the time from the date of randomization to the date of event defined as the first disease progression to AP/BC or the date of death from any cause, whichever is earlier. This variable was analyzed in 2 ways:

* On-treatment: included progressions to AP/BC or deaths occurring only on-treatment in the study as events. The time was censored at the date of last on-treatment assessment (hematology, extramedullary disease or cytogenetic evaluation) in the study before the cut-off date of the analysis for patients without event.
* On-study: included progressions to AP/BC or deaths occurring in the study or during the follow-up period after discontinuation of study treatment as events. The time was censored at the last assessment date in the study for patients who were still being treated and at the date of last contact for patients who discontinued treatment.

Patients who discontinued study treatment early or completed the study protocol and did not enter into the extension protocol were to be followed for survival every 3 months for up to 2 calendar years from the date the last patient randomized received the first dose of study drug and every 6 months until Last Patient Last Visit. Overall survival (all deaths) was defined as the time between date of randomization and date of death due to any cause at any time during the study, including the follow-up period after discontinuation of treatment, i.e. overall survival on-study. The time was censored at the date of last assessment in the study for patients who are still being treated and at the date of last contact for patients who discontinued treatment.

CHR was defined as having all of the following criteria present at any assessment, which was confirmed by another assessment at least after 4 weeks: • WBC count \< 10 x 10E9 /L • Platelet count \< 450 x 10E9 /L • Basophils \< 5% • No blasts and promyelocytes in peripheral blood • Myelocytes + metamyelocytes \< 5 % in peripheral blood • No evidence of extramedullary involvement. The assessment was not considered CHR, if there were any values indicative of CML in AP or BC (i.e. by blasts in bone marrow). For confirmation of CHR, both the initial CHR as well as the confirming assessment (at least 4 weeks after the initial assessment) had to satisfy all criteria mentioned above, without any assessment in between which indicated 'No response'.

Patients satisfying criteria for several "modified ELN 2009" categories are presented once under the worst category (Optimal\> Suboptimal \> Treatment failure). Patients in the "Discontinued" category are those who discontinued before the time point considered without satisfying any of the ELN 2009 criteria. Patients in the "Missing" category are those ongoing in the trial at the time point considered but with only missing or non evaluable data for ELN 2009 criteria.

Total dose/time on treatment (periods of zero dose were included).

The safety set consisted of all patients who received at least one dose of study medication. Two patients (1 in each arm) who were randomized but never treated were excluded from the safety set.

Patients received 400 mg qd (400 mg/day; may be increased to 600 mg/day).

Imatinib 400 mg qd

Patients received 300 mg bid (600 mg/day)

Nilotinib 300 mg Bid

Total

Age, Continuous

Sex: Female, Male

Study Director

Patients in the FAS consisted of all patients who were randomized into the study. Following the intent-to-treat principle, patients were analyzed according to the treatment group to which they were assigned at randomization.

Major Molecular Response (MMR) at 12 Months - With Imputation.

3 Months

6 Months

9 Months

12 Months

15 Months

18 Months

21 Months

24 Months

36 Months

MMR Rate at Each Time Point

Overall

Month 3

Month 6

Month 9

Month 12

Month 15

Month 18

Month 21

Month 24

Month 36

Best MMR by Each Timepoint

Kaplan-Meier Estimates of Time to First MMR

Durable MMR Rate at 24 Months

Kaplan-Meier Estimates of Duration of First MMR Among Patients Who Achieved MMR

Month 30

Best Complete Cytogenic Response (CCyR) Rate by Each Time Point

Kaplan-Meier Estimates of Time to First CCYR

Patients in the FAS consisted of all patients who were randomized into the study. Following the intent-to-treat principle, patients were analyzed according to the treatment group to which they were assigned at randomization

Kaplan-Meier Estimates of Duration of First CCyR Among Patients Who Achieved CCyR

Kaplan-Meier Estimates of Time to Progression to Accelerated Phase/Blast Crisis (AP/BC) on Treatment

Kaplan-Meier Estimates of Event-free Survival (EFS) on Treatment

Kaplan-Meier Estimates of Progression-free Survival (PFS) on Treatment

Kaplan-Meier Estimates of Overall Survival (OS) on Treatment

Month 1

Month 4

Month 5

Best Complete Hematologic Response (CHR)

Optimal Response

Suboptimal Response

Treatment Failure

Discontinued

Modified ELN2009 Criteria

Safety set consisted of all randomized patients who received at least one dose of study medication.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety and Efficacy of Nilotinib vs. Imatinib in the Treatment of Newly Diagnosed Chinese Ph+ CML-CP Patients	NCT01275196	Chronic Myeloid...	Nilotinib Imatinib	18 Years -	Novartis
Safety and Efficacy of Nilotinib vs. Imatinib in the Treatment of Newly Diagnosed Chinese Ph+ CML-CP Patients	NCT01275196	Chronic Myeloid...	Nilotinib Imatinib	18 Years -	Novartis

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