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

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