This phase IB/II trial studies the best dose of TP-0903 and how well it works when given alone or with azacitidine in treating patients with FLT3 gene mutated acute myeloid leukemia. TP-0903 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as azacitidine, 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 TP-0903 alone or with azacitidine may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To determine a tolerable dose of dubermatinib (TP-0903) monotherapy for relapsed/refractory patients with FLT3 acute myeloid leukemia (AML).

II. To determine the maximum tolerated dose (MTD) of TP-0903 with azacitidine in untreated unfit patients with FLT3 AML.

III. To determine the complete remission (CR) or complete remission with partial hematologic recovery (CRh) rate following induction therapy with TP-0903 in relapsed/refractory patients or TP-0903 with azacitidine therapy in untreated unfit patients with FLT3 AML.

SECONDARY OBJECTIVES:

I. To determine the toxicity profile of TP-0903 as a single agent and in combination with or azacitidine.

II. To determine disease-free survival for patients achieving CR/CRh in each cohort.

III. To determine overall survival for patients in each cohort. IV. To determine the proportion of patients who go to transplant.

EXPLORATORY OBJECTIVES:

I. To conduct pharmacokinetic studies of TP-0903 alone and in combination with azacitidine.

II. To examine changes in circulating AXL, Gas6, FLT3 ligand, and other cytokines/chemokines by TP-0903.

III. To determine the impact of TP-0903 on the inhibition of kinase signaling (AXL, FLT3, STAT5, AURKA), and metabolomics in AML cells.

IV. To determine differentially expressed genes in bone marrow stromal cells and AML cells upon TP-0903 treatment.

V. To examine sensitivity and resistance patterns associated with TP-0903 by genomic, epigenomic, and transcriptomic profiling.

OUTLINE: This is a phase Ib, dose-escalation study of dubermatinib followed by a phase II study.

(FLT3 AML WITH RELAPSED/REFRACTORY DISEASE):

INDUCTION: Patients receive dubermatinib orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients with clinical or hematologic response and not transplant eligible may continue dubermatinib until loss of response/clinical benefit. Patients with clinical or hematologic response and transplant eligible may continue dubermatinib until one week prior to admission.

After completion of study treatment, patients are followed up followed every 3 months for up to 2 years from registration and then every 6 months for up to 5 years from registration.

Inclusion Criteria:

• Patients with AML and the presence of FLT3-ITD mutation
• Patients with secondary AML or therapy related disease (t-AML) are eligible
• If the patient has co-morbid medical illness, life expectancy attributed to this must be greater than 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Total bilirubin < 2.0mg/dL unless due to Gilbert's disease
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x institutional upper limit of normal
• Creatinine (Cr) clearance > 50 mL/min by Cockcroft-Gault calculation
• New York Heart Association (NYHA) Congestive Heart Failure (CHF) class II or better
• Cardiac ejection fraction ≥40%
• Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose
• Ability to understand and willingness to sign the written informed consent document
• Human immunodeficiency virus (HIV) infection without history of acquired immunodeficiency syndrome (AIDS) and sufficiently high CD4 cells (> 400/mm^3) and low HIV viral loads (< 30,000 copies/ml plasma) not requiring anti-HIV therapy are eligible

Exclusion Criteria:

• Patients with acute promyelocytic leukemia
• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Treatment with hydoxyurea is permitted during cycle 1 to maintain white blood cell (WBC) < 40,000/uL
• Patients receiving any other investigational agents or patients that have received other investigational agents within 14 days of enrollment
• Patients with active central nervous system (CNS) malignancy
• Major surgery within 2 weeks before day 1
• Uncontrolled active infection. Patients with infection requiring parenteral antibiotics are eligible if the infection is controlled
• Patients with significantly diseased or obstructed gastrointestinal tract
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, myocardial infarction within 6 months prior to enrollment, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
• Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Pregnant women or women who are breastfeeding are excluded from this study. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women
• Patients with advanced malignant solid tumors
• Patients who are not able to swallow capsules or tablets