A Combination of Cladribine, Idarubicin, Cytarabine (CLIA) and Quizartinib for the Treatment of Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS))
A Combination of Cladribine, Idarubicin, Cytarabine (CLIA) and Quizartinib for the Treatment of Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (MDS))
This phase I/II trial studies the side effects and how well cladribine, idarubicin, cytarabine, and quizartinib work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that is newly diagnosed, has come back (relapsed), or does not respond to treatment (refractory). Drugs used in chemotherapy, such as cladribine, idarubicin, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving quizartinib with cladribine, idarubicin, and cytarabine may help to control acute myeloid leukemia or high-risk myelodysplastic syndrome.
PRIMARY OBJECTIVES:
I. To determine the efficacy of quizartinib (AC220) in combination with cladribine, idarubicin and cytarabine (ara-C) induction chemotherapy in newly diagnosed or relapsed/refractory patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
II. To determine the safety of the combination.
SECONDARY OBJECTIVES:
I. To determine the overall survival and disease-free survival of patients treated with this combination.
II. To investigate correlations of response to this combination with a 81-gene panel of gene mutations both in patients with and without FLT3 mutations.
III. To identify individual treatment-resistant cell populations and their signaling state that may relate to clinical outcomes using CyTOF (cytometry by time of flight) and single cell sequencing.
OUTLINE:
INDUCTION: Patients receive idarubicin intravenously (IV) over 1 hour on days 1-3, cladribine IV over 1-2 hours on days 1-5, cytarabine IV over 2 hours on days 1-5 (or days 1-3 for patients over age 60), and quizartinib orally (PO) once daily (QD) on days 6-19. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: Patients who achieve complete response (CR) or CR with incomplete platelet recovery (CRp) after Induction receive idarubicin IV over 1 hour on days 1-2, cladribine IV over 1-2 hours on days 1-3, cytarabine IV over 2 hours on days 1-3, and quizartinib PO QD on days 4-28. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients who achieve CR or CR with incomplete bone marrow recovery (CRi)/CR with partial hematologic recovery (CRh) after Consolidation receive quizartinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6-12 months.
Inclusion Criteria:
Diagnosis of
Frontline cohort: Patients aged 18 to 65 years
Relapse cohort: Patients aged >=18 years old
Patients may be newly diagnosed (Frontline cohort) or with prior therapy (Relapsed cohort) as follows:
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Creatinine < 1.5 mg/dl
Total bilirubin < 1.5 mg/dL, unless increase is due to hemolysis or congenital disorder
Transaminases (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal (ULN)
Potassium, magnesium, and calcium (normalized for albumin) levels should be at least within institutional normal limits
Ability to take oral medication
Ability to understand and provide signed informed consent
Baseline test of left ventricular ejection fraction >= 50%
Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 7 days
WOCBP must use appropriate method(s) of contraception such as oral contraceptive pills (OCP), birth control shots, intrauterine device (IUD) etc. WOCBP should use an adequate method to avoid pregnancy until 30 days after the last dose of investigational drug. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile) as well as men with known azoospermia do not require contraception
Patients with isolated extramedullary myeloid neoplasm will be eligible
Exclusion Criteria:
Any coexisting medical condition that in the judgment of the treating physician is likely to interfere with study procedures or results
Breastfeeding women
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 be in remission for less than 6 months or have active disease
Active clinically serious and uncontrolled infection. Patients with recent infections must have no temperature of >= 101 degrees Fahrenheit (F) for at least 48 hours (hrs) (before first dose, day 1)
Patients with known significant impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of quizartinib
Documented active central nervous system leukemia (patients with history of central nervous system [CNS] leukemia without active disease are allowed)
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
Impaired cardiac function including any of the following:
myilmaz@mdanderson.org713-794-5783