The objectives of this study are to determine the safety and tolerability of ASP2215 as well as the maximum tolerated dose (MTD) based on the onset of dose limiting toxicity (DLT) and/or determine the recommended dose (RD) of ASP2215 for the next phase in subjects with relapsed or treatment-refractory acute myeloid leukemia (AML).

This study will be conducted to determine the safety, tolerability, PK, PD, and efficacy of single and repeated oral dosing of ASP2215 once daily in patients with relapsed or refractory AML. After the determination of the MTD and/or RD, an expansion cohort might be set to further investigate the safety and efficacy of ASP2215.

This study will consist of a single-dose period (Cycle 0, 2 days) and a repeated-dose period (Cycle 1 and subsequent cycles, each cycle consisting of 28 days). The enrolled subjects will orally receive their assigned single dose in Cycle 0 (Day -2), followed by a 2-day observation period (dosing day inclusive). In Cycle 1 and subsequent cycles (one cycle is defined as 28 days), the subjects will receive oral ASP2215 once daily repeatedly until one of the discontinuation criteria is met. Another dosing regimen may be considered such as dosing twice daily based on the safety and PK data that will become available.

In this study, the Bayesian-Continual Reassessment Method (hereinafter, Bayesian-CRM) will be used as a reference for dose-escalation procedures, and based on the onset of DLTs, the RD level of the subsequent cohort will be set higher or lower. DLTs will be assessed during Cycle 0 and Cycle 1 (30 days).

ASP2215 may be escalated by one dose level if the subject meets the criteria at the end of each cycle after Cycle 1 and the investigator/sub-investigator judges escalation of ASP2215 is of clinical benefit. Dose reduction of ASP2215 will be considered if study drug-related toxicities are observed in a subject.

Inclusion Criteria:

• Subject is defined as morphologically documented primary or secondary acute myeloid leukemia (AML) according to the World Health Organization (WHO) criteria (2008) and fulfills one of the following:

  • Refractory to prior induction chemotherapy
  • Relapsed after achieving remission with prior therapy

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

• Subject's interval from prior treatment to the time of study drug administration is at least 14 days for antineoplastic agents other than ASP2215 (except for hydroxyurea, which is given to control blast cells).

• Subject's interval from prior treatment to the time of study drug (ASP2215) administration is at least 5 half-lives (if the half-life is unknown, 14 days) for other investigational products or drugs used for immunosuppressive therapy posthematopoietic stem cell transplantation (HSCT).

Exclusion Criteria:

• Subject was diagnosed with acute promyelocytic leukemia (APL).

• Subject has breakpoint cluster region-abelson (BCR-ABL)-positive leukemia (chronic myelogenous leukemia in blast crisis)

• Subject has active malignant tumors other than AML or myelodysplastic syndrome (MDS)

• Subject has persistent non-hematological toxicities of ≥ Grade 2 (CTCAE v4), with symptoms and objective findings, due to prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, investigational products, radiation therapy, and surgery)

• Subject has received hematopoietic stem cell transplant (HSCT) and falls under either of the following:

  • Is within 2 months of transplant
  • Has persistent and clinically significant graft-versus-host disease requiring treatment
  • Has persistent non-hematological toxicities of ≥ Grade 2 related to the transplant

• Subject has clinically active central nervous system leukemia

• Subject has disseminated intravascular coagulation (DIC)

• Subject has had major surgery within 28 days prior to the first study drug administration

• Subject has had radiation therapy within 28 days prior to the first study drug administration

• Subject has congestive heart failure of NYHA class 3 or 4, or subject with a past history of congestive heart failure of NYHA class 3 or 4 and in whom echocardiogram or Multiple Gate Acquisition (MUGA) scan performed within 3 months prior to screening or at screening showed a left ventricular ejection fraction (LVEF) of < 45%.

• Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of CYP3A4 or of P-gp with such exceptions of antibiotics, antifungals, and antivirals that are considered absolutely essential for prevention or treatment of infections and for which the physician judged that there are no interchangeable drugs.

• Subject requires treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR receptors or sigma nonspecific receptors, with the exception of drugs that are considered absolutely essential for treatment of the subject.

• Subject has an active uncontrollable infection

• Subject is known to have human immunodeficiency virus (HIV) infection

• Subject has active hepatitis B or C or other active hepatic disorders

Access to anonymized individual participant level data will not be provided for this trial. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.