Decitabine and Midostaurin in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia (AML) With Multilineage Dysplasia Following Myelodysplastic Syndrome, in Adults; AML (Adult) With 11q23 (MLL) Abnormalities; AML (Adult) With Del (5q); AML (Adult) With Inv (16) (p13; q22); AML (Adult) With t (16;16) (p13; q22); AML (Adult) With t (8; 21) (q22; q22); Secondary AML (Adult); Untreated AML (Adult)
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
Intervention: Decitabine; Midostaurin
Intervention description: Given IV; Given PO
Intervention MeSH terms: Decitabine; Azacitidine; Midostaurin; Staurosporine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 60 Years
Healthy volunteers: No

Summary:

      This phase 2 study evaluates the sequential combination of decitabine then midostaurin for
      the treatment of newly-diagnosed acute myeloid leukemia (AML) in older patients.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Newly-diagnosed acute myeloid leukemia (AML) per the World Health Organization [WHO]
             2008 classification [except t (15; 17)], including:

               -  De novo AML

               -  Secondary AML

               -  Secondary AML arising from previously-diagnosed myelodysplastic syndromes (MDS)
                  treated with deoxyribonucleic acid (DNA) methyltransferase inhibitor (DNMTi) (ie,
                  decitabine or azacitidine)

          -  FLT3-ITD mutation confirmed in bone marrow aspirate

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper
             limit of normal (ULN)

          -  Serum bilirubin ≤ 2.5 ULN

          -  Serum creatinine ≤ 1.5 mg/dL and/or creatinine clearance ≥ 50 mL/min

          -  Ejection fraction ≥ 50% by echocardiogram

          -  Unwillingness or inability to receive conventional chemotherapy

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Ability to adhere to the study visit schedule and other protocol requirements

          -  Life expectancy > 2 months

        Exclusion Criteria:

          -  Receiving concomitant treatment with other anti-neoplastic agents (EXCEPTION:
             hydroxyurea). Prior treatment with DNMTi therapy (ie, decitabine or azacitidine) for
             MDS is allowed

          -  Received anti-neoplastic treatment within 4 weeks prior to enrollment (EXCEPTION:
             hydroxyurea)

          -  Received any surgical procedure, excluding central venous catheter placement or other
             minor procedures (eg, skin biopsy) within 14 days of study day 1

          -  Received any investigational agent within 4 weeks prior to enrollment

          -  Previous or current history of a myeloproliferative disease

          -  Known active central nervous system (CNS) malignancy

          -  Any other known disease (except carcinoma in-situ), concurrent severe and/or
             uncontrolled medical condition which could compromise participation in the study (eg,
             uncontrolled diabetes; cardiovascular disease including congestive heart failure;
             myocardial infarction within 6 months with poorly controlled hypertension; chronic
             renal disease; active uncontrolled infection)

          -  Active opportunistic infection or treatment for opportunistic infection within 4 weeks
             of first day of study drug dosing

          -  Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active
             viral hepatitis

          -  Known impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of midostaurin

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to midostaurin and/or decitabine

          -  Impaired cardiac function including any of the following:

               -  Screening electrocardiogram (ECG) with a corrected QT interval (QTc) > 450 msec

               -  Bradycardia defined as heart rate (HR) < 50 beats per minute (bpm)

               -  Right bundle branch block + left anterior hemiblock (bifascicular block)

               -  Patients with myocardial infarction or unstable angina < 3 months prior to
                  starting study drug

               -  Congestive heart failure (CHF) New York (NY) Heart Association class 3 or 4

          -  Inability to swallow or absorb drug

          -  Other medical or psychiatric illness or organ dysfunction or laboratory abnormality
             which in the opinion of the investigator would compromise the patient's safety or
             interfere with data interpretation

          -  Unwillingness or inability to comply with the protocol

          -  Pregnant

          -  nursing (lactating)

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, UNLESS they are using highly effective methods of contraception
             during dosing and for 3 months after midostaurin medication; highly effective
             contraception methods as follows:

               -  Total abstinence, when this is in line with the preferred and usual lifestyle of
                  the subject [periodic abstinence (eg, calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception]

               -  Female sterilization (surgical bilateral oophorectomy with or without
                  hysterectomy; or tubal ligation at least six weeks before taking study
                  treatment). In case of oophorectomy alone, reproductive status must be confirmed
                  by follow-up hormone level assessment

               -  Male sterilization, at least 6 months prior to screening (for female subjects on
                  the study, the vasectomized male partner should be the sole partner for that
                  subject)

               -  Combination of any two of the following (a+b or a+c, or b+c):

                    -  Use of oral, injected or implanted hormonal methods of contraception or
                       other forms of hormonal contraception that have comparable efficacy (failure
                       rate < 1%), eg, hormone vaginal ring or transdermal hormone contraception.
                       For oral contraception, women should have been stable on the same pill for a
                       minimum of 3 months before taking study treatment

                    -  Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    -  Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
                       suppository