Phase I/II Study of the Combination of Quizartinib (AC220) with 5-Azacytidine or Low-Dose Cytarabine for the Treatment of Patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)
The goal of the Phase 1 part of this clinical research study is to find the highest tolerable dose of AC220 (quizartinib) that can be given with either 5-azacitidine (azacitidine) or cytarabine to patients with AML or MDS. The goal of the Phase 2 part of the study is to learn if quizartinib with either azacitidine or cytarabine can help to control AML or MDS. The safety of these combinations will also be studied.
Disease Group: Leukemia
Treatment Agent: 5-Azacytidine,AC220,Cytarabine
Treatment Location: Only at MDACC
Sponsor: Ambit Biosciences,Celgene,Leukemia SPORE
Primary Objectives Phase I: To determine the DLT and MTD of the combination of quizartinib (AC220) with either 5-azacitidine (AZA) or low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Phase II: To determine the clinical activity of the combination of quizartinib with either AZA or LDAC in patients with AML or MDS. Secondary Objectives Phase I: To determine the clinical activity of the combination of quizartinib with either AZA or LDAC in patients with AML or MDS. Phase II: To determine the safety of the combination of quizartinib with either AZA or LDAC in patients with AML or MDS. Both To determine the induction of hypomethylation, DNA damage and FLT3 signaling during therapy with this combination and its correlation with response. To determine the effect of this combination therapy on plasma levels of FLT3-ligand To determine the pharnacodynamicvs of this combination therapy in patients with AML or high-risk MDS.
IRB Review and Approval Date: 11/12/2013
Recruitment Status: Open
Projected Accrual: N/A
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
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: 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: 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
6) For Phase II only: Patients must have evidence of FLT3 ITD in their most recent assessment.
7) For Phase I and II: ECOG Performance Status </= 2
8) For Phase I and II: Adequate liver (bilirubin </=2x ULN, ALT </=2.5x ULN) and renal (creatinine </=2x ULN) function. For patients with suspected liver infiltration from leukemia ALT should be </= 5 ULN.
9) For Phase I and II: Serum potassium, magnesium, and calcium (normalized for albumin) levels should be at least within institutional normal limits.
10) For Phase I and II: Patients must provide written informed consent.
11) 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.
12) 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.
13) For Phase I and II: Negative urine or serum pregnancy test.
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.
Information and next steps
Phase I/Phase II
For general questions about clinical trials: