Phase II Trial of Alisertib With Induction Chemotherapy in High-risk AML
Condition: Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Alisertib; Cytarabine; Idarubicin; Daunorubicin
Intervention description: Can be used in place of idarubicin
Intervention MeSH terms: Cytarabine; Daunorubicin; Idarubicin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Myeloid Leukemia

Summary:

      This research study is studying a targeted therapy (a form of treatment that uses drugs or
      other substances to identify and attack specific types of cancer cells with less harm to
      normal cells) as a possible treatment for high-risk acute myeloid leukemia.

      The names of the study interventions involved in this study are:

        -  Alisertib / MLN8237

        -  Cytarabine / Cytosine Arabinoside

        -  Idarubicin / Idarubicin hydrochloride

        -  Daunorubicin (Can be used in place of idarubicin)
    

Eligibility criteria:

        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 greater than or equal to 65 years

               -  Poor risk karyotype, as per Leukemianet criteria

               -  Antecedent or underlying myelodysplastic syndrome or myeloproliferative neoplasm

               -  AML with MDS-related changes

          -  Adults, age 18 years or older at the time of diagnosis, eligible for standard
             induction chemotherapy according to their treating physician.

          -  ECOG performance status 0-2 (Karnofsky ≥60%, see Appendix A)

          -  Left ventricular ejection fraction > 50% as measured by echocardiogram or 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 (APL, M3-AML),
             although if confirmed to have APL these patients will be excluded from the study.

          -  Adequate renal function as defined by: calculated creatinine clearance ≥40 mL/min
             (Cockcroft-Gualt Formula)

          -  Direct bilirubin < 2.0 x upper limit of normal (ULN), SGOT (AST) and SGPT (ALT)< 2.5 x
             ULN. AST and/or ALT may be up to 5X ULN if thought to be secondary to leukemia.

          -  The effects of alisertib on the developing human fetus are unknown. For this reason
             and because other chemotherapeutic agents are known to be teratogenic, women of
             child-bearing 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 do not otherwise fulfill criteria
             mentioned in bullet 3.1.1, and are found to harbor "intermediate" or "favorable" risk
             cytogenetics 41:

          -  In such patients, a sample to evaluate patient cytogenetics will be sent at the time
             of diagnosis per standard clinical care and the absence of favorable or
             intermediate-risk cytogenetics must be confirmed by Day 8. If the cytogenetic analysis
             reveals that the patient harbors non-poor risk cytogenetics, or if the cytogenetic
             results are not received prior to Day 8, the participant will be removed from the
             study.

          -  Patients with acute bilineal/biphenotypic leukemia

          -  Participants who have had chemotherapy or radiotherapy within 14 days prior to
             entering the study, except for hydroxyurea or 6-MP as noted.

          -  Participants who are receiving or have received any other investigational agents
             within 14 days of enrollment.

          -  Chemo-, hormono-, radio- or 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

               -  Tested positive for the presence of at least 1 of the following 3 markers in
                  blood (evaluated at screening): hepatitis B surface antigen (HBsAG), antibodies
                  against hepatitis B core antigen (anti-HBc), or hepatitis B viral load (HBV DNA).

          -  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 (LVEF <50%, as
             measured by MUGA scan or echocardiogram). Prior to study entry, any 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 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 because alisertib, along with standard
             induction chemotherapy, carries the potential for teratogenic or abortifacient
             effects. Because there is an unknown but potential risk for adverse events in nursing
             infants secondary to treatment of the mother with alisertib as well as cytarabine and
             idarubicin, breastfeeding should be avoided. Confirmation that the subject is not
             pregnant must be established by a negative serum ß-human chorionic gonadotropin (
             ß-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
             required for post-menopausal or surgically sterilized women.

          -  Although not absolute exclusion criteria, because of known drug-drug interactions,
             below are issues that should be considered during enrollment:

          -  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.