Quizartinib With Azacitidine or Cytarabine in Treating Participants With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the
combination of quizartinib (AC220) with either azacitidine (5-azacitidine [AZA]) or low-dose
cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic
syndrome (MDS). (Phase I) II. To determine the clinical activity of the combination of
quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the clinical activity of the combination of quizartinib with either AZA or
LDAC in patients with AML or MDS. (Phase I) II. To determine the safety of the combination of
quizartinib with either AZA or LDAC in patients with AML or MDS. (Phase II) III. To determine
the induction of hypomethylation, deoxyribonucleic acid (DNA) damage and FLT3 signaling
during therapy with this combination and its correlation with response. (Phase I and II) IV.
To determine the effect of this combination therapy on plasma levels of FLT3-ligand. (Phase I
and II) V. To determine the pharmacodynamics of this combination therapy in patients with AML
or high-risk MDS. (Phase I and II)

OUTLINE: This is a phase I, dose-escalation study of quizartinib followed by a phase II
study. Participants are assigned to 1 of 2 arms.

ARM I: Participants receive quizartinib orally (PO) once daily (QD) on days 5-28 of course 1
and on days 1-28 of subsequent courses and azacitidine subcutaneously (SC) or intravenously
(IV) over 10-40 minutes on days 1-7. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

ARM II: Participants receive quizartinib PO QD on days 5-28 of course 1 and on days 1-28 of
subsequent courses and cytarabine SC twice daily (BID) on days 1-10. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 6-12 months.

Inclusion Criteria:

1. For Phase I Only: Refractory or relapsed disease defined as follows: Patients with MDS
or CMML should have failed prior therapy (e.g., with a hypomethylating agent,
clofarabine, and/or with lenalidomide); Patients with AML should have failed any prior
induction therapy or have relapsed after prior therapy; Patients (any age) with MDS or
CMML who received therapy with a hypomethylating agent and progress to AML are
eligible at the time of diagnosis of AML regardless any prior therapy for AML. The WHO
classification will be used for AML; Patients with any of the eligible diagnoses who
have received no prior therapy are eligible if not candidates to receive standard
intensive therapy (ie, high-dose cytarabine-based chemotherapy).

2. For Phase I Only: Patients are eligible regardless of their FLT3 mutation status.

3. For Phase I Only: Age >/=18 years

4. For Phase II Only: two cohorts will be enrolled: Cohort 2A - FLT3-ITD: Patients with
MDS, CMML or AML who are either: Age 60 years or older and newly diagnosed, previously
untreated. Prior therapy with hydroxyurea or single agent ara-C for the purpose of
control of WBC is acceptable.; Age 18 years or older and with refractory or relapse
disease who have received no more than one prior treatment regimen and will be
receiving first salvage. For this purposes, a second induction cycle with the same
drugs used during the first cycle, consolidation chemotherapy or stem cell transplant
in CR (or CRp or CRi) will be considered part of the prior regimen. Prior therapy for
MDS (or other malignancies) is not considered a prior regimen for AML in patients who
progress from MDS (or other malignancies).;

5. For Phase II only: two cohorts will be enrolled: Cohort 2A - FLT3-ITD: Patients (any
age) with MDS or CMML who received therapy with a hypomethylating agent and progress
to AML are eligible regardless of any prior therapy for AML. The WHO classification
will be used for AML

6. For Phase II only: two cohorts will be enrolled: Cohort 2A - FLT3-ITD: Patients must
have evidence of FLT3 ITD in their most recent assessment.

7. For Phase II only: two cohorts will be enrolled: Cohort 2B - FLT3-WT: Patients with
MDS, CMML or AML who are either: Age 60 years or older and newly diagnosed, previously
untreated. Prior therapy with hydroxyurea or single agent ara-C for the purpose of
control of WBC is acceptable or Age 18 years or older and with refractory or relapse
disease who have received no more than two prior treatment regimens and will be
receiving second salvage, or who have received a prior SCT and will be receiving their
first salvage. For this purposes, a second induction cycle with the same drugs used
during the first cycle, consolidation chemotherapy or stem cell transplant in CR (or
CRp or CRi) will be considered part of the prior regimen. Prior therapy for MDS (or
other malignancies) is not considered a prior regimen for AML in patients who progress
from MDS (or other malignancies).

