A Safety and Efficacy Study of LGH447 in Patients With Acute Myeloid Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)

Inclusion Criteria

-Male or female patients ≥18 years of age who present with one of the following:

LGH447 monotherapy arm

- Refractory/Relapsed AML following no more than 2 prior therapies, or in previously
untreated AML patients who are not candidates for standard therapy.

- High and very high risk MDS according to the revised International Prognostic Scoring
System (rIPSS) who have failed prior therapies, such as azacitidine and decitabine

- Patients with rIPSS score of > 4.5

LGH447 and midostaurin combination arm

- Refractory/Relapsed AML following no more than 2 prior therapies, or in previously
untreated AML patients who are not candidates for standard therapy. AML patients may
have either FLT3 wild type or FLT3-ITD/TKD mutant disease, and FLT3 mutation status
needs to be defined at study entry.

- For AML patients, peripheral blast counts < 50,000 blasts/mm3

- For MDS patients;

- Platelet count > 25,000/mm3

- Neutrophils > 500/mm3

- Blood transfusions are allowed to maintain clinically adequate hemoglobin and
hematocrit levels

- Patients with active central nervous system (CNS) disease are eligible to
participate and may be treated concurrently with intrathecal (or intra Ommaya)
chemotherapy

- Patients who are maintained on prophylactic antibiotics are eligible to
participate as long as agents comply with the list of approved concomitant
medications

- Performance status ≤ 2

- Meet other lab criteria

Exclusion Criteria

- Systemic antineoplastic therapy (including unconjugated therapeutic antibodies and
toxin immunoconjugates) or any experimental therapy within 7 days or 5 half-lives,
whichever is longer, before the first dose of LGH447 monotherapy or LGH447 in
combination with midostaurin

- Radiotherapy with a wide field of radiation within 28 days or radiotherapy with a
limited field of radiation for palliation within 7 days of the first dose of LGH447
monotherapy or LGH447 in combination with midostaurin

- Patients who received CNS irradiation for meningeal leukemia, except if radiotherapy
occurred > 3 months previously

- Major surgery within 4 weeks before the first dose of LGH447 monotherapy or LGH447 in
combination with midostaurin

- Ongoing therapy with corticosteroids greater than 10 mg of prednisone or its
equivalent per day. Inhaled and topical steroids are permitted

- Patients who are currently receiving hydroxyurea to control peripheral blood leukemic
blasts and cannot be discontinued for at least 48 hours prior to obtaining PD
biomarkers at screening/baseline and during the study

- Patients who are currently receiving treatment with prohibited medication and that
cannot be discontinued at least one week prior to the start of treatment with LGH447
monotherapy or LGH447 in combination with midostaurin

- Active infection requiring systemic therapy or other severe infection, including
pneumonia, within 2 weeks before the first dose of LGH447 monotherapy or LGH447 in
combination with midostaurin

- Known human immunodeficiency virus (HIV) positive

- Corrected QT interval (QTc) of > 450 milliseconds (ms) in males and > 470 milliseconds
(ms) in females on baseline electrocardiogram (ECG) (using corrected QT interval using
Fridericia [QTcF] or local standards).

- Uncontrolled cardiovascular condition, including ongoing cardiac arrhythmias,
congestive heart failure, angina, or myocardial infarction within the past 6 months

- Pregnant or nursing