MEK Inhibitor MEK162, Idarubicin, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. Determine maximum tolerated dose (MTD) of MEK162 (MEK inhibitor MEK162) in patients with
RAS-mutated acute myeloid leukemia (AML) when combined with sequential induction chemotherapy
(3+4) as measured by development of grade 3-4 dose-limiting toxicities (DLT).

SECONDARY OBJECTIVES:

I. Analyze downstream inhibition of RAS signaling following therapy with single-agent MEK162
with exploratory pharmacodynamics (PD) studies.

II. Perform preliminary efficacy analysis of combination of MEK162 and induction chemotherapy
(3+4) in patients with RAS-mutated AML by measuring complete remission rate, 2-year overall
survival, and duration of response.

OUTLINE:

INDUCTION THERAPY: Patients receive MEK inhibitor MEK162 orally (PO) twice daily (BID) on
days -4 to -1 and days 5-18, cytarabine intravenously (IV) continuously over 24 hours on days
1-4, and idarubicin IV over 1 hour on days 1-3. Patients may receive a second course of
induction at the discretion of the principal investigator.

POST-REMISSION THERAPY: Patients receive cytarabine IV continuously over 24 hours on days
1-3, idarubicin IV over 1 hour on days 1 and 2, and MEK inhibitor MEK 162 PO BID on days
4-17. Treatment repeats every 28 days for up to 4 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Prior morphological diagnosis of AML other than acute promyelocytic leukemia according
to the 2001 World Health Organization (WHO) diagnostic criteria; patients with
biphenotypic, RAS-mutated acute leukemia are also eligible

- Requiring salvage chemotherapy for persistent/refractory or relapsed disease after at
least one course of conventional chemotherapy, e.g. with "7+3", as defined by
persistence of >= 20% myeloid blasts on bone marrow aspirate or peripheral blood
smear; a bone marrow biopsy is not routinely required, but should be obtained if the
aspirate is dilute, hypocellular, or inaspirable; outside bone marrow examinations
performed within the stipulated time period are acceptable for screening as long as
the slides are reviewed at the study institution; flow cytometric analysis of the bone
marrow aspirate should be performed according to institutional practice guidelines

- Confirmed RAS mutation (NRAS or KRAS) or confirmed PTPN11 mutation, measured on
peripheral blood or bone marrow aspirate as part of screening prior to study
enrollment; mutation status must be confirmed within 45 days of initiation of therapy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times upper
limit of normal (ULN)

- Serum bilirubin =< 2 times ULN

- Serum creatinine =< 1.5 mg/dl and/or creatinine clearance >= 50 mL/min

- Ejection fraction >= 50% by echocardiogram

- Corrected QT (QTc) interval =< 480 ms

- Ability to take oral medications

- Ability to understand and the willingness to sign a written informed consent document

- Ability to undergo standard induction chemotherapy

- Ability to adhere to the study visit schedule and other protocol requirements

- Life expectancy of greater than 2 months

- Negative serum beta-human chorionic gonadotropin (HCG) test (female patient of
childbearing potential only) performed locally within 72 hrs prior to first dose

Exclusion Criteria:

- Concomitant treatment with other anti-neoplastic agents, with the exception of
hydroxyurea

- Anti-neoplastic treatment less than 14 days prior to enrollment, with the exceptions
of hydroxyurea or, in the case of a patient with primary refractory AML, prior
induction chemotherapy

- Prior therapy with a MEK inhibitor

- Uncontrolled opportunistic infection or treatment for opportunistic infection within 4
weeks of first day of study drug dosing

- Other medical or psychiatric illness or organ dysfunction or laboratory abnormality
which in the opinion of the investigator would compromise the patient's safety or
interfere with data interpretation, e.g., infection/inflammation, intestinal
obstruction, unable to swallow medication, social/ psychological issues, etc.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MEK162, anthracycline, or cytarabine

- Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of MEK162 (e.g., ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)

- Previous or concurrent malignancy with the following exceptions:

- Carcinoma in situ

- Adequately treated skin basal cell or squamous cell carcinoma (adequate wound
healing is required prior to study entry)

- In situ carcinoma of the cervix, treated curatively and without evidence of
recurrence for at least 3 years prior to the study

- A primary malignancy which has been completely resected and in complete remission
for >= 5 years

- Impaired cardiovascular function or clinically significant cardiovascular diseases,
including any of the following:

- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting [CABG], coronary angioplasty, or
stenting) < 6 months prior to screening

- Symptomatic chronic heart failure

- Evidence of clinically significant cardiac arrhythmias and/or conduction
abnormalities < 6 months prior to screening except atrial fibrillation and
paroxysmal supraventricular tachycardia

- Uncontrolled arterial hypertension despite appropriate medical therapy

- Patients who have neuromuscular disorders that are associated with elevated creatine
kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
sclerosis, spinal muscular atrophy)

- Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or active
viral hepatitis (hepatitis B or hepatitis C)

- Any surgical procedure, excluding central venous catheter placement, bone marrow
biopsy, lumbar puncture, or other minor procedures (e.g., skin biopsy) within 14 days
of day 1; patients who have undergone major surgery =< 21 days prior to starting study
drug or who have not recovered from side effects of such procedure are ineligible for
the study

- Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test

- Women of child-bearing potential unless they are using highly effective methods
of contraception throughout the study and for 30 days after study drug
discontinuation

- Sexually active males unless they use a condom during intercourse while taking the
drug and for 30 days after stopping treatment and should not father a child in this
period; a condom is required to be used also by vasectomized men in order to prevent
delivery of the drug via seminal fluid

- Unwillingness or inability to comply with the protocol

- Known active leukemia of the central nervous system

- Known history of Gilbert's syndrome

- History or current evidence of retinal pigment epithelial detachment (RPED), retinal
vein occlusion (RVO), or predisposing factors to RPED or RVO (e.g. uncontrolled
glaucoma or ocular hypertension, uncontrolled diabetes mellitus, hyperviscosity or
hypercoagulability syndromes)

- History of retinal degenerative disease