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Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Myeloproliferative Disorders

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Disease Attributes

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Nilotinib

Dasatinib

Enzyme Inhibitors

Imatinib Mesylate

Protein Kinase Inhibitors

Tyrosine Kinase Inhibitors

Tyrosine

Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis.

Resistant or Intolerant to either imatinib or dasatinib

Resistant or intolerant to either imatinib or dasatinib - at the end no patients were enrolled in this arm.

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).

nilotinib

Novartis Pharmaceuticals

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).

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.

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

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

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

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.

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.

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.

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.

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.

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

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.

* 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.

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

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.

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

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 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.

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)

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.

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.

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

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

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.

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).

Emerging signs of resistance to nilotinib

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

Patients resistant or intolerant to either imatinib or dasatinib

Resistant/Intolerant Ph+ CML in CP

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

Newly Diagnosed and Untreated Ph+ CML in First CP

All of the patients enrolled in the study.

All Patients

Total

1 to < 12 years

12 to < 18 years

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

Age, Customized

Sex: Female, Male

Caucasian

Black

Asian

Native American

Other

Race/Ethnicity, Customized

Study Director

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

Rate of Major Molecular Response (MMR) at 6 Cycles for Ph+ CML CP Patients Resistant or Intolerant to 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.

MMR Rate by 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients

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

By cycle 3

By cycle 6

By cycle 9

By cycle 12

By cycle 18

By cycle 24

By cycle 36

By cycle 48

By cycle 66

MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib

MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients

<=0.0032%

> 0.0032% - ≤ 0.01%

>0.01% - ≤ 0.1%

>0.1% - ≤ 1%

>1% - ≤ 10%

> 10%

Atypical transcripts at baseline

Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall

≤ 0.0032%

>0.0032% - ≤ 0.01%

>10%

Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall

Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR

Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR

Duration of First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib Who Achieved MMR

Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR

Major cytogenetic response: Complete

Major cytogenetic response: Partial

Minimal

None

Missing

Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall

Best Complete Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients - Overall

Summary of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients

Kaplan-Meier Estimates of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients

Kaplan-Meier Estimates of Duration of First Complete Cytogenic Response (CCyR) Among Patients Who Achieved CCyR in Newly Diagnosed Ph+ CML-CP Patients

by cycle 6

by cycle 12

by cycle 18

by cycle 24

by cycle 36

by cycle 48

by cycle 66

Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients

Summary of Time to First Major Cytogenetic Response (MCyR) Among Patients Who Achieved MCyR in Newly Diagnosed CML-CP Patients

Kaplan-Meier Estimates of Time to First Major Cytogenetic Response (MCyR) in Newly Diagnosed CML-CP Patients

by cycle 3

by cycle 9

Best Complete Hematological Response (CHR) by Time Point

Summary of Time to First Complete Hematological Response (CHR) Among Patients Who Achieved Confirmed CHR in Newly Diagnosed CML-CP Patients

Kaplan-Meier Estimates of Time to First Complete Hematological Response (CHR) in Newly Diagnosed CML-CP Patients

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

Event Free Survival in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients

Event Free Survival in Newly Diagnosed CML-CP Patients

Overall Survival (OS) in Imatinib/Dasatinib Resistant/Intolerant CML-CP - Kaplan-Meier Estimates

Overall Survival (OS) in Newly Diagnosed CML-CP Patients

By Cycle 3

By Cycle 6

By Cycle 9

By Cycle 12

By Cycle 18

By Cycle 24

By Cycle 36

By Cycle 48

By Cycle 66

Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle

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.

Pharmacokinetics (PK): Steady State Concentration of Nilotinib in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients

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

Pharmacokinetics: Steady State Concentration of Nilotinib in Newly Diagnosed CML-CP Patients

Decrease from baseline of 1 SDS category (n=32,24)

Decrease from baseline of 2 SDS categories (n=32, 24)

Decrease from baseline of 3 SDS categories(n= 32, 24)

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

Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort

Cycle (C) 1 Day (D) 1: Completed questionnaire - Patients

C1D1: Completed questionnaire - Parents/Caregivers

C1D1: Patients who swallowed capsule whole

C1D1: Patients had capsule mixed with apple sauce

C1D1: Patients who reported no taste/unable to answer question

C1D1: Patients who reported taste as good/very good

C1D1: Patients who reported taste as not good/not bad

C1D1: Reported capsule to be very easy/easy to administer

C1D28: Completed questionnaire - Patients

C1D28: Completed questionnaire - Parents/Caregivers

C12D28: Completed questionnaire - Patients

C12D28: Completed questionnaire - Parents/Caregivers

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

Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation

Patients with >=1 evaluable post-baseline mutational analysis

Patients with any emergent mutation on treatment

Patients with multiple emergent mutations on treatment

Resistant/i Ntolerant Ph+ CML in CP

Mutational Assessment of BCR-ABL

X-ray (n= 6, 0)

DEXA (n = 14, 10)

Long Term Effect of Nilotinib on Bone Metabolism

On-treatment deaths

Total Deaths

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.

Clinical Database Population: All treated participants.

Spots Global Cancer Trial Database for leukemia, myleiod