Combination of Decitabine and Midostaurin in Patients Older Than 60 With Newly Diagnosed or Relapsed Refractory Acute Myeloid Leukemia

The development of a primarily outpatient treatment option for AML that is also capable of
providing significant disease control is a priority for most clinicians. To address the need
for less toxic, more effective treatments for older patients with AML, the purpose of this
Phase 1 single institution study is to evaluate the safety and efficacy of midostaurin and
decitabine administered in combination.

Decitabine is an epigenetic modifier of gene expression that has been shown to be
well-tolerated in this population at the dose schedule proposed in this study, with
reasonable efficacy. Although its precise mechanism of action is incompletely understood, it
is postulated to work by reactivating the expression of key tumor suppressor genes silenced
in tumor cells by reversing a pattern of hypermethylation of promotor elements.

Midostaurin is an oral agent that has been shown to inhibit FLT3 kinase in preclinical in
vitro and in vivo studies, as well as clinically in patients with both ITD and TKD FLT3
mutations (FLT3mut). Both directly and indirectly, midostaurin also potently inhibits
multiple other molecular targets thought to be important for the pathogenesis of AML. These
targets include VEGFR-1, a VEGF receptor; c-kit; H- and K-ras; as well as the multidrug
resistant gene, MDR.

The addition of midostaurin to a decitabine regimen of previously established efficacy and
tolerability will allow us to evaluate the hypothesis that two drugs that are believed to
work through distinct mechanisms of action may act together to improve the responses of
patients treated with decitabine alone, without significant additional toxicity.

Inclusion Criteria:

- ≥ 60 years of age with newly diagnosed AML that is not eligible for standard induction
or ≥ 18 years of age with relapsed/refractory AML

- Histologically documented AML (except t(15;17)according to the World Health
Association (WHO) criteria

- Karnofsky performance status ≥ 70

- Must have the following lab values:

- AST and ALT < or equal to 2.5 x Upper Limit of Normal (ULN)

- Serum Bilirubin < or equal to 2.5 x ULN

- Serum Creatinine < or equal to 2.5 x ULN

- Must give written informed consent

- Left ventricular ejection fraction ≥ 50%

Exclusion Criteria:

- Prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell
transplant less than 2 months previously

- Uncontrolled active infection

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

- Female patients who are pregnant or breast-feeding or adults of reproductive potential
not using an effective method of birth control. Barrier contraceptives must be used
throughout the study in both sexes. Women of childbearing potential must have a
negative serum pregnancy test 48 hours prior to administration of midostaurin. Women
considered not of childbearing potential include any of the following: no menses for
at least 5 years or menses within 5 years but amenorrheic for at least 2 months and
luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal
range (according to definition of postmenopausal for laboratory used) or bilateral
oophorectomy or radiation castration and amenorrheic for at least 3 months.

- Other known disease (except carcinoma in-situ) concurrent severe and/or uncontrolled
medical condition (eg 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.

- Impaired cardiac function including any of the following:

- Screening ECG with a QTc > 450 msec

- Congenital long QT syndrome

- History or presence of sustained ventricular tachycardia

- Any history of ventricular fibrillation or torsades de pointes

- Bradycardia defined as HR less than 50 bpm

- Right bundle branch block + left anterior hemiblock (bifascicular block)

- Myocardial infarction or unstable angina < 6 months prior to starting study drug

- CHF NY Heart Association class III or IV

- Ejection fraction < 50% assessed by MUGA or ECHO scan within 14 days of Day 1

- Known confirmed diagnosis of HIV infection or active viral hepatitis

- Received any investigational agent within 30 days prior to Day 1

- Any surgical procedure, excluding central venous catheter placement, bone marrow
biopsy or other minor procedures (eg skin biopsy) within 14 days of Day 1

- Unwilling or unable to comply with the protocol

- Known malignant disease of the central nervous system

- Any pulmonary infiltrate including those suspected to be of infectious origin. In
particular, patients with resolution of clinical symptoms of pulmonary infection but
with residual pulmonary infiltrates on chest x-ray are not eligible until pulmonary
infiltrates have completely resolved

- Patients with prior midostaurin (PKC412) treatment are excluded

- Patients receiving any other investigational agents or have received other
investigational agents within 30 days of enrollment

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