Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML)
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Compound AC220
Intervention description: Precomplexed powder in bottle formulation supplied as 200 mg in a 60 cc polyethylene terephthalate (PET) plastic bottle. Requires reconstitution by a pharmacist, must be stored securely, and protected from light.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 333.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: AML; AC220; acute; FLT3; inhibitor; kinase; leukemia; leukaemia; myeloid; relapsed; refractory

Summary:

      AC220 will be administered as a once daily oral solution given continuously as 28-day
      treatment cycles, without any rest periods, until disease progression, relapse, intolerance
      to the drug, or elective allogeneic hematopoietic stem cell transplantation (HSCT).
    

Eligibility criteria:

        Current enrollment is open only to FLT3-ITD positive, Cohort 1.

        Inclusion Criteria:

          1. Males and females age ≥18 years in second relapse or refractory.

          2. Males and females age ≥60 years in first relapse or refractory.

          3. Must have baseline bone marrow sample taken.

          4. Morphologically documented primary AML or AML secondary to myelodysplastic syndrome
             (MDS with ≥20% bone marrow or peripheral blasts), as defined by the World Health
             Organization (WHO) criteria, confirmed by pathology review at treating institution.

          5. Able to swallow the liquid study drug.

          6. Eastern Cooperative Oncology Group performance status of 0 to 2

          7. In the absence of rapidly progressing disease, the interval from prior treatment to
             time of AC220 administration will be at least 2 weeks for cytotoxic agents or at least
             5 half-lives for noncytotoxic agents. The use of chemotherapeutic or antileukemic
             agents other than hydroxyurea is not permitted during the study with the possible
             exception of intrathecal (IT) therapy at the discretion of the Investigator and with
             the agreement of the Sponsor.

          8. Persistent chronic clinically significant non-hematological toxicities from prior
             treatment must be ≤Grade 1.

          9. Prior therapy with FLT3 inhibitors is permitted, except previous treatment with AC220.

         10. Serum creatinine ≤1.5 × upper limit of normal (ULN) and glomerular filtration rate
             (GFR) > 30 mL/min

         11. Serum potassium, magnesium, and calcium levels should be at least within institutional
             normal limits.

         12. Total serum bilirubin ≤1.5 × ULN

         13. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5 × ULN

         14. Females of childbearing potential must have a negative pregnancy test (urine β-hCG).

         15. Females of childbearing potential and sexually mature males must agree to use a
             medically accepted method of contraception throughout the study.

         16. Written informed consent must be provided.

        Exclusion Criteria:

          1. Patients over the age of 85 years except at the discretion of the Investigator and
             with agreement of the Sponsor.

          2. Diagnosis of acute promyelocytic leukemia

          3. Diagnosis of chronic myelogenous leukemia (CML) in blast crisis

          4. AML in relapse or refractory after 3 or more previous lines of chemotherapy (and/or
             HSCT) treatment

          5. AML or antecedent MDS secondary to prior chemotherapy

          6. Persistent clinically significant non-hematological toxicity that is Grade >1 by NCI
             CTCAE v4 from prior chemotherapy

          7. Patients who have had HSCT and are within 100 days of transplant and/or are still
             taking immunosuppressive drugs and/or have clinically significant graft-versus-host
             disease requiring treatment and/or have >Grade 1 persistent non hematological toxicity
             related to the transplant

          8. Clinically active central nervous system (CNS) leukemia. Patients with CNS leukemia,
             which is controlled, but who are still receiving IT therapy at study entry may be
             considered eligible and continue receive IT therapy at the discretion of the
             Investigator and with agreement of the Sponsor.

          9. Patients who have previously received AC220

         10. Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical
             assessment)

         11. Major surgery within 4 weeks prior to enrollment in the study

         12. Radiation therapy within 4 weeks prior to, or concurrent with study

         13. Use of concomitant drugs that prolong the time between the start of the Q wave and the
             end of the T wave (QT)/corrected interval between the Q wave and T wave (QTc) interval
             and/or are CYP3A4 inhibitors are prohibited with the exception of antibiotics,
             antifungals, and other antimicrobials that are used as standard of care to prevent or
             treat infections and other such drugs that are considered absolutely essential for the
             care of the patient.

         14. Uncontrolled or significant cardiovascular disease

         15. Women who are pregnant, lactating, or unwilling to use contraception if of
             childbearing potential

         16. Men who are unwilling to use contraception if their partners are of childbearing
             potential

         17. Active, uncontrolled infection

         18. Human immunodeficiency virus positivity

         19. Active hepatitis B or C or other active liver disease

         20. History of cancer, except Stage 1 cervix or nonmelanotic skin cancer, with the
             possible exception of patients in complete remission