A Study of DSP-2033 (Alvocidib) in Patients With Acute Myeloid Leukemia

This study consists of 2 cohorts of the ACM regimen part for Japanese relapsed/refractory AML patients and 1 cohort of the A+7+3 regimen part for Japanese newly diagnosed AML patients. The purpose of this study are as below.

• To evaluate the safety of DSP-2033 (Alvocidib) in combination with cytarabine/mitoxantrone (ACM regimen) in Japanese patients with relapsed or refractory AML and to confirm its tolerability.
• To evaluate the safety of DSP-2033 （Alvocidib) in combination with cytarabine/daunorubicin (A+7+3 regimen) in Japanese newly diagnosed AML patients and to confirm its tolerability.

Inclusion criteria

[For all parts]

• Japanese patients diagnosed with AML by the 4th edition of WHO criteria.
• Patients aged between 20 and 64 at acquisition of informed consent.
• Have received an adequate explanation of the objectives/contents of the clinical study, anticipated therapeutic effects/pharmacology, and risks to his/her understanding, and voluntarily provide written informed consent to participation in the clinical study.
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2 at entry.
• Have a left ventricular ejection fraction (LVEF) ≥ 50% determined by echocardiography or multigated acquisition (MUGA) scan within 14 days prior to entry.
• Have an arterial oxygen saturation (SpO2) ≥ 90% within 14 days prior to entry.
• The laboratory test within 14 days prior to entry (for multiple tests, the most recent before the entry) meet the following criteria for major organ function.

• Serum creatinine ≤ 1.5 x the upper limit of normal (ULN) of the institutional reference standard
• AST and ALT ≤ 2 x ULN of the institutional reference standard
• Total bilirubin ≤ 2.0 mg/dL
• Female patients of childbearing potential must have negative pregnancy test results at entry.
• Female patients or patients with partners of childbearing potential must agree to use an appropriate method of contraception for a period between acquisition of informed consent and 6 months (180 days) after the final dose so that patients or female partners would not become pregnant.

[ACM regimen part] In addition to the inclusion criteria for all parts, patients must meet the following criterion.

• AML patients who could not attain remission after 1 or 2 cycles of potent chemotherapy with anthracycline, cytarabine, and etoposide, or potent chemotherapy with anthracycline and cytarabine. Or patients with 1st or 2nd recurrent AML after complete remission following initial therapy.

[A+7+3 regimen part] In addition to the inclusion criteria for all parts, patients must meet the following criterion

• Treatment naive AML patients.

Exclusion criteria

[For all parts]

• Diagnosed with acute promyelocytic leukemia (APL) (FAB classification: M3).
• Received a transplantation such as hematopoietic stem cell transplant.
• Have active central nervous system (CNS) leukemia.
• Complicated by ≥ Grade 3 infection as specified in Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03).
• HIV antibody, HBs antigen, or HCV antibody tested positive within 90 days prior to entry.
• Have New York Heart Association (NYHA) cardiac function classification III or IV heart disease or a history, ≥ Grade 3 arrhythmia, angina pectoris or abnormal electrocardiogram (ECG) findings as specified in CTCAE v4.03 or a history of these above.
• Have a disease that may interfere with the study treatment, such as interstitial pneumonia, pulmonary fibrosis, or active tuberculosis.
• Complicated by uncontrolled disseminated intravascular coagulation.
• Have other active malignancies (synchronous multiple malignancies and metachronous multiple malignancies with a disease-free interval not more than 5 years. However, carcinoma in situ that is determined to be cured by local treatment or lesions equivalent to mucosal carcinoma are not included in active multiple malignancies.)
• Have an uncontrolled complication.
• Complicated by mental deficits or have a history of mental deficits. However, patients who are able to comply with the study protocol can be included at the discretion of a physician.
• Complicated by varicella.
• Received any previous treatment with DSP-2033 or other CDK inhibitors.
• Received any investigational product or post-marketing clinical study drug within 3 months (90 days) prior to entry.
• Pregnant or lactating women*)

*) If a lactating woman agrees to discontinue breast feeding between acquisition of informed consent and 6 months (180 days) after the final dose, she could be included in the study.

• Patients who are determined to be inappropriate for participation in this study by the investigator or subinvestigator.

[ACM regimen part] In addition to the exclusion criteria cfor all parts, patients who meet any one of the following criteria 17 to 21 will be excluded from the ACM regimen part.

• Have the cumulative total exposure of anthracycline, daunorubicin-equivalent dose, exceeds 360 mg/m2 (body surface area) at entry.
• Received other leukemia treatment within 21 days prior to entry.
• Have a history of radiation therapy on the mediastinum.
• Have sustained ≥ Grade 2 adverse drug reaction (except alopecia) as specified in CTCAE v4.03, which developed by the previous treatment.
• Have a history of hypersensitivity against any one of cytarabine, mitoxantrone, or contained excipients.

[A+7+3 regimen part] In addition to the exclusion criteria for all parts, patients who meet any one of the following criteria 22 to 23 will be excluded from the A+7+3 regimen part.

• Have the cumulative total exposure of anthracycline, daunorubicin-equivalent dose, exceeds 100 mg/m2 (body surface area) at entry.
• Have a history of hypersensitivity against any one of cytarabine, daunorubicin, or contained excipients.