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Philadelphia Chromosome

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Hematologic Diseases

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Myeloid Leukemia

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Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Nilotinib

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Administered orally as a single agent on a continuous daily schedule given 400 mg bid (twice daily) with food. One cycle comprised of 28 days.

Imatinib

Administered orally as a single agent on a continuous daily schedule of 400 mg bid (2 x 200 mg twice daily) without food. Once cycle comprised of 28 days.

Nilotinib (AMN107)

Novartis Pharmaceuticals

In this study, the efficacy and safety of nilotinib 400 mg twice daily, will be compared with imatinib 400 mg twice daily in patients with a suboptimal response to imatinib for their Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia in the chronic phase (CML-CP).

This trial was to evaluate the CCyR rate at 12 months of nilotinib therapy when compared to imatinib treatment in patients with suboptimal response to imatinib. The patients were stratified by prior duration of initial imatinib treatment, and were randomized to receive either 400 mg/twice daily of continuous nilotinib or imatinib treatment. The first stratum patients were treated with imatinib = 6 to \< 12 months and having at least a minimal cytogenetic, but no partial cytogenetic response; and the second stratum patients were treated with imatinib = 12 months to \< 18 months and having partial cytogenetic response (PCyR), but no CCyR.

Nilotinib vs Imatinib in Adult Patients With Philadelphia (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

A Phase III Randomized, Open- Label Multi-center Study of Nilotinib Versus Imatinib in Adult Patients With Ph+ Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Who Have a Suboptimal Cytogenetic Response (CyR) on Imatinib

Due to early termination of the trial, the number of patients was too small and imbalanced and therefore analysis was not performed.

Patients received 400 mg twice daily, 2 x 200 mg capsules twice daily.

Patients received 400 mg twice daily. Capsules were available in 100 mg and 400 mg formulations.

Total

Age, Categorical

Age Continuous

Sex: Female, Male

Belgium

Germany

Japan

Korea, Republic of

Poland

Region of Enrollment

Study Director

Complete Cytogenetic Response Rate(CCyR) in Patients Who Had a Suboptimal Cytogenetic Response on Imatinib

The trial was terminated early, so only 6 patients were enrolled.

Durable Complete Cytogenetic Response Rate

Overall Study

Translocation, Genetic

Chromosome Aberrations

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.

nilotinib

Imatinib was supplied as 100 mg and 400 mg tablets and administered orally at 400 mg QD (once a day).

imatinib

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.

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.

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

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)

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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.

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.

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".

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.

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.

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)

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)

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.

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.

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.

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.

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).

Time to CCyR is defined as the time from the date of randomization to the date of first documented CCyR

Duration of CCyR is defined as the time from date of first documented CCyR to the earliest date of loss of CCyR.

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

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

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.

Actual dose intensity is defined as total dose over time on treatment

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.

Cmax is defined as the maximum serum concentration after dose

Cmin is defined as the minimum serum concentration after dose

Tmax is defined as the sampling time when maximum measured serum concentration occurs

AUC0-last is defined as area under concentration-time curve from time zero to the last measurable sample, calculated by log-linear trapezoidal method

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.

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))

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)

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.

Adverse Event (AE): Any sign or symptom that occurs during the study treatment plus 28 days post treatment.

Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated

Imatinib 400 mg QD

Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

Nilotinib 300 mg BID

Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.

Nilotinib 400 mg BID

All patients randomized in the study to all 3 arms and received at least one dose of study drug.

All Patients

Nilotinb 300 mg BID

<35 years

>= 35 - <45 years

>=45 - <55 years

>=55 - < 65 years

>=65 years

Age, Customized

Caucasian

Black

Asian

Native American

Other

Missing patient that cannot be identified

Race/Ethnicity, Customized

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation

Sokal risk group = Low

Sokal risk group = Interm.

Sokal risk group = High

Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation

Rates of Durable MMR at 24 Months Between All 3 Arms

CCyR at M12

CCyR at M24

CCyR at M36

CCyR at M48

CCyR at M60

CCyR at M72

Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months

Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms

MMR at M6

MMR at M12

MMR at M24

MMR at M36

MMR at M48

MMR at M60

MMR at M72

MMR at M84

MMR at M96

MMR at M108

MMR at M120

Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms

Molecular response of <=0.01% at 6 months

Molecular response of <=0.01% at 12 months

Molecular response of <=0.01% at 24 months

Molecular response of <=0.01% at 36 months

Molecular response of <=0.01% at 48 months

Molecular response of <=0.01% at 60 months

Molecular response of <=0.01% at 72 months

Molecular response of <=0.01% at 84 months

Molecular response of <=0.01% at 96 months

Molecular response of <=0.01% at 108 months

Molecular response of <=0.01% at 120 months

Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib

Molecular response of <=0.0032% at 6 months

Molecular response of <=0.0032% at 12 months

Molecular response of <=0.0032% at 24 months

Molecular response of <=0.0032% at 36 months

Molecular response of <=0.01032 at 48 months

Molecular response of <=0.0032% at 60 months

Molecular response of <=0.0032% at 72 months

Molecular response of <=0.0032% at 84 months

Molecular response of <=0.0032% at 108 months

Molecular response of <=0.0032% at 120 months

Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib

Time to First MMR

Duration of MMR

time to first molecular response of <=0.01%

time to first molecular response of <=0.0032%

Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts

duration of first molecular response of <=0.01%

duration of first molecular response of <=0.0032%

Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received

Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts

Complete hematologic response (CHR) by M12

CHR by M24

CHR Overall

Rate of Hematologic Response

Time to Complete Cytogenic Response (CCyR)

Duration of CCyR

Progression-free Survival (PFS)

Event-free Survival (EFS)

Overall Survival (OS)

Safety Set: Safety set contained 836 patients who received at least one dose of study medication.

Actual Dose-intensity

Time to Progression to AP/BC

Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.

Pharmacokinetics: Cmax

Pharmacokinetics: Cmin

Pharmacokinetics: Tmax

Pharmacokinetics: AUC0-last

Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)

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 Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)

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)

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)

Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nilotinib vs Imatinib in Adult Patients With Philadelphia (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)	NCT00519090	Myelogenous Leu...	Imatinib Nilotinib (AMN1...	18 Years -	Novartis
Nilotinib vs Imatinib in Adult Patients With Philadelphia (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)	NCT00519090	Myelogenous Leu...	Imatinib Nilotinib (AMN1...	18 Years -	Novartis
A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)	NCT00471497	Myelogenous Leu...	nilotinib imatinib	18 Years -	Novartis

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