Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics of ASP2215 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

The objective of this study was to assess the safety and tolerability, including the maximum tolerated dose, of gilteritinib in participants with relapsed or treatment-refractory acute myeloid leukemia (AML). This study also determined the pharmacokinetic (PK) parameters of gilteritinib.


Eligibility Criteria:
Inclusion Criteria:

* Subject is defined as morphologically documented primary or secondary AML by the World Health Organization (WHO) criteria (2008) and fulfills one of the following:

  * Refractory to at least 1 cycle of induction chemotherapy
  * Relapsed after achieving remission with a prior therapy
* Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Subject's interval from prior treatment to time of study drug administration is at least 2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), or at least 5 half-lives for prior experimental agents or noncytotoxic agents.
* Subject must meet the following criteria as indicated on the clinical laboratory tests\*:

  * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<2.5 x institutional upper limit normal (ULN)
  * Total serum bilirubin \< 1.5x institutional ULN
  * Serum creatinine \< 1.5 x institutional ULN or an estimated glomerular filtration rate (eGFR) of \> 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation.
* Subject agrees not to participate in another interventional study while on treatment.

Exclusion Criteria:

* Subject was diagnosed as acute promyelocytic leukemia (APL).
* Subject has 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 nonhematological toxicities of \>= Grade 2 (Common Terminology Criteria for Adverse Events v4), with symptoms and objective findings, from prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery).
* Subject has had hematopoietic stem cell transplant (HSCT) and meets any of the following:

  * Is within 2 months of transplant from C1D1
  * Has clinically significant graft-versus-host disease requiring treatment
  * Has \>= Grade 2 persistent non-hematological toxicity related to the transplant. Donor lymphocytes infusion (DLI) is not permitted \<= 30 days prior to study registration or during the first cycle of treatment on the study in Cohort 1 and first two cycles of the treatment in Cohort 2
* Subject has clinically active central nervous system leukemia
* Subject has disseminated intravascular coagulation abnormality (DIC)
* Subject has had major surgery within 4 weeks prior to the first study dose.
* Subject has had radiation therapy within 4 weeks prior to the first study dose
* Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%
* Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of Cytochrome P450-isozyme3A4 (CYP3A4) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care post-transplant or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the subject
* Subject required treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
* Subject has an active uncontrolled infection
* Subject is known to have human immunodeficiency virus infection
* Subject has active hepatitis B or C, or other active hepatic disorder