Open Label Study to Evaluate Safety and Efficacy of 2 Doses of Quizartinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia
Condition: Leukemia, Myeloid, Acute
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: AC220
Intervention description: oral
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 76.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: FLT3-ITD positive Acute Myeloid Leukemia (AML); AC220; Relapse; Refractory

Summary:

      This study will evaluate two doses of Quizartinib in patients with relapsed or refractory
      acute myeloid leukemia who are also FMS-like tyrosine kinase - internal tandem duplication (
      FLT3-ITD) positive. Patient will be randomly assigned in a 1:1 ratio to one of two treatment
      arms. Both treatment arms will receive Quizartinib but at different doses. The study
      treatment is taken orally in 28 day cycles until either disease progression occurs or an
      unacceptable toxicity occurs. In addition to the study assessments to evaluate the disease,
      blood will be drawn to measure drug levels and biomarkers. Patients will be followed for
      survival at three month intervals after the end of treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject has morphologically documented primary acute myeloid leukemia (AML) or AML
             secondary to myelodysplastic syndrome (MDS) as defined by the World Health
             Organization (WHO) criteria, as determined by pathology review at the treating
             institution and has relapsed or is refractory after 1 second line (salvage) regimen or
             after hematopoietic stem cell transplantation (HSCT)

          -  Subject is positive for FLT3-ITD activating mutation in bone marrow or peripheral
             blood (>10% allelic ratio)

          -  Eastern Cooperative Oncology Group performance status of 0 to 2

          -  In the absence of rapidly progressing disease clearly documented by the investigator,
             the interval from prior treatment to time of AC220 administration will be at least 2
             weeks (14 days) for prior cytotoxic agents or at least 5 half-lives for prior
             noncytotoxic agents, including immunosuppressive therapy post HSCT

          -  Persistent chronic clinically significant nonhematological toxicities from prior
             treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental
             agents, radiation, HSCT, or surgery) must be Grade ≤ 1

          -  Patients - both males and females - with reproductive potential are eligible

        Exclusion Criteria:

          -  Subject received previous treatment with AC220

          -  Subject has a diagnosis of acute promyelocytic leukemia

          -  Subject has a diagnosis of chronic myelogenous leukemia (CML) in blast crisis

          -  Subject has AML or antecedent MDS secondary to prior chemotherapy

          -  Subject has had HSCT and has either of the following:

          -  Donor lymphocyte infusion (DLI) is not permitted during the study or < 30 days prior
             to study entry

          -  Subject has clinically active central nervous system (CNS) leukemia. A subject is
             considered eligible if CNS leukemia is controlled and subject is receiving intrathecal
             (IT) therapy at study entry. Subjects should continue to receive IT therapy (or
             cranial radiation) as clinically indicated

          -  Subject has received concurrent chemotherapy, immunotherapy, or radiotherapy within 14
             days prior to the first dose of AC220, or any ancillary therapy that is considered to
             be investigational (i.e., used for non-approved indications(s) and in the context of a
             research investigation) within 30 days or 5 half-lives (whichever is longer) prior to
             the first dose of study drug

          -  Subject requires treatment with concomitant drugs that prolong QT/QTc interval or with
             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 requires treatment with anticoagulant therapy

          -  Subject has a known positive test for human immunodeficiency virus, hepatitis C, or
             hepatitis B surface antigen

          -  Subject had major surgery within 4 weeks prior to first dose of AC220

          -  Subject has uncontrolled or significant cardiovascular disease, including

          -  Subject has a pre-existing disorder predisposing the subject to a serious or
             life-threatening infection (e.g. cystic fibrosis, congenital or acquired
             immunodeficiency, bleeding disorder, or cytopenias not related to AML)

          -  Subject has an active uncontrolled acute or chronic systemic fungal, bacterial, viral,
             or other infection

          -  Subject has any of the following laboratory values:

          -  Subject is a female with a positive pregnancy test, pregnant, or breastfeeding

          -  Subject has any medical, psychiatric, addictive or other kind of disorder which
             compromises the ability of the subject to give written informed consent and/or to
             comply with procedures