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Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine SC or IV over 10-40 minutes on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC BID on days 1-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Yesid Alvarado, MD

This phase I/II trial studies the side effects and best dose of quizartinib when given in combination with azacitidine or cytarabine in treating patients with acute myeloid leukemia or myelodysplastic syndrome that have come back (relapsed) or are not responding to treatment (refractory). Quizartinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine 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. Giving quizartinib with azacitidine or cytarabine may work better in patients with 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: 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.

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

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)

(complete remission \[CR\]+complete response with incomplete bone marrow recovery \[CRI\]+partial remission \[PR\]+ hematologic improvement \[HI\]). Complete Rmission (CR) is bone marrow blasts of \</= 5%, platelets \>/= 100 and Absolute Neutrophil Count of \>/= 1000. complete response with incomplete bone marrow recovery \[CRI\] is is bone marrow blasts of \</= 5%, platelets \>/= 100 or Absolute Neutrophil Count of \>/= 1000. Hematologic improvement \[HI\]) is Bone Marrow Blasts \</= 5%. Partial remission \[PR\] is bone marrow blasts of \</= 5% with \> 50% reduction, platelets \>/= 100 and Absolute Neutrophil Count of \>/= 1000.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and azacitidine SC or IV over 10-40 minutes on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Azacitidine: Given SC or IV

Quizartinib: Given PO

Phase 1 Arm I (Quizartinib, Azacitidine)

Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC BID on days 1-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cytarabine: Given SC

Quizartinib: Given PO

Phase 1 Arm II (Quizartinib, Cytarabine)

Phase 2 Arm I (Quizartinib, Azacitidine)

Patients receive quizartinib PO QD on days 5-28 of cycle 1 and on days 1-28 of subsequent cycles and cytarabine SC BID on days 1-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cytarabine: Given SC

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Quizartinib With Azacitidine or Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome	NCT01892371	FLT3 Gene Mutat... FLT3 Internal T... Recurrent Acute... Recurrent Chron... Recurrent Myelo... Refractory Acut... Refractory Chro... Refractory Myel...	Azacitidine Cytarabine Quizartinib	18 Years -	M.D. Anderson Cancer Center
Quizartinib With Azacitidine or Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome	NCT01892371	FLT3 Gene Mutat... FLT3 Internal T... Recurrent Acute... Recurrent Chron... Recurrent Myelo... Refractory Acut... Refractory Chro... Refractory Myel...	Azacitidine Cytarabine Quizartinib	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for flt3 internal tandem duplication positive