Study Evaluating SKI-606 (Bosutinib) In Japanese Subjects With Philadelphia Chromosome Positive Leukemias
Condition: Chronic Myelogenous Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome
Intervention: SKI-606 (Bosutinib)
Intervention description: Formulation: 100 mg Capsule for Part 1, 100 mg tablet for Part1 and Part 2.
SKI-606 (Bosutinib) will be taken by mouth with water and food as continuous once-daily dosing.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 63.0
Sex: All
Minimum age: 20 Years
Maximum age: 74 Years
Healthy volunteers: No
Keywords: CML. Chronic myelocytic leukemia. Philadelphia Chromosome. Japanese. SKI-606. Bosutinib. Imatinib resistant. Imatinib intolerant

Summary:

      This is a two-part safety and efficacy study of SKI-606 in subjects who have Philadelphia
      chromosome positive leukemias (CML). Part 1 will be a dose-escalation study, in which an
      escalating dose of SKI-606 (Bosutinib), up to 600 mg, will be studied in subjects with
      imatinib resistant/refractory or imatinib intolerant chronic phase CML. Part 2 will evaluate
      the safety and efficacy of the maximum tolerated dose (MTD) of SKI-606 (Bosutinib)identified
      in Part 1 of the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Cytogenetic or Polymerase Chain Reaction based diagnosis of Chronic phase of
             Philadelphia Chromosome Positive Chronic Myelogenous Leukemia:

        (Part 1), any phase of Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (Part
        2), whose disease is resistant/refractory to full-dose imatinib (400 mg for chronic phase
        subjects/600 mg for advanced leukemia subjects), or are intolerant of any dose of imatinib.

          -  Adequate duration of prior imatinib therapy.

          -  No prior exposure to Src, Abl, or Src/Abl kinase inhibitors other than imatinib.

          -  Eastern Cooperative Oncology Group Performance Status of 0 or 1 for chronic phase
             subjects, and 0, 1 or 2 for Advanced Stage subjects.

          -  At least 7 days since any anti-proliferative treatment (including intrathecal
             chemotherapy) before the first dose of SKI-606, (except hydroxyurea).

          -  Recovered to National Cancer Institute grade 0-1, or to baseline, from any toxicities
             of prior anti-tumor treatment, other than alopecia or thrombocytopenia due to active
             prior treatment (intolerant subjects).

          -  At least 3 months post allogeneic stem cell transplantation before the first dose of
             SKI-606.

          -  Able to take daily oral capsules reliably.

          -  Absolute neutrophil count greater than 1,000/mL (Part 1)

          -  Adequate hepatic, and renal function.

          -  Documented normal INR if not on oral anticoagulant therapy, or, if on oral
             anticoagulant therapy consistent target INR less than 3.

          -  Age should be greater than 20 years and less than 75 years (Part 1), greater than 20
             years (Part 2), including women of childbearing potential.

          -  Willingness of male and female subjects, who are not surgically sterile or
             postmenopausal, must agree and commit to the use of reliable methods of birth control
             (oral contraceptives, intrauterine devices, or barrier methods used with a spermicide)
             for the duration of the study and for 30 days after the last dose of SKI-606.

        Exclusion Criteria:

          -  Subjects with Philadelphia chromosome negative Chronic Myelogenous Leukemia.

          -  Overt leptomeningeal leukemia. Subjects must be free of CNS involvement according to
             the symptoms for a minimum of 2 months before the first dose of SKI-606. Subjects with
             CNS symptoms must have a diagnostic lumbar puncture prior to study enrollment.

          -  Subjects with extramedullary disease only.

          -  Ongoing requirement for warfarin or other oral anticoagulant therapy (Part 1).

          -  Ongoing requirement for hydroxyurea (Part 1).

          -  Graft Versus Host Disease. a. no previous Graft Versus Host Disease allowed (Part 1).
             b. no treated or untreated Graft Versus Host Disease within 60 days of first dose
             (Part 2).

          -  Major surgery within 14 days or radiotherapy within 7 days before the first dose of
             SKI-606 (recovery from any previous surgery should be complete before day 1).

          -  Ongoing clinical requirement for administration of a strong inhibitor or inducer of
             CYP-3A4 (Part 1).

          -  History of clinically significant or uncontrolled cardiac disease including: a.
             history of a clinically significant ventricular arrhythmia (such as ventricular
             tachycardia, ventricular fibrillation, or Torsades de pointes) b. diagnosed or
             suspected congenital or acquired prolonged QT syndrome c. history of prolonged QTc d.
             unexplained syncope e. history of or active congestive heart failure f. myocardial
             infarction within 12 months. g. Uncontrolled angina or hypertension within 3 months.

          -  Baseline QTcF greater than 0.45 sec (average of triplicate readings).

          -  Concomitant use of or need for medications known to prolong the QT interval.

          -  Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.

          -  Recent (within 14 days before the first dose of SKI-606) or ongoing clinically
             significant gastrointestinal disorder.

          -  Pregnant or breastfeeding women.

          -  Evidence of serious active infection, or significant medical or psychiatric illness.