An Ascending Dose Study of KW-2449 in Acute Leukemias, Myelodysplastic Syndromes, and Chronic Myelogenous Leukemia
Condition: Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndromes; Chronic Myelogenous Leukemia
MeSH terms: Leukemia; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Syndrome
Intervention: KW-2449
Intervention description: Sequential ascending oral doses of KW-2449 given for 14 or 28 days (modified by protocol amendment to only 14 days dosing).
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: AML; ALL; MDS; CML; Kinase Inhibitor

Summary:

      Non-randomized, open, dose ranging and dose scheduling study of ascending doses of KW-2449 in
      subjects with AML, ALL, MDS and CML.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologically confirmed diagnosis of:

               -  AML (including APL refractory to all-trans retinoic acid and arsenic) that has
                  relapsed or was not responsive to prior chemotherapy;

               -  Relapsed/refractory ALL;

               -  CML that has failed to respond or has lost a response to imatinib; and

               -  Advanced MDS (INT-2 and High risk by IPSS) with failure or intolerance to
                  approved therapy.

          2. ECOG Performance Status score of 0, 1, or 2;

          3. Male or female, at least 18 years of age;

          4. Signed written informed consent;

          5. Serum creatinine ≤ 2.0 mg/dL;

          6. Serum SGOT (AST) and SGPT (ALT) ≤ 5x ULN; serum bilirubin ≤ 2 mg/dL (serum bilirubin
             may be ≤ 3.0 mg/dL in any subject with Gilbert's Syndrome); and

          7. For females of childbearing potential, a negative serum pregnancy test. Subjects, of
             childbearing potential, must use an Investigator-approved method of birth control.

        Exclusion Criteria:

          1. Candidates for approved therapies;

          2. Concomitant treatment with any investigational agent, chemotherapy, radiotherapy, or
             immunotherapy;

          3. Active CNS leukemia;

          4. Previous or concurrent malignancy except noninvasive non-melanomatous skin cancer, in
             situ carcinoma of the cervix, or other solid tumor treated curatively, and without
             evidence of recurrence for at least 2 years prior to study entry;

          5. Uncontrolled systemic infection (viral, bacterial, or fungal);

          6. Uncontrollable disseminated intravascular coagulation;

          7. Major surgery within the 28 days preceding the first dose KW-2449;

          8. Radiotherapy, or lack of recovery of any radiotherapy-related acute toxicity, within
             the 28 days preceding the first dose KW-2449;

          9. Treatment with systemic therapy for the underlying hematologic condition, or lack of
             recovery of toxicity from such treatment, within 28 days of the first dose of KW-2449,
             with the following exceptions: hydroxyurea for treatment of hyperleukocytosis
             (discontinued for at least 48 hours prior to the first dose of KW-2449); imatinib
             (discontinued for at least 48 hours prior to the first dose of KW-2449); and
             interferon (discontinued for at least 7 days prior to the first dose of KW-2449);

         10. Treatment with any other investigational agent, or lack of recovery of toxicity from
             such treatment, within the 28 days preceding the first dose of KW-2449;

         11. Positive serology for HIV;

         12. Clinically significant cardiac dysfunction (New York Heart Association Class 3 or 4)
             at the time of screening, or a history of myocardial infarction or heart failure
             within 3 months preceding the first dose of KW-2449;

         13. Any evidence of chronic Graft versus Host Disease;

         14. Active autoimmune disease requiring immunosuppressive therapy;

         15. Female subjects who are pregnant or breast feeding;

         16. Subjects of childbearing potential, unwilling to use an approved, effective means of
             contraception in accordance with the institution's standards;

         17. Known current drug or alcohol abuse;

         18. Other severe, acute, or chronic medical or psychiatric condition, or laboratory
             abnormality that may compromise the safety of the subject during the study, affect the
             subject's ability to complete the study, or interfere with interpretation of study
             results; or

         19. For any reason is judged by the Investigator to be inappropriate for study
             participation, including an inability to communicate or cooperate with the
             Investigator.

         20. Hematopoietic growth factors (i.e., such as erythropoietin or darbepoetin alpha,
             filgrastim [granulocyte colony-stimulating factor {G-CSF }], sargramostim
             [granulocyte-macrophage colony-stimulating factor {GM-CSF}], or other thrombopoietic
             agents) and corticosteroids within 14 days of study entry.