A multi-center, open-label, pharmacokinetic study of oral nilotinib in pedriatric patients with Gleevec (imatinib)-resistant/intolerant Ph+ CML chronic phase (CP) or accelerated phase (AP) or with refractory/relapsed Ph+ ALL.;Met protocol amendment #03 verandert de titel als volgt:
*A multi-center, open-label, pharmacokinetic study of oral nilotinib in pediatric patients with newly diagnosed chronic phase (CP) Ph+ CML, with CP or accelerated phase (AP) Ph+ CML resistant/intolerant to imatinib

1. Male or female patients less than 18 years and more than 1 year of age at study entry.
2. Patients must have one of the following: newly diagnosed CP Ph+ CML, CP or AP Ph+ CML resistant/-intolerant to imatinib and/or dasatinib, or Ph+ ALL either relapsed after or refractory to standard therapy.
a.
• Imatinib or dasatinib resistance in Ph+ CML is defined as:
• Increasing WBC or platelet count while on imatinib or dasatinib therapy indicative of a
hematological relapse or primary resistance to imatinib or dasatinib
• Cytogenetic or molecular response consistent with suboptimal response or failure criteria adapted from ELN (European Leukemia Net) recommendations
• Progression to accelerated phase or blast crisis while on imatinib or dasatinib therapy.
• Reappearance of Ph+ bone marrow cells after a complete cytogenetic response to
Imatinib or dasatinib.
• A greater than 30% increase in Ph+ cells in peripheral blood or bone marrow cytogenetics while on
imatinib or dasatinib therapy.
• Loss of molecular response on imatinib or dasatinib therapy.
b.
• Imatinib/dasatinib intolerance (at any dose or duration) is defined as the development of AEs
requiring discontinuation of imatinib or dasatinib therapy.
c.
Newly diagnosed CP Ph+ CML is defined as:
• Patients with Ph+ CML-CP within 6 months of diagnosis (date of initial
diagnosis is the date of first cytogenetic analysis).
• Diagnosis of chronic myelogenous leukemia in chronic phase with
cytogenetic confirmation of Philadelphia chromosome with (9;22)
translocation (to confirm the presence of BCR-ABL and review of a
minimum 20 metaphases is required). Standard conventional cytogenetic
analysis must be done on bone marrow. FISH cannot be used for study purposes.
3. Performance status: Karnofsky >= 50% for patients > 10 years of age, and Lansky >= 50 for
patients <= 10 years of age.
4. Patients must have adequate renal, hepatic and pancreatic function and normal electrolytes
defined as:
• Creatinine clearance or radioisotope GFR >= 70 ml/min/1.73 m2, or
a serum creatinine based on age as follows:
Age (Years) Maximum Serum Creatinine (mg/dL)
1 < age <= 5 0.8
5 < age <= 10 1.0
10< age <= 15 1.2
> 15 1.5
• Total bilirubin (sum of conjugated + unconjugated) <= 1.5 x upper limit of normal
(ULN) for age.
• Serum amylase and lipase <= 1.5 x ULN
• SGPT (ALT) and SGOT (AST) <= 2 x upper limit of normal (ULN) for age.
5. Patients must have the following laboratory values (>=LLN (lower limit of normal) or
corrected to within normal limits with supplements prior to the first dose of study
medication):
• Potassium >= LLN
• Magnesium >= LLN
• Phosphorus >= LLN
• Total calcium (corrected for serum albumin) >= LLN

Patients meeting any of the following criteria will be excluded from entry into or continuation
in the study:
1. Patients actively receiving therapy with strong CYP3A4 inhibitors and the treatment
cannot be either discontinued or switched to a different medication at least 14 days prior to starting study
drug.
2. Patients who are currently receiving treatment with any medications that have a known
risk or potential risk to prolong the QT interval and the treatment cannot be either
discontinued or switched to a different medication prior to starting study drug.
3. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of study drug(e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea,
mal-absorption, small bowel resection, or gastric bypass surgery).
4. Acute or chronic liver, pancreatic or severe renal disease considered unrelated to CML or ALL.
5. History of pancreatitis within 12 months of study entry or past medical history of chronic
pancreatitis.
6. No active or systemic bacterial, fungal, or viral infection as documented by positive
cultures, radiological imaging techniques, or septic shock syndrome
7. Impaired cardiac function including any one of the following:
• Inability to determine the QT interval on ECG
• Complete left bundle branch block
• Use of a ventricular-paced pacemaker
• Congenital long QT syndrome or a known family history of long QT syndrome.
• History of or presence of clinically significant ventricular or atrial tachyarrhythmias
• Clinically significant resting brachycardia (<50 beats per minute)
• QTcF > 450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and
electrolytes are not within normal ranges, electrolytes should be corrected and then the
patient re-screened for QTcF
• History of clinically documented myocardial infarction within 12 months of study
entry
• History of unstable angina within 12 months of study entry
• Other clinically significant heart disease (e.g. congestive heart failure or uncontrolled
hypertension).
8. Patients who have received dasatinib therapy within the past 3 days.
9. Patients who have received imatinib therapy within the past 5 days.
10. a) Patients who have received myelosuppressive chemotherapy within 14 days prior to
first dose of study drug.
b) Patients who have not recovered from all acute toxicities from all prior
myelosuppressive chemotherapy to <= Grade 1 (except alopecia) prior to starting study
drug.
11. Patients receiving greater than 14 days of hydroxyurea for the treatment of Ph+ CML or corticosteroids for the treatment of
Ph+ ALL and has not been discontinued at least one week prior to initiation of nilotinib (see section 6.6.4 for details on permitted concomitant use of hydroxyurea and corticosteroids).
12. Patients who have received hematopoietic growth factors within 7 days of study start or
Pegfilgrastim (Neulasta®) within 14 days of study start.
13. Stem Cell Transplant (SCT) or Rescue without total body irradiation (TBI): Evidence of
active graft vs. host disease and < 3 months since SCT.
14. External beam radiation therapy (XRT):
• < 2 weeks after local palliative XRT (small port)
• < 3 months after prior total body irradiation, or craniospinal radiation, or >= 50%
radiation of pelvis
• < 6 weeks after other substantial BM irradiation
15. Patients with a known T315I mutation in BCR-ABL.
16. Patients with known Hepatitis B, Hepatitis C, or HIV infection.