iCare4: Genomic Signatures With Midostaurin in Acute Myeloid Leukemia (UF-HEM-004)

Clinical trials have shown that the multi-kinase inhibitor midostaurin improves survival in
patients with AML. The main objective of this study is to investigate its effect (in
conjunction with cytarabine) on progression free survival, as well as overall survival and
morphologic response rate in patients with relapsed or refractory AML. This study will also
attempt to identify specific populations of patients with relapsed or refractory AML who best
respond to treatment with midostaurin to enhance treatment planning.

Inclusion Criteria:

- Written informed consent obtained from the subject prior to registration on the study
and the ability for the subject to adhere to the study visit schedule and all the
study-related procedures.

- A diagnosis of relapsed or refractory AML. For the purpose of this study, refractory
AML is defined as failure to achieve CR after one cycle of induction chemotherapy and
relapsed AML is defined as any evidence of disease recurrence after achieving CR of
any duration.

- Both males and females ≥ eighteen years of age

- Karnofsky Performance Status of ≥ 70% or Eastern Cooperative Oncology Group (ECOG)
performance status < 2 (unless poor performance status is related to the disease).

- Adequate organ function defined as:

- AST and ALT < 2.5 times the upper limit of normal (ULN),

- Serum bilirubin < 2.5 x ULN, and

- Serum creatinine < 1.5 mg/dL or creatinine clearance > 50 mL/min.

- Laboratory values can be outside of this range if secondary to AML disease.

- An ejection fraction of > 45% confirmed by echocardiogram.

- Life expectancy of greater than one month.

- Subjects who previously received midostaurin are allowed if the last dose of
midostaurin was given ≥ six months prior to disease relapse.

- Females who are non-pregnant and non-nursing.

- Females of reproductive age and males must agree to avoid getting pregnant or to
father a child while on therapy and for five months after the last dose of
chemotherapy.

- Women of child-bearing potential (WOCBP) must either agree to continued abstinence
from heterosexual intercourse or begin one of the following acceptable methods of
birth control: IUD, tubal ligation, or partner must use a latex condom during any
sexual contact, even if the partner has undergone a successful vasectomy. Hormonal
contraception is an inadequate method of birth control.

- Males must use a latex condom during any sexual contact with WOCBP, even if they have
undergone a successful vasectomy (while on therapy and for five months after the last
dose of chemotherapy)

Exclusion Criteria:

- Age ≥ of seventy-six years.

- Subjects with the inability to swallow oral medications.

- Clinical evidence of active CNS leukemia.

- A medical history of receiving an allogeneic hematopoietic stem cell transplantation
(HSCT).

- Subjects must not have any uncontrolled or intercurrent illness including, but not
limited to,

- ongoing or active infection,

- symptomatic congestive heart failure,

- unstable angina pectoris,

- cardiac arrhythmia,

- myocardial infarction within three months,

- poorly controlled hypertension,

- uncontrolled diabetes, or psychiatric illness/social situation that would limit
compliance with protocol requirements.

- Females or males of childbearing potential who are unwilling or unable to use an
acceptable method to avoid pregnancy for the entire study period and for at least five
months after the last dose of chemotherapy.

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of PKC412.

- Previous therapy with midostaurin within six months prior to relapse.

- History of any other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of protocol therapy or that might affect the interpretation of
the results of the study or that puts the subject at high risk for treatment
complications, in the opinion of the treating physician.

- Prisoners or subjects who are involuntarily incarcerated.

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical illness.

- Subjects demonstrating an inability to comply with the study and/or follow-up
procedures.