Nintedanib and Azacitidine in Treating Participants With HOX Gene Overexpression Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria: * ESCLATION COHORT: Patients must have a diagnosis of newly diagnosed and/ or relapsed/refractory AML with any of the following: * Confirmed translocation involving 11q23 * Partial tandem duplication(PTD) of the MLL gene (on 11q23) * FLT3-ITD (internal tandem duplication) * Increased Fgf2 in serum (2 standard deviations above control serum samples) * HOX(A9/A10) over-expression in bone marrow ( 2 standard deviations above control values in CD34+ cells from normal subjects) * Note: Relapsed or refractory AML is defined as either: * Recurrence of disease after a complete remission (CR), or * Failure to achieve CR with initial therapy * EXPANSION COHORT: Patients must have a diagnosis of newly diagnosed AML with any of the following: * Confirmed translocation involving 11q23 * Partial tandem duplication (PTD) of the MLL gene (on 11q23) * FLT3-ITD (internal tandem duplication) * Increased Fgf2 in serum (2 standard deviations above control serum samples) * HOX(A9/A10) over-expression in bone marrow (2 standard deviations above control values in CD34+ cells from normal subjects) * Note: Patients with secondary AML are eligible for enrollment into the trial (in both cohorts); secondary AML is defined as AML that has developed in a person with a history of antecedent blood count abnormalities, or myelodysplastic syndromes (MDS), or a myeloproliferative disorder (excluding chronic myeloid leukemia); or a history of prior chemotherapy or radiation therapy for a disease other than AML * Patients who are not candidates for, or decline, intensive therapy * Patients must exhibit an ECOG performance status 0-3 * International normalized ratio (INR) ? 2 (If coagulopathy is related to disease, this criterion does not apply) within14 days prior to registration * Prothrombin time (PT) and partial thromboplastin time (PTT) ? 1.5 x of institutional upper limit of normal (ULN) (Note: If coagulopathy is related to disease, this criteria do not apply) within14 days prior to registration * Total bilirubin ? 1.5 x of institutional ULN within14 days prior to registration * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SPGT\]) 1.5 X institutional upper limit of normal (ULN) within14 days prior to registration * Creatinine 2 x ULN OR creatinine clearance \> 30 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation * Females of child-bearing potential (FOCBP) and males must agree to use medically acceptable method of contraception (e.g. a method which results in a low failure rate of less than 1% per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, latex condoms for participating males, sexual abstinence) prior to study entry, for the duration of study participation, and for 3 months following completion of therapy; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; if the female partner of a male participant becomes pregnant he should inform the treating physician and the female partner should contact her treating physician immediately * NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months) * FOCBP must have a negative pregnancy test (beta-human chorionic gonadotropin \[HCG\] test in urine or serum) within 7 days prior to registration on study (Note: The test will have to be repeated if cycle 1 day1 is more than 3 days from registration) * Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study * Patients must agree/be able to comply with all protocol specific requirements Exclusion Criteria: * Patients who have received chemo-, hormone-, radio or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 14 days prior to start of treatment or those who have not recovered from adverse events attributed to the agent to grade 1 or baseline * Exceptions for prior treatments are: * Hydroxyurea for increased blast count (no washout period required; it can be continued throughout the first cycle of therapy) * Leukapheresis for leukocytosis (no wash out period required; it can be continued during the study) * Note: If patient is registered prior to completion of washout, start date of treatment will need to be confirmed prior to registration; please see assigned quality assurance monitor (QAM) with questions * Patients who have received any other investigational product within14 days of treatment are not eligible for this study; a wash out period ? 14 days or 5 half- lives (whichever is greater) is required from investigational treatment, prior to start of study treatment; please Note: * If patient is registered prior to completion of washout, start date of treatment will need to be confirmed prior to registration; please see assigned QAM with questions * The ?5 half-lives? time period will be determined by investigational pharmacy * If half life is not known and cannot be predicted, then wash out of ? 14 days is required * Patients who have had major injuries and/or surgery within the past 4 weeks (\< 28 days) prior to registration with incomplete wound healing and/or planned surgery while the patient is on study treatment * Patients who have proteinuria CTCAE version (v)4.03 grade 2 or greater within \< 30 days of registration * Patients who have significant cardiovascular diseases are not eligible; these are: * Uncontrolled hypertension * Unstable angina * History of infarction within the past 12 months prior to start of study treatment * Congestive heart failure \> New York Heart Association (NYHA) II * Serious uncontrolled cardiac arrhythmia * Pericardial effusion * Patients requiring therapeutic anticoagulation with drugs requiring INR monitoring or anti-platelet therapy, except for acetylsalicylic acid (aspirin) ? 325 mg per day, are not eligible * Patients with acute promyelocytic leukemia (APL) are not eligible * Patients with known or suspected central nervous system (CNS) leukemia are not eligible * Patients with known extramedullary leukemia are not eligible * Patients who have received prior treatment with nintedanib or any other VEGFR inhibitor are not eligible * Patients with known hypersensitivity to nintedanib or 5-azacitidine or who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nintedanib or 5-azacitidine are not eligible * Patients with hypersensitivity to mannitol are not eligible; patients who have known hypersensitivity to peanut or soya, any other trial drug, or their excipients, or to contrast media are not eligible * Patients with known active or history of chronic hepatitis C and/or B infection, known HIV infection and active alcohol or drug abuse are not eligible. * Patient with HIV who require anti-viral or supportive care that interacts with the study drugs are not eligible * Patients must not have a concurrent active malignancy for which they are receiving treatment * Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible: * Active uncontrolled infection * Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastrointestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study * Psychiatric illness/social situations that would limit compliance with study requirements * Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient?s safety or study endpoints * Female patients who are pregnant or nursing are not eligible * Patients who are unable to swallow oral gel capsules are not eligible * Patients who have gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug are not eligible