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

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

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.

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

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 - 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).

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

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.

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)

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

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 First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib 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.

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.

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

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.

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.

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

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.

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

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.

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

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

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

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

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

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

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

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 for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier Estimates

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)

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.

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.

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

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.

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

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

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).

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.

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

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

Hijiya N, Maschan A, Rizzari C, Shimada H, Dufour C, Goto H, Kang HJ, Guinipero T, Karakas Z, Bautista F, Ducassou S, Yoo KH, Zwaan CM, Millot F, Patterson B, Samis J, Aimone P, Allepuz A, Titorenko K, Sosothikul D. A phase 2 study of nilotinib in pediatric patients with CML: long-term update on growth retardation and safety. Blood Adv. 2021 Jul 27;5(14):2925-2934. doi: 10.1182/bloodadvances.2020003759.

Hijiya N, Maschan A, Rizzari C, Shimada H, Dufour C, Goto H, Kang HJ, Guinipero T, Karakas Z, Bautista F, Ducassou S, Yoo KH, Zwaan CM, Millot F, Aimone P, Allepuz A, Quenet S, Hourcade-Potelleret F, Hertle S, Sosothikul D. Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia. Blood. 2019 Dec 5;134(23):2036-2045. doi: 10.1182/blood.2019000069.