Accrual factor

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.

Treatment with decitabine, a cytidine analog, then midostaurin, a multi-target protein kinase inhibitor (PKI), may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

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