Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia

This study assesses the activity and safety profile of twice-daily oral doses of midostaurin
in patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) with or
without associated clonal hematological non-mast cell lineage disease (AHNMD).

Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are characterized by
excessive bone marrow production of mast cells which can can infiltrate tissues and release
harmful substances, resulting in organ damage. These diseases have very limited treatment
options and poor prognosis. Existing treatments for in advanced mast cell disease, eg,
interferon-alpha; corticosteroids; and/or cladribine, exhibit low response rates that are
usually partial in nature.

Inclusion criteria

- At least 18 years of age.

- Karnofsky performance status (KPS) of > 30% (equivalent to ECOG 0 to 3)

- Mast cell disease, histologically confirmed and documented to be

- Aggressive systemic mastocytosis (ASM) OR

- Mast cell leukemia (MCL) meeting the following criteria

- Meets criteria for systemic mastocytosis

- Biopsy indicates diffuse infiltration by atypical, immature mast cells

- Bone marrow aspirate smears show at least 20% mast cells

- Confirmed availability of tissue sample within 6 months prior to entry into study, for
evaluation of KIT mutation status of the tumor cells. Subjects who have systemic
mastocytosis PLUS eosinophilia AND known positivity for FIP1L1-PDGFR-alpha fusion are
eligible only if they have demonstrated relapse or disease progression on prior
imatinib therapy

- Blood levels of liver enzymes within normal limits (EXCEPTION: If the sole cause of
elevated blood levels of liver enzymes is ASM/MCL, then AST and ALT ≤ 4X upper limit
of normal (ULN), and/or bilirubin ≤ 4X ULN)

- Serum creatinine < 2.0 mg/dL

- If ANC < 1500/mm3; Hb < 10 g/dL; platelets < 75,000/mm3; AND/OR other blood values are
> grade 2, then the relationship of these cytopenia(s) should be established as
related to ASM or MCL on the basis of presence of mast cell infiltrate in the
screening bone marrow exam and/or the presence of disease-related hypersplenism

- Prior use of glucocorticoids must be tapered off within 14 days of Day 1 of
midostaurin treatment (EXCEPTION: If in the opinion of the investigator, the subject
can be tapered off glucocorticoids, then dosage should be tapered to the minimal dose
possible before first treatment with midostaurin)

- Negative serum pregnancy test for women of childbearing potential within 48 hours
prior to administration of study drug

- Written informed consent.

- Anyone of reproductive potential must agree to use barrier contraceptives for the
duration of the study

- Women of childbearing potential must have a negative serum pregnancy test 48 hours
prior to administration of study drug, and must agree to:

- Use barrier contraception for the duration of the study

- Use barrier contraception for 3 months post-study

- Not breast-feed

Exclusion criteria

- Active pulmonary disease based on physical assessment or lateral chest X-ray,
considered by the investigator to be unrelated to mastocytosis

- Any pulmonary infiltrate or abnormality on the baseline chest X-ray known to be new in
the previous 4 weeks (EXCEPTION: pleural effusion related to systemic mastocytosis,
eg, secondary to ascites, AND not causing symptomatic respiratory complaints, may be
eligible)

- Cardiovascular disease, including congestive heart failure

- Myocardial infarction within 6 months

- Poorly-controlled hypertension with any Grade 3/4 cardiac problems (per New York Heart
Association Criteria)

- Uncontrolled diabetes

- Chronic renal disease

- Active uncontrolled infection

- Known malignant disease involving the central nervous system (CNS)

- Known confirmed diagnosis of HIV infection or active viral hepatitis.

- Any other known disease, or concurrent severe and/or uncontrolled medical condition
which could compromise participation in the study, including but not limited to:

- Received any investigational agent, chemotherapy, or 2-chlorodeoxyadenosine (2-CdA)
within 30 days prior to Day 1 of PKC412 treatment.

- Received interferon-alpha within 30 days prior to Day 1 of midostaurin treatment.

- Received hematopoietic growth factor support within 14 days of Day 1 of midostaurin
treatment.

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

- Pregnant or breast-feeding

- Unwilling or unable to comply with the protocol