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: Patients receive quizartinib orally (PO) once daily (QD) on days 5-28 of cycle 1 and
on days 1-28 of subsequent cycles and azacitidine subcutaneously (SC) or intravenously (IV)
over 10-40 minutes on days 1-7. Cycles repeat every 28 days in the absence of disease
progression or unacceptable toxicity.
ARM II: Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of
subsequent cycles and cytarabine SC twice daily (BID) on days 1-10. Cycles repeat every 28
days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6-12 months.
Inclusion Criteria:
- PHASE I
- Refractory or relapsed disease defined as follows: patients with MDS or chronic
myelomonocytic leukemia (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 World Health Organization (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 (i.e., high-dose
cytarabine-based chemotherapy).
- Patients are eligible regardless of their FLT3 mutation status.
- PHASE II
- COHORT 2A: 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 white blood cells (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 purpose, a
second induction cycle with the same drugs used during the first cycle, consolidation
chemotherapy or stem cell transplant in complete remission (CR) (or complete response
with incomplete platelet recovery [CRp] or complete response with incomplete bone
marrow recovery [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).
- COHORT 2A: 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.
- COHORT 2A: Patients must have evidence of FLT3 ITD in their most recent assessment.
- COHORT 2B: 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)
- COHORT 2B: 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
- COHORT 2B: Patients must have no evidence of FLT3 mutations in their most recent
assessment
- PHASE I AND II
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
- Bilirubin =< 2 x upper limit of normal (ULN).
- Alanine aminotransferase (ALT) =< 2.5 x ULN.
- For patients with suspected liver infiltration from leukemia ALT should be =< 5
ULN.
- Creatinine =< 2 x ULN.
- Serum potassium, magnesium, and calcium (normalized for albumin) levels should be at
least within institutional normal limits.
- Patients must provide written informed consent.
- 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
principal investigator (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.
- 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.
- Negative urine or serum pregnancy test.
Exclusion Criteria:
- Patients with known allergy or hypersensitivity to quizartinib, mannitol, AZA,
cytarabine or any of their components.
- 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.
- Patients with known significant impairment of gastrointestinal (GI) function or GI
disease that may significantly alter the absorption of quizartinib.
- 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.
- Patients with a known confirmed diagnosis of human immunodeficiency virus (HIV)
infection or active viral hepatitis.
- Patients who have had any major surgical procedure within 14 days of day 1.
- Patients with known malignant disease of the central nervous system.
- Impaired cardiac function including any of the following: screening
electrocardiography (ECG) with a corrected QT (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; congestive heart failure (CHF) New York (NY)
Heart Association class III or IV. 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.
- Known family history of congenital long QT syndrome.
