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INDUCTION: Patients receive idarubicin Intravenous over 1 hours on days 1-3, cladribine intravenous over 1-2 hours on days 1-5, cytarabine Intravenous over 3 hours on days 1-5 (or days 1-3 for patients over age 60), and quizartinib by mouth daily 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 CR or CRp after Induction receive idarubicin Intravenous over 1 hours on days 1-2, cladribine Intravenous over 1-2 hours on days 1-3, cytarabine Intravenous over 3 hours on days 1-3, and quizartinib by mouth daily 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 CRi/CRh after Consolidation receive quizartinib by mouth daily on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Musa Yilmaz

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.

Cladribine, Idarubicin, Cytarabine, and Quizartinib in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

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))

Will be estimate using the Kaplan-Meier method for each patient cohort. In addition, efficacy EFS will be analyzed in the intent to treat (ITT) population per cohort.

Defined as any clinically significant treatment-related grade 3 or greater non-hematologic toxicity. Patient toxicity data will be summarized using frequency and percentages, by type, grade and relationship to the study drugs.

Will be estimate using the Kaplan-Meier method for each patient cohort. In addition, efficacy OS will be analyzed in the ITT population per cohort.

Will be estimate using the Kaplan-Meier method for each patient cohort. In addition, efficacy DFS will be analyzed in the ITT population per cohort.

The rate of response will be estimated for each 28-gene panel of gene mutations for each patient cohort.

Will also explore the change of FLT3 ligand level before and after treatment using summary statistics, by patient cohort and by other subgroups (i.e. age).

Will also explore the change in the presence of other gene mutations before and after treatment using summary statistics, by patient cohort and by other subgroups (i.e. age).

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for blasts 20 percent or more of bone marrow nucleated cells