Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

In this study, patients will receive either the experimental agent (midostaurin) or placebo
combined with chemotherapy treatment. Patients are stratified according to FLT3 mutation
status (internal tandem duplication [ITD] allelic ratio < 0.7 vs ITD allelic ratio ≥ 0.7 vs
tandem kinase domain [TKD]). There are three parts to the study treatment: remission
induction therapy, remission consolidation therapy and continuation therapy.

Remission Induction Therapy:

- Cytarabine 200 mg/m2/day by continuous intravenous infusion on days 1-7

- Daunorubicin 60 mg/m2/day by intravenous push or short infusion on days 1-3

- Midostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) twice a
day by mouth on days 8-21

- A bone marrow aspiration will be performed in all patients on Day 21 to determine the
need for a second induction cycle.

Remission Consolidation (Four Remission Consolidation Cycles):

- High dose cytarabine 3000 mg/m2 will be given by intravenous infusion over 3 hours every
12 hours on days 1, 3 and 5. Serial neurologic evaluation will be performed before and
following the infusion of high-dose cytarabine.

- Dexamethasone 0.1% or other corticosteroid ophthalmic solution 2 drops to each eye once
daily to begin 6-12 hours prior to the initiation of the cytarabine infusion and to
continue for at least 24 hours after the last cytarabine dose.

- Midostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) twice a
day by mouth on days 8-21

Midostaurin/Placebo Continuation Therapy:

- Midostaurin 50 mg (two 25 mg capsules) or placebo for midostaurin (2 capsules) by mouth
twice a day for 28 days. Each cycle will be 28 days in length. Continuation therapy with
midostaurin/placebo will continue until relapse or for 12 cycles maximum.

The primary and secondary objectives of this study are:

Primary objective:

- To determine if the addition of midostaurin to daunorubicin/cytarabine induction,
high-dose cytarabine consolidation, and continuation therapy improves overall survival
(OS) in both the mutant FLT3-ITD and FLT3-TKD AML patients

Secondary objectives:

- To compare the overall survival (OS) in the two groups using an analysis in which
patients who receive a stem cell transplant are censored at the time of transplant

- To compare the complete response (CR) rate between the two treatment groups

- To compare the event-free survival (EFS) between the two treatment groups

- To compare the disease free survival (DFS) of the two treatment groups

- To compare the disease free survival rate one year after completion of the continuation
phase of the two groups

- To assess the toxicity of the experimental combination

- To describe the interaction between treatment outcome and pretreatment characteristics
such as age, performance status, white blood cell (WBC) count, morphology, cytogenetics,
and molecular and pharmacodynamic features

- To assess the population pharmacokinetics (popPK) of midostaurin and its two major
metabolites (CGP52421 and CGP62221). The potential association(s) between PK exposure
and FLT3 status, OS, EFS and clinical response will be explored

There is a pharmacokinetic sub-study (CALGB 60706) within CALGB 10603. This embedded
companion study must be offered to all patients enrolled on CALGB 10603, although patients
may opt not to participate in CALGB 60706.

After study entry, patients are followed periodically for up to 10 years.

1. Documentation of Disease:

- Unequivocal diagnosis of AML ( > 20% blasts in the bone marrow based on the WHO
classification), excluding M3 (acute promyelocytic leukemia). Patients with
neurologic symptoms suggestive of CNS leukemia are recommended to have a lumbar
puncture. Patients whose CSF is positive for AML blasts are not eligible.

- Documented FLT3 mutation (ITD or point mutation), determined by analysis in a
protocol- designated FLT3 screening laboratory.

2. Age Requirement:

- Age ≥ 18 and < 60 years

3. Prior Therapy:

- No prior chemotherapy for leukemia or myelodysplasia with the following
exceptions:

- emergency leukapheresis

- emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 5 days

- cranial RT for CNS leukostasis (one dose only)

- growth factor/cytokine support

- AML patients with a history of antecedent myelodysplasia (MDS) remain eligible
for treatment on this trial, but must not have had prior cytotoxic therapy (e.g.,
azacitidine or decitabine)

- Patients who have developed therapy related AML after prior RT or chemotherapy
for another cancer or disorder are not eligible.

4. Cardiac Function: Patients with symptomatic congestive heart failure are not eligible.

5. Initial Laboratory Value: Total bilirubin < 2.5 x ULN (Upper Limit of Normal)

6. Pregnancy and Nursing Status:

- Non-pregnant and non-nursing due to the unknown teratogenic potential of
midostaurin in humans, pregnant or nursing patients may not be enrolled.

- Women of childbearing potential must have a negative serum or urine pregnancy
test within a sensitivity of at least 50 mIU/mL within 16 days prior to
registration.

- Women of child-bearing potential must either commit to continued abstinence from
heterosexual intercourse or commit to TWO acceptable methods of birth control:

- one highly effective method (eg, IUD, hormonal (non-oral contraceptive),
tubal ligation, or partner's vasectomy) and

- one additional effective method (e.g., latex condom, diaphragm or cervical
cap)

- The two acceptable methods of birth control must be used AT THE SAME TIME, before
beginning midostaurin/placebo therapy and continuing for 12 weeks after
completion of all therapy.

- Note that oral contraceptives are not considered a high effective method because
of the possibility of a drug interaction with midostaurin.

- Women of childbearing potential is defined as a sexually active mature woman who
has not undergone a hysterectomy or who has not had menses at any time in the
preceding 24 consecutive months.

- Men must agree not to father a child and must use a latex condom during any
sexual contact with women of childbearing potential while taking
midostaurin/placebo and for 12 weeks after therapy is stopped, even if they have
undergone a successful vasectomy.