Cladribine Based Induction Therapy With All-Trans Retinoic Acid and Midostaurin in Relapsed/Refractory AML

The main purpose of this study is to gather information about the use of a drug called
midostaurin when given with ATRA and CLAG chemotherapy. Midostaurin is an investigational
drug. It is a drug that inhibits FLT3 that is mutated or overexpressed in a significant
proportion of AML patients. Research has shown that midostaurin and drugs like midostaurin
may work better in combination with chemotherapy, like CLAG. ATRA is known to promote
myeloid differentiation and has also been shown to augment cancer cell death in combination
with chemotherapy. CLAG is a combination of cladribine, cytarabine, and G-CSF which is
approved by the FDA and used to treat AML. This study will look at how safe this
combination is, how you tolerate the treatment, and to see what dose of midostaurin is
appropriate.

Inclusion Criteria:

- Patient must be ≥18 of age. Because no dosing or adverse event data are currently
available on the use of midostaurin in combination with ATRA and CLAG in patients <18
years of age, children are excluded from this study but will be eligible for future
pediatric phase 2 combination trials.

- Patient must be diagnosed with refractory or relapsed AML. For the purpose of the
study, refractory AML is defined as failure to achieve CR after 2 cycles of induction
chemotherapy or persistent > 40% bone marrow blasts after one cycle of chemotherapy
induction. Relapsed AML is defined as any evidence of disease recurrence after
achieving CR. Early relapse is defined as relapse occurring earlier than 12 months
and late relapse is defined as relapse occurring later than 12 months.

- Patient must have a Karnofsky Performance Status of ≥ 70% (unless poor performance
status is related to the disease).

- Patient must have the following laboratory values:

- AST and ALT ≤ 1.5 x Upper Limit of Normal (ULN),

- Serum Bilirubin ≤ 1.5 x ULN,

- Serum Creatinine ≤ 1.5 x ULN. Laboratory values can be outside this range if
secondary to AML disease.

- Patient must able to understand and willing to sign a written informed consent
document prior to registration on study.

- Both men and women and members of all races and ethnic groups are eligible for this
trial.

Exclusion Criteria:

- Patient must not have newly diagnosed AML.

- Patient must not have acute promyelocytic leukemia

- Patient must not have known CNS leukemia

- Patient must not have a history of allergic reactions to compounds of similar
chemical or biologic composition to midostaurin or other agents used in the study.

- Patient 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 6 months,
poorly controlled hypertension, uncontrolled diabetes, chronic renal disease, or
psychiatric illness/social situation that would limit compliance with study
requirements.

- Patient must not have any condition, including the presence of laboratory
abnormalities, which places him/her at unacceptable risk if s/he were to participate
in the study or confounds the ability to interpret data from the study.

- Patient may not concurrently use other anti-cancer agents or treatments (with the
exceptions of hydroxyurea, steroids, and leukopheresis).

- Female patients must not be pregnant or breastfeeding.

- Adults of reproductive potential must employ 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; 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); bilateral oophorectomy amenorrheic for at least
3 months.

- Patient must not have impaired cardiac function including any of the following:

- Screening ECG with a QTc > 450 msec

- Patients with congenital long QT syndrome

- History or presence of sustained ventricular tachycardia

- Any history of ventricular fibrillation or torsades de pointes

- Bradycardia defined as HR < 50 bpm

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

- Patients with myocardial infarction or unstable angina < 6 months prior to starting
study drug

- CHF NY Heart Association class III or IV

- Patients with an ejection fraction < 50% assessed by MUGA or ECHO scan within 14 days
of Day 1.

- Patients must not have a known confirmed diagnosis of HIV infection or active viral
hepatitis.

- Patient may not have received any investigational agent within 30 days prior to Day
1. Patient may not be receiving any other investigational agents while on this
trial.

- Patients must not have had any surgical procedure, excluding central venous catheter
placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1.

- Patients must not have 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.