8. For Phase II only: two cohorts will be enrolled: Cohort 2B - FLT3-WT: Patients (any
age) with MDS or CMML who received therapy with a hypomethylating agent and progress
to AML are eligible at the time of diagnosis of AML regardless any prior therapy for
AML. The WHO classification will be used for AML.

9. For Phase II only: two cohorts will be enrolled: Cohort 2B - FLT3-WT: Patients must
have no evidence of FLT3 mutations in their most recent assessment.

10. For Phase I and II: ECOG Performance Status
11. For Phase I and II: Adequate liver (bilirubin (creatinine leukemia ALT should be
12. For Phase I and II: Serum potassium, magnesium, and calcium (normalized for albumin)
levels should be at least within institutional normal limits.

13. For Phase I and II: Patients must provide written informed consent.

14. For Phase I and II: Patients must have been off chemotherapy for 2 weeks prior to
entering this study, unless there is evidence of rapidly progressive disease, and must
have recovered from the toxic effects of that therapy to at least grade 1. Use of
hydroxyurea for patients with rapidly proliferative disease is allowed before the
start of study therapy and for the first four weeks on therapy. The additional days of
Hydrea after 28 is permitted as clinically indicated, on case by case basis after
discussion with the PI. Other agents given transiently with the intention to control
rapid proliferation such as 1-2 doses of single agent ara-C or few doses of sorafenib
are also allowed.

15. For Phase I and II: Women of childbearing potential must practice contraception. Women
considered not of childbearing potential include any of the following: no menses for
at least 2 years or menses within 2 years but amenorrheic for at least 2 months and
luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal
range (according to definition of postmenopausal for laboratory used) or bilateral
oophorectomy or radiation castration and amenorrheic for at least 3 months. Females of
childbearing potential should practice effective methods of contraception Effective
methods of contraception include barrier methods (e.g., condoms, diaphragm),
spermicidal jelly or foam, oral, depo provera, or injectable contraceptives,
intrauterine devices, tubal ligation, and abstinence. Male patients with female
partners who are of childbearing potential should also practice contraception.

16. For Phase I and II: Negative urine or serum pregnancy test.

Exclusion Criteria:

1. Patients with known allergy or hypersensitivity to quizartinib, mannitol, AZA,
cytarabine or any of their components.

2. Patients with electrolyte abnormalities at study entry defined as follows: Serum
potassium < 3.5 mEq/L despite supplementation, or > 5.5 mEq/L; Serum magnesium above
or below the institutional normal limit despite adequate management; Serum calcium
(corrected for albumin levels) above or below institutional normal limit despite
adequate management.

3. Patients with known significant impairment of gastrointestinal (GI) function or GI
disease that may significantly alter the absorption of quizartinib.

4. Patients with any other known disease concurrent severe and/or uncontrolled medical
condition (e.g. uncontrolled diabetes, cardiovascular disease including congestive
heart failure, myocardial infarction within 6 months and poorly controlled
hypertension, chronic renal disease, or active uncontrolled infection) which could
compromise participation in the study. Patients with current active malignancies or
any remission for < 6 months, except patients with carcinoma in situ or with
non-melanoma skin cancer who may have active disease or be in remission for less than
6 months.

5. Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis.

6. Patients who have had any major surgical procedure within 14 days of Day 1.

7. Patients with known malignant disease of the central nervous system.

8. Impaired cardiac function including any of the following: Screening ECG with a QTc
>450 msec. The QTc interval will be calculated by Fridericia's correction factor
(QTcF) at Screening and on Day 5 prior to the first dose of AC220. The QTcF will be
derived from the average QTcF in triplicate.; If QTcF>450 msec on Day 5, AC220 will
not be given; Patients with congenital long QT syndrome; History or presence of
sustained ventricular tachycardia requiring medical intervention; Any history of
clinically significant ventricular fibrillation or torsades de pointes; Known history
of second or third degree heart block (may be eligible if the patient currently has a
pacemaker); Sustained heart rate of <50/minute on pre-entry ECG; Right bundle branch
block + left anterior hemiblock (bifascicular block); Patients with myocardial
infarction or unstable angina within 6 months prior to starting study drug; CHF NY
Heart Association class III or IV.

9. **continued from above: Atrial fibrillation documented within 2 weeks prior to first
dose of study drug; Patients who require treatment with concomitant drugs that prolong
QT/QTc interval or strong CYP3A4 inhibitors or inducers with the exception of
antibiotics, antifungals, and antivirals 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 subject.

10. Known family history of congenital long QT syndrome.