Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients

Inclusion Criteria:

• Male or female patients ≥ 18 years of age

• Minimum of 2 calendar years of nilotinib treatment with at least the last 12 monthsof nilotinib treatment prior to pre-screening at approved total daily dose of 600 mgBID or at a reduced dose of 400 mg QD if required from the perspective of tolerancefor BCR-ABL positive CML in documented chronic phase at the time of diagnosis

• Evidence of typical BCR-ABL transcripts (b3a2 and/or b2a2) at the time of CML-CPdiagnosis i.e. prior to first start of TKI treatment which are amenable tostandardized RT-PCR quantification"

• Patient in MR4.5 at prescreening at Novartis designated lab

• ECOG performance status of 0-2

• Adequate end organ function as defined by:

• Direct bilirubin ≤ 1.5 x ULN except for i) patients with documented Gilbert'ssyndrome for whom any bilirubin value is allowed and ii) for patients withasymptomatic hyperbilirubinemia (liver transaminases and alkaline phosphatasewithin normal range).

• SGOT(AST) and SGPT(ALT) ≤ 3 x ULN i.e. equivalent to ≤ Grade 1 NCI-CTCAE v.4.03

• Serum lipase ≤ 2 x ULN i.e. equivalent to ≤ Grade 2 NCI-CTCAE v.4.03

• Alkaline phosphatase ≤ 2.5 x ULN

• Serum creatinine < 1.5 x ULN

• Patients must have the following electrolyte values within normal limits orcorrected to be within normal limits with supplements prior to first dose of studymedication:

• Potassium (suggested keep to prevent issues with QT and/or rhythmabnormalities)

• Magnesium (suggested keep to prevent issues with QT and/or rhythmabnormalities)

• Total calcium (corrected for serum albumin)

• Patients must have normal marrow function as defined:

• Absolute Neutrophil Count (ANC) ≥ 1.5 x 10E9/L

• Hemoglobin ≥ 9.0 g/dL

• Platelets ≥ 100 x 10E9/L

• Documented chronic phase CML must meet all the criteria defined by:

• < 15% blasts in peripheral blood and bone marrow,

• < 30% blasts plus promyelocytes in peripheral blood and bone marrow,

• < 20% basophils in the peripheral blood,

• ≥ 100 x 109/L (≥ 100,000/mm3) platelets,

• No evidence of extramedullary leukemic involvement, with the exception ofhepatosplenomegaly

• Patients must tolerate a minimum total daily dose of nilotinib of 400 mg

Exclusion Criteria:

• Previous treatment with BCR-ABL inhibitors other than nilotinib for more than atotal cumulative duration of 4 weeks

• Previous treatment with alpha-interferon of any duration

• Previous anticancer agents for CML other than nilotinib except for cytoreductionafter CML diagnosis until up to 4 weeks after first dose of nilotinib

• Known second chronic phase of CML after previous progression to AP/BC

• Poorly controlled diabetes mellitus (defined as HbA1c > 9%)

• Impaired cardiac function including any one of the following:

• LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher)

• Inability to determine the QT interval on ECG, except for patients withevidence of measurable QT interval at the time of CML diagnosis (e.g. prior tofirst start of TKI treatment) and who have no documented clinical signs ofcardiovascular disease and/or clinical signs of conduction abnormality.

• Complete left bundle branch block

• Right bundle branch block plus left anterior or posterior hemiblock

• 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 atrialtachyarrhythmias

• Clinically significant resting bradycardia

• QTc > 450 msec on the average of three serial baseline ECG (using the QTcFformula). If QTcF > 450 msec and electrolytes are not within normal ranges,electrolytes should be corrected and then the patient re-tested for QTc.Thisexclusion criterion is not applicable for patients with non-measurable QTinterval who have evidence of measurable QT interval at the time of CMLdiagnosis (e.g. prior to first start of TKI treatment) and who have nodocumented clinical signs of cardiovascular disease and/or clinical signs ofconduction abnormality.

• History or clinical signs of myocardial infarction within 1 year of study entry

• History of unstable angina within 1 year of study entry

• Other clinically significant heart disease (e.g. congestive heart failure,cardiomyopathy or uncontrolled hypertension)

• History of acute pancreatitis within 1 year of study entry or past medical historyof chronic pancreatitis

• Known presence of significant congenital or acquired bleeding disorder unrelated tocancer

• Severe and/or uncontrolled concurrent medical disease that in the opinion of theinvestigator could cause unacceptable safety risks or compromise compliance with theprotocol (e.g. uncontrolled diabetes, uncontrolled infection)

• History of another active malignancy within 5 years prior to study entry with theexception of previous or concomitant basal cell skin cancer and previous carcinomain situ treated curatively

• Treatment with other investigational agents (defined as not used in accordance withthe approved indication) within 4 weeks of Day 1

• Patients who have not recovered from prior surgery

• Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers,and the treatment cannot be either discontinued or switched to a differentmedication prior to starting study drug.

• Patients actively receiving therapy with herbal medicines that are strong CYP3A4inhibitors and/or inducers, and the treatment cannot be either discontinued orswitched to a different medication prior to starting study drug. These herbalmedicines may include Echinacea, (including E. purpurea, E. angustifolia and E.pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo.

• Patients who are currently receiving treatment with any medications that have thepotential to prolong the QT interval and the treatment cannot be either safelydiscontinued or switched to a different medication prior to starting study drug. (see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for alist of agents that prolong the QT interval)

• Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea,vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypasssurgery)

• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of afemale after conception and until the termination of gestation, confirmed by apositive hCG laboratory test.

• Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using highly effective methods of contraceptionduring the study and for 14 days after the final dose of nilotinib. Highly effectivecontraception is defined as either:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy) or tubal ligation at least six weeks before taking studytreatment. In case of oophorectomy alone, only when the reproductive status ofthe woman has been confirmed by follow up hormone level assessment.

• Male sterilization (at least 6 months prior to enrolling). For female patientson the study the vasectomized male partner should be the sole partner for thatpatient.

• Use of a combination of any two of the following:

1. Use of oral, injected or implanted hormonal methods of contraception orother forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermalhormone contraception.
2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm orcervical/vault caps) with spermicidal foam/gel/film/cream/vaginalsuppository.

In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to enrolling. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

If a study patient becomes pregnant or suspects being pregnant during the study or within 30 days after the final dose of nilotinib, the Study Doctor needs to be informed immediately and ongoing study treatment with nilotinib has to be stopped immediately.