An Ascending Dose Study of KW-2449 in Acute Leukemias, Myelodysplastic Syndromes, and Chronic Myelogenous Leukemia

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

Detailed Description
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This is a Phase I open-label dose escalation study of KW-2449 in subjects with acute leukemias, high risk MDS, and CML who are not candidates for approved therapy. Over an 18-month period, the investigative sites collectively will enroll up to a total of 96 subjects. Subjects will be enrolled sequentially into 1 of 7 dose groups to evaluate 2 dosing schedules (Arm A = 14 consecutive days of dosing followed by a 7-28 day rest period as determined by recovery from any acute hematologic and non-hematologic toxicities, or Arm B = 28 consecutive days of dosing followed by a 7-28 day rest period, as determined by recovery from any acute hematologic and non-hematologic toxicities). The safety of a dose level in Arm A (14-day dosing regimen) will be established prior to enrollment of subjects in the same dose level in Arm B (28-day dosing regimen). In April 2007 the protocol was amended to discontinue Arm B (28 consecutive days of dosing). The protocol will continue as planned for Arm A (14 days of consecutive dosing). Enrollment will proceed until a maximum tolerated dose (MTD) has been established for each study Arm. Once the MTD has been reached, 12 additional subjects, with 1 or more of the hematologic conditions included in this study, may be enrolled at the MTD as an expanded safety cohort.

Official Title
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Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of KW-2449 in Acute Leukemias (AML), Myelodysplastic Syndromes (MDS), and Chronic Myelogenous Leukemia (CML)

Conditions
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Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes, Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: KW-2449


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. ECOG Performance Status score of 0, 1, or 2; Male or female, at least 18 years of age; Signed written informed consent; Serum creatinine ≤ 2.0 mg/dL; 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 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: Candidates for approved therapies; Concomitant treatment with any investigational agent, chemotherapy, radiotherapy, or immunotherapy; Active CNS leukemia; 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; Uncontrolled systemic infection (viral, bacterial, or fungal); Uncontrollable disseminated intravascular coagulation; Major surgery within the 28 days preceding the first dose KW-2449; Radiotherapy, or lack of recovery of any radiotherapy-related acute toxicity, within the 28 days preceding the first dose KW-2449; 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); 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; Positive serology for HIV; 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; Any evidence of chronic Graft versus Host Disease; Active autoimmune disease requiring immunosuppressive therapy; Female subjects who are pregnant or breast feeding; Subjects of childbearing potential, unwilling to use an approved, effective means of contraception in accordance with the institution's standards; Known current drug or alcohol abuse; 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 For any reason is judged by the Investigator to be inappropriate for study participation, including an inability to communicate or cooperate with the Investigator. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KW-2449<br>Treatment with ascending doses of KW-2449 | Drug: KW-2449<br>* Sequential ascending oral doses of KW-2449 given for 14 or 28 days (modified by protocol amendment to only 14 days dosing).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of KW-2449 - Number of Participants With Treatment-related Adverse Events (TEAEs) as Assessed by NCI-CTCAE v3.0 | In addition to the number of TEAEs, the number of serious TEAEs, the number of related TEAEs, the number of Grade 3-4 TEAEs, and the number of subjects who died or discontinued due to TEAEs were also assessed. The maximally tolerated dose (MTD) was also to be determined, but it was not actually reached in either arm. | Baseline up to Cycle 2, Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed Peak Plasma Concentration (Cmax) |  | Days 1 and 14 (and Day 28 for Arm B) of Cycle 1 | 
| Time to Peak Plasma Concentration (Tmax) |  | Days 1 and 14 (and Day 28 for Arm B) of Cycle 1 | 
| Area Under the Plasma Concentration-time Curve From 0 to Tau (AUC (0-tau, Tau is the Dosing Interval)) |  | Days 1 and 14 (and Day 28 for Arm B) of Cycle 1 | 
| Terminal Half Life (t 1/2) |  | Days 1 and 14 (and Day 28 for Arm B) of Cycle 1 | 
| Accumulation Ratio (AUC 0-tau Day 14 or 28 / AUC 0-tau Day 1) |  | Day 1 and either Day 14 or Day 28 of Cycle 1 | 
| Disease Response | Disease response (i.e., complete or partial remission) based on standard criteria: Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-4649. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000 Dec 1;96(12):3671-3674. VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. Criteria for use of Imatinib Mesylate (Gleevec®) [updated March 2002; cited 2005 Nov 16]. Available from: http://www.pbm.va.gov/archive/imatinibcriteria.pdf | Day 14 (Arm A) or Day 28 (Arm B) for all cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, ALL, MDS, CML, Kinase Inhibitor