Trial to Evaluate the Improvement of Chronic Low-grade AEs in Patients With Ph+ CML With Optimal Response to Imatinib When Switched to Nilotinib
Condition: Philadelphia Positive (Ph+) Chronic Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Intervention: Nilotinib
Intervention description: supplied in 150 mg capsules to be taken orally
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Ph+ CML, chronic myeloid leukemia

Summary:

      Primary Objective for this study is to evaluate changes in chronic low grade
      non-hematological adverse events experienced by patients who have been treated with at least
      6 months of imatinib and who have not responded to supportive measures, when they are
      switched to nilotinib (CTCAE grading system).
    

Eligibility criteria:

        Inclusion criteria:

        Male or female patients ≥ 18 years of age 2. ECOG ≤ 2 3. Diagnosis of CML-CP < 15% blasts
        in peripheral blood and bone marrow

          -  < 30% blasts plus promyelocytes in peripheral blood and bone marrow

          -  < 20% basophiles in the peripheral blood

          -  ≥ 100 x 109 /L platelets

          -  No evidence of extramedullary leukemic involvement, with the exception of
             hepatosplenomegaly. 4. Minimal treatment duration before inclusion is 6 months. 5.
             Optimal response to imatinib at the time of inclusion according to LeukemiaNet 2009
             criteria defined as:

          -  Patients treated with imatinib for ≥6 and <12 months must be in MCR Patients treated
             with imatinib for ≥12 and <18 months must be in CCR

          -  Patients treated with imatinib for ≥18 months must be in MMR (MMR response defined
             either as 3 log reduction of bcr-abl/abl ratio or as 0,1% by IS). 6. Initial treatment
             with 400mg imatinib with current treatment with imatinib 400 or 300 mg QD 7. Imatinib
             dose interruptions are allowed prior to inclusion but should not exceed 28 consecutive
             days 8. Persistent Grade 1- 2 non-hematological adverse events for at least 2 months
             despite best supportive care. Toxicity was to be evaluated by treating physician using
             CTCAE criteria. 9. In case of several types of non-hematological AEs no one can exceed
             grade 2 and at least one should last at least 2 months. 10. Adequate end organ
             function defined by:

          -  Total bilirubin < 1.5 x ULN

          -  AST and ALT < 2.5 x ULN

          -  Creatinine < 1.5 x ULN

          -  Serum amylase and lipase ≤ 1.5x ULN

          -  Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related 11. Serum potassium,
             magnesium, phosphorus and calcium values within normal range or corrected to within
             normal limits with supplements prior to first dose of study medication. 12. Patients
             must have an imatinib washout period of at least 3 days and not to exceed 7 days prior
             to the first dose of nilotinib. 13. Ability to provide written informed consent prior
             to any study related screening procedures being done

        Exclusion criteria:

          1. Patients who have experienced any Grade 3 or higher non-hematologic toxicity 30 days
             prior to screening

          2. Loss of response (hematologic, cytogenetic, molecular) any time prior to inclusion

          3. Prior accelerated phase or blast phase CML

          4. Previously documented T315I mutation

          5. Chromosomal abnormalities (trisomy 8) and/or clonal evolution other than Ph+.

          6. Previous treatment with imatinib >400 mg any time prior to inclusion.

          7. Previous treatment with any other tyrosine kinase inhibitors except for only imatinib

        Impaired cardiac function including any of the following:

          -  LVEF < 45% as determined by echocardiogram reading or MUGA

          -  Complete left bundle branch block

          -  Long QT syndrome or a known family history of long QT syndrome

          -  History or presence of clinically significant ventricular or atrial tachyarrhythmias

          -  Clinically significant resting bradycardia (< 50 beats per minute)

          -  QTcF > 450 msec on baseline ECG. If QTcF > 450 and electrolytes are not within normal
             ranges, electrolytes were to be corrected and then the patient re-screened for QTcF

          -  Myocardial infarction within 1 year of starting study drug

          -  Other clinically significant heart disease (e.g., unstable angina, congestive heart
             failure, or uncontrolled hypertension) 9. Patients receiving therapy with inhibitors
             of CYP3A4 or medications that prolong the QT interval and cannot be either
             discontinued or switched to a different medication prior to starting study drug. 10.
             Treatment with strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampin,
             rifabutin, rifapentin, phenobarbital, St. John's Wort), that cannot be discontinued or
             switched to a different medication prior to starting study drug. 11. Impaired
             gastrointestinal (GI) function or GI disease that may significantly alter the
             absorption of study drug. 12. History of acute pancreatitis within 1 year of study
             entry. 13. Known cytopathologically confirmed CNS infiltration (in absence of
             suspicion of CNS involvement, lumbar puncture not required). 14. Any other malignancy
             that is clinically significant or requires active intervention.

             15. Severe or uncontrolled medical conditions (i.e., uncontrolled diabetes, active or
             uncontrolled infection). 16. Acute or chronic liver or severe renal disease considered
             unrelated to cancer.

             17. History of significant congenital or acquired bleeding disorder unrelated to
             cancer.

             18. Previous radiotherapy to ≥ 25% of the bone marrow. 19. Major surgery within 4
             weeks prior to Day 1 of study or patients who have not recovered from prior surgery.
             20. Treatment with other investigational agents within 30 days of Day 1. 21. History
             of non-compliance to medical regimens or inability to grant consent 22. Women who are
             pregnant, breast feeding, or of childbearing potential without a negative urinary test
             at baseline