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A Phase II Study of Decitabine in Combination With Midostaurin (PKC412) for Elderly Patients With Newly Diagnosed FLT3-ITD/TKD Positive Acute Myeloid Leukemia

Phase 2
60 Years
Not Enrolling
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

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Trial Information

A Phase II Study of Decitabine in Combination With Midostaurin (PKC412) for Elderly Patients With Newly Diagnosed FLT3-ITD/TKD Positive Acute Myeloid Leukemia


I. To determine the efficacy of midostaurin when administered in combination with a fixed
dose of decitabine, administered sequentially, in elderly patients (age >= 60 years) with
fms-related tyrosine kinase 3 (FLT3)- internal tandem duplication (ITD)/tyrosine kinase
domain (TKD)-positive acute myeloid leukemia (AML) (as measured by complete remission rate).

II. To assess the safety profile of this combination in elderly patients with
FLT3-ITD/TKD-positive AML for both induction and post-remission therapy (adverse events
[AEs]/serious adverse events [SAEs] as determined by Common Terminology Criteria for Adverse
Events [CTCAE] version 4.0).


I. To determine overall survival for all patients and duration of response during the time
period of study monitoring.


INDUCTION THERAPY: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10
and midostaurin orally (PO) twice daily (BID) on days 11-28. Treatment repeats every 28 days
until documented bone marrow response is achieved or for up to 12 courses in the absence of
disease progression or unacceptable toxicity. Patients achieving documented bone marrow
response by course 6 continue treatment with induction therapy; patients achieving response
after course 6 proceed to post-remission therapy.

POST-REMISSION THERAPY: Patients receive decitabine IV over 1 hour on days 1-5 and
midostaurin PO BID on days 6-28. Treatment repeats every 28 days for up to 12 courses
(including induction therapy) in the absence of disease progression or unacceptable

After completion of study treatment, patients are followed up for up to 1 year.

Inclusion Criteria:

- Newly diagnosed AML (according to 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)
(i.e., decitabine or azacitidine)

- Confirmed FLT3-ITD or FLT3-TKD mutation, measured on bone marrow aspirate as part of
screening prior to study enrollment; sample will be submitted to Stanford clinical
lab and sent out for commercially available test at Laboratory for Personalized
Molecular Medicine

- 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 x 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 of greater than two months

Exclusion Criteria:

- Patients receiving concomitant treatment with other anti-neoplastic agents, with the
exception of hydroxyurea; however, prior treatment with DNMTi therapy (i.e.,
decitabine or azacitidine) for MDS is allowed

- Anti-neoplastic treatment less than 4 weeks prior to enrollment, with the exception
of hydroxyurea

- Inability to swallow or absorb drug

- Active opportunistic infection or treatment for opportunistic infection within four
weeks of first day of study drug dosing

- 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

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to midostaurin and/or decitabine

- Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of midostaurin

- Any other known disease (except carcinoma in-situ), concurrent severe and/or
uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular disease
including congestive heart failure, myocardial infarction within 6 months and poorly
controlled hypertension, chronic renal disease, or active uncontrolled infection)
which could compromise participation in the study

- A known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active
viral hepatitis because of uncertain toxicity profile of midostaurin in this patient

- Patients who have received any investigational agent within 4 weeks of enrollment

- Patients who have had any surgical procedure, excluding central venous catheter
placement or other minor procedures (e.g. skin biopsy) within 14 days of day 1

- Unwillingness or inability to comply with the protocol

- Known active central nervous system (CNS) malignancy

- Previous or current history of a myeloproliferative disease

- 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 III or IV

- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive human chorionic gonadotropin (hCG) laboratory test

- 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 include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of
the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study
treatment; in case of oophorectomy alone, only when the reproductive status of
the woman has been 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

- 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%), for example hormone vaginal ring or transdermal hormone contraception

- 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

- In case of use of oral contraception women should have been stable on the
same pill for a minimum of 3 months before taking study treatment

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Complete remission (CR) rate

Outcome Time Frame:

Up to 1 year

Safety Issue:


Principal Investigator

Bruno C. Medeiros

Investigator Role:

Principal Investigator

Investigator Affiliation:

Stanford University Hospitals and Clinics


United States: Federal Government

Study ID:




Start Date:

May 2013

Completion Date:

Related Keywords:

  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia



Stanford University Cancer InstituteStanford, California  94305