Phase II Trial of Alisertib With Induction Chemotherapy in High-risk AML

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied.

As part of this research study, the participant will take alisertib in combination with
conventional chemotherapies, idarubicin and cytarabine. Alisertib has not been approved by
the FDA (U.S. Food and Drug Administration) for acute myeloid leukemia (AML). However,
cytarabine and idarubicin have both been approved by the FDA for treatment of AML. It also
means that the FDA (U.S. Food and Drug Administration) has not approved giving alisertib with
idarubicin and cytarabine for use in participants, including participants with this type of
cancer.

Earlier pre-clinical studies and clinical trials have suggested the alisertib may have
clinical promise as a single agent in acute myeloid leukemia. Alisertib is a selective small
molecule inhibitor of Aurora A kinase, an enzyme which may play a role in the survival of
leukemia cells. Alisertib is being studied for the treatment of advanced malignancies,
including AML. Essentially, this means that alisertib may work to halt the growth of
malignancy (abnormal cells dividing without control and invading nearby tissues) through a
targeted mechanism. By combining alisertib with standard chemotherapy, the hope is to enhance
the efficacy of current treatment used for acute myeloid leukemia. An earlier study of this
combination has completed accrual, and demonstrated that the regimen is well tolerated.

Through this study, the investigators would like to determine if the addition of alisertib to
standard 7+3 chemotherapy improves efficacy as measured by the rate of complete remission (a
decreased or disappearance of signs and symptoms of cancer).

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.