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.

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