Alisertib in Combination with Cytarabine and Idarubicin in Treating Patients with High-Risk Acute Myeloid Leukemia

Inclusion Criteria

• Participants must have pathologically confirmed, newly diagnosed high-risk acute myeloid leukemia, as defined by at least one of the following criteria: * Age >= 65 years * Age >= 18 years with adverse risk karyotype, as per European Leukemia Net Guidelines * Age >= 18 years with antecedent or underlying myelodysplastic syndrome, chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm * Age >=18 years with acute myeloid leukemia (AML) with myelodysplastic syndrome (MDS)-related changes ** Note: For patients in category A, a sample to evaluate patient cytogenetics will be sent at the time of diagnosis per standard clinical care and the absence of favorable risk cytogenetics must be confirmed by day 8; if the cytogenetic analysis reveals that the patient harbors favorable risk cytogenetics, or if the cytogenetic results are not received prior to day 8, the participant will be removed from the study; patients removed due to presence of favorable cytogenetics would be considered to be inevaluable and will be replaced; in addition, patients who receive less than half of their total alisertib dose during induction would be considered to be inevaluable and will be replaced
• Eligible for standard induction chemotherapy according to their treating physician
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >= 60%)
• Left ventricular ejection fraction > 50% as measured by echocardiogram or multi gated acquisition (MUGA) scan
• Must not have received systemic antineoplastic therapy including radiation therapy within 14 days of the study enrollment, except hydroxyurea or 6-mercaptopurine for the purposes of cytoreduction; patients may also have received all-trans retinoic acid (ATRA) if there is an early suspicion of acute promyelocytic leukemia (acute promyelocytic leukemia [APL], M3-AML), although if confirmed to have APL these patients will be excluded from the study
• Calculated creatinine clearance >= 40 mL/min (Cockcroft-Gault formula)
• Direct bilirubin < 2.0 x upper limit of normal (ULN)
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x ULN; AST and/or ALT may be up to 5 X ULN if thought to be secondary to leukemia
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation, and 6 months after completion of therapy
• Subject must be able to take oral medication and to maintain a fast as required for 2 hours before and 1 hour after alisertib administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients will be excluded from this study if they are found to harbor “favorable” risk cytogenetics
• Patients with acute bilineal/biphenotypic leukemia
• Participants who have had systemic chemotherapy or radiotherapy within 14 days prior to entering the study, except for hydroxyurea or 6-mercaptopurine (MP) as noted; empiric intrathecal chemotherapy during a diagnostic lumbar pucture is allowed, as long as central nervous system (CNS) disease is not suspected
• Participants who are receiving or have received any other investigational agents within 14 days of enrollment
• Immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug
• Persistence of clinically relevant therapy related toxicity from previous anti-cancer therapy
• Prior allogeneic bone marrow or organ transplantation
• Individuals with a history of a different malignancy are ineligible except for the following circumstances; individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
• Current clinical central nervous system (CNS) symptoms deemed by the investigator to be related to leukemic CNS involvement (no lumbar puncture required, clinical assessment per investigator’s judgment is sufficient)
• If applicable, patient with >= grade 2 peripheral neuropathy within 14 days before enrollment
• Prior treatment with alisertib
• Known history of hepatitis C infection or suspected currently active hepatitis C infection; known or suspected history of hepatitis B infection will be excluded when any of the following conditions are met: * Received hematopoietic stem cell transplantation (either allogenic or autologous), or * Received any rituximab-containing treatment regimen in the last 12 months before entering the study, or * Active hepatitis B as deemed by serology or viral load
• Current or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (left ventricular ejection fraction [LVEF] < 50%, as measured by MUGA scan or echocardiogram); prior to study entry, any electrocardiography (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
• Known hypersensitivity to the trial drugs or other contraindication to standard “7+3” induction chemotherapy
• Known history of uncontrolled sleep apnea syndrome, or sleep apnea requiring supplemental oxygen, and other conditions that could result in excessive daytime sleepiness
• A medical condition requiring use of proton pump inhibitors (PPIs); or histamine 2 (H2) receptor antagonists; patients who intermittently use these medications, must meet the following criteria: * No use of PPIs within 5 days before the first dose of alisertib * No use of H2 antagonist or pancreatic enzymes within 24 hours before the first dose of alisertib
• Patients with mental deficits or psychiatric conditions that preclude them from giving informed consent or following protocol
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Known gastrointestinal (GI) disease or GI procedures that could interfere with the oral absorption or tolerance of alisertib; examples include, but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease
• Pregnant women are excluded from this study; breastfeeding should be avoided; confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women
• Treatment with clinically significant enzyme-inducing drugs, including known P-glycoprotein inducers (including St. John’s Wort and rifampicin) should be used only if absolutely necessary and considered to be the best available choice for the patient; if possible, it is recommended that alternatives to known substrates, inhibitors or inducers of P-glycoprotein be considered; cases should be discussed with the principal investigator, and may be allowed as per his/her discretion
• Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up
• Patients who are otherwise felt unable to comply with the protocol, in the opinion of the investigator