Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Study of KW-2449 in Acute Myelogenous Leukemia (AML) (Protocol Number: 2449-US-002)

Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Study of KW-2449 in Acute Myelogenous Leukemia

To determine the maximum tolerated dose of KW-2449 in people with acute myelogenous leukemia who are not candidates for approved therapy. As well, the study will determine the response rate to KW-2449.

Phase 1: To determine the maximum tolerated daily dose (MTDD) of KW 2449 when administered to subjects with AML who are not candidates for approved therapy.

This was originally a Phase 1/Phase 2 study. However, a tolerable dose that had the potential for efficacy could not be identified in Phase 1. Therefore, Phase 2 was never conducted.

Inclusion Criteria:

1. Histologically confirmed diagnosis of AML (excluding acute promyelocytic leukemia) that has relapsed or was not responsive to prior chemotherapy.

   Phase 2: Only subjects with the FLT3/ITD mutation will be enrolled in Phase 2.

2. Eastern Cooperative Oncology Group (ECOG) Scale score17 of 0, 1, or 2 (refer to Appendix 1);

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 the upper limits of normal (ULN); serum bilirubin ≤ 2 mg/dL (serum bilirubin must be ≤ 3.0 mg/dL in any subject with Gilbert's Syndrome); and

7. For women of childbearing potential, a negative serum pregnancy test must be obtained prior to administration of KW-2449.

Exclusion Criteria:

1. Subjects who are candidates for approved therapies for their underlying condition;
2. Prior treatment with KW-2449;
3. Concomitant treatment with chemotherapy (systemic or intrathecal), radiotherapy, immunotherapy, or any investigational agent;
4. Evidence of active central nervous system (CNS) leukemia;
5. 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;
6. Uncontrolled systemic infection (viral, bacterial, or fungal);
7. Uncontrolled disseminated intravascular coagulopathy;
8. Major surgery within the 28 days preceding the first dose KW-2449;
9. Radiotherapy within the 28 days preceding the first dose KW-2449, or lack of recovery from any radiotherapy-related acute adverse event;
10. Treatment with approved systemic therapy for the underlying hematologic condition within 14 days of the first dose of KW-2449 with the exception of hydroxyurea (Hydrea®) or leukapheresis for hyperleukocytosis and/or thrombocytosis (see Concomitant Medication and Treatment), or lack of recovery from any adverse event from prior systemic therapy.
11. Treatment with another investigational agent within the 28 days preceding the first dose of KW-2449, or lack of recovery from any adverse event from such treatment;
12. Known positive serology for human immunodeficiency virus (type 1 and/or 2);
13. 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;
14. Chronic Graft versus Host Disease (GVHD) with the exception of mild (Grade 1) skin GVHD;
15. Phase 1 only: ≥ Grade 2 nausea or vomiting within 7 days preceding the first dose KW 2449;
16. Active autoimmune disease requiring immunosuppressive therapy;
17. Female subjects who are pregnant or breast feeding; Pregnant women are excluded from this study because the embryotoxic potential of KW-2449 is unknown. It is not known whether KW-2449 passes into human breast milk. Nursing mothers should not use KW-2449.
18. Male or female subjects of childbearing potential, unwilling to use an approved, effective means of contraception in accordance with the institution's standards; Pregnancy should be avoided in women receiving KW 2449 and in female partners of men receiving KW-2449. All subjects receiving KW-2449 should implement appropriate contraceptive methods.
19. Known current drug or alcohol abuse;
20. 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;
21. Subject is judged by the Investigator to be inappropriate for study participation for any reason, including an inability to communicate or cooperate with the Investigator;
22. Use of hematopoietic growth factors (i.e., such as erythropoietin or darbepoetin alfa, filgrastim [granulocyte colony-stimulating factor {G-CSF}], sargramostim [granulocyte-macrophage colony-stimulating factor {GM-CSF}], or thrombopoietic agents) within 14 days preceding the first dose of KW-2449; or
23. Monoamine oxidase-B (MAO-B) or aldehyde oxidase (AOX) inhibitors within 7 days preceding the first dose KW-2449.