Pevonedistat and Decitabine in Treating Patients With High Risk Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. Determine if the addition of pevonedistat to standard dose decitabine is safe and
tolerable by the evaluation of toxicities including: type, frequency, severity, attribution,
time course, reversibility and duration.

II. Determine the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of
pevonedistat when given in combination with standard dose decitabine.

SECONDARY OBJECTIVES:

I. Obtain preliminary estimates of complete remission (CR) rate, overall response rate (ORR:
CR+CRi [incomplete CR]), duration of response, and survival probabilities: overall survival
(OS) and event-free survival (EFS) at 1-year and 2-years.

II. Demonstrate down-modulation of micro ribonucleic acid (miR)-155 and increased expression
of miR-155 targets (SHIP1 and PU.1) in vivo.

III. Examine the impact of the combination on leukemia stem cells (LSCs); enriched blast cell
subpopulations.

IV. Evaluate possible associations between changes in levels of miR-155, miR-155 gene targets
(PU.1, SHIP1) and toxicity and/or clinical response.

OUTLINE: This is a dose-escalation study of pevonedistat.

Patients receive pevonedistat intravenously (IV) over 1 hour on days 1, 3, and 5 and
decitabine IV over 1 hour on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24
courses in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are follow up for 30 days, monthly for 1 year,
and bi-monthly for another year.

Inclusion Criteria:

- Patients diagnosed with acute myeloid leukemia (AML) by World Health Organization
(WHO) classification, meeting one of following criteria:

- Age 60 or older, newly diagnosed, untreated, who are unwilling to undergo or not
candidates for conventional induction chemotherapy with cytarabine/anthracyclines

- Age 60 or older with relapsed or refractory disease

- Younger adult patients with previously untreated high-risk disease (complex
karyotype, inv[3] or t[3;3], t[6;9], monosomal karyotype, therapy-related and
secondary disease) that are unwilling to undergo or not candidates for
conventional induction chemotherapy with cytarabine/anthracyclines and/or
allogeneic stem cell transplantation

- Younger patients with refractory/relapsed AML who are otherwise not candidates
for allogeneic stem cell transplantation

- Patients with extramedullary disease who meet one of the above criteria may be
included

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Patients with co-morbid medical illness, life expectancy attributed to this must be
greater than 6 months

- Women of child-bearing potential and men must agree to use effective contraception
(hormonal or barrier method of birth control or abstinence) prior to study entry and
for 4 months following duration of study participation; should a woman become pregnant
or suspect that she is pregnant while participating on the trial, she should inform
her treating physician immediately

- Female patients must be:

- Postmenopausal for at least 1 year before the screening visit, OR

- Surgically sterile, OR

- If they are of childbearing potential

** Agree to practice 1 highly effective method and one additional effective
(barrier) method of contraception, at the same time, from the time of signing the
informed consent through 4 months after the last dose of study drug , (female and
male condoms should not be used together), OR

- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject; (periodic abstinence [e.g., calendar, ovulation,
symptothermal, postovulation methods] withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception)

- Male patients, even if surgically sterilized (i.e., status post-vasectomy) must:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 6 months after the last dose of study drug (female
and male condoms should not be used together), or

- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject; (periodic abstinence [e.g., calendar, ovulation,
symptothermal, postovulation methods for the female partner] withdrawal,
spermicides only, and lactational amenorrhea are not acceptable methods of
contraception)

- Creatinine < 1.5 X institutional upper limit of normal

- OR creatinine clearance >= 60 mL/min for patients with creatinine levels above 1.5 X
institutional upper limit of normal

- Cardiac ejection fraction >= 50%

- Albumin > 2.7 g/dL

- Total bilirubin =< institutional upper limit of normal (ULN) (except in patients with
Gilbert's syndrome; patients with Gilbert's syndrome may enroll if direct bilirubin is
=< 1.5 x ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 ULN unless
higher levels are related to leukemic infiltration

- Hemoglobin > 8 g/dL; patients may be transfused to receive this value; elevated
indirect bilirubin due to post-transfusion hemolysis is allowed

- All subjects must have the ability to understand and the willingness to sign a written
informed consent

- The following patients are allowed:

- Patients may have been treated for AML or antecedent hematologic disorder with
myeloid growth factors, recombinant erythropoietin, thalidomide, lenalidomide,
5-azacitidine or decitabine

- Any prior chemo therapy must have been completed >= 2 weeks prior to day 1 of
study treatment and the participant must have recovered to eligibility levels
from prior toxicity

- There is no limit for prior chemo regimens

- Patients may have received hematopoietic stem cell transplantation for AML or
other diseases

- Hydroxyurea is allowed prior to day 1 of study treatment for count control and
during cycle 1; the use of hydroxyurea is not allowed beyond completion of cycle
1

Exclusion Criteria:

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pevonedistat or decitabine

- Patients have received prior chemotherapy or radiation for AML < two weeks before
study enrollment, or those who have not recovered from the adverse events due to
agents administered

- Females who are both lactating and breastfeeding or who have a positive serum
pregnancy test during the screening period or a positive urine pregnancy test on day 1
before first dose of study drug

- Patients with additional (other than AML) active malignancies, other than curatively
treated carcinoma in situ (CIS) of the cervix, or basal or squamous cell carcinoma of
the skin; patients are not considered to have a "currently active" malignancy if they
have completed therapy for a prior malignancy and disease free from prior malignancies
for > 2 years

- Life-threatening illness unrelated to cancer

- Known cardiopulmonary disease defined as one of the following:

- Unstable angina

- Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg,
diastolic blood pressure > 95 mm Hg)

- Cardiomyopathy or history of ischemic heart disease

- Arrhythmia (eg, history of polymorphic ventricular fibrillation or torsade de
pointes); permanent atrial fibrillation (a fib) defined as continuous a fib >= 6
months; persistent a fib defined as sustained a fib lasting > 7 days and/or
requiring cardioversion in the 4 weeks before screening; however, patients with <
grade 3 atrial fibrillation (a fib) for a period of at least 6 months may enroll;
grade 3 a fib is symptomatic and incompletely controlled medically, or controlled
with device (e.g., pacemaker), or ablation; patients with paroxysmal a fib are
permitted to enroll

- Implantable cardioverter defibrillator

- Congestive heart failure (New York Heart Association [NYHA] class III or IV; or
class II with a recent decompensation requiring hospitalization or referral to a
heart failure clinic within 4 weeks before screening),

- Myocardial infarction and/or revascularization (eg, coronary artery bypass graft,
stent) within 6 months of first dose of study drug

- Patients who had ischemic heart disease who have had ACS, MI, and/or
revascularization greater than 6 months before screening and who are without
cardiac symptoms may enroll

- Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)

- Pulmonary hypertension

- Patients with uncontrolled coagulopathy or bleeding disorder

- Prolonged rate corrected QT (QTc) interval of >500 msec, calculated according to
institutional guidelines

- Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or
radionuclide angiography

- Known moderate to severe chronic obstructive pulmonary disease (COPD), interstitial
lung disease, and pulmonary fibrosis

- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of study procedures

- Treatment with any investigational products within 14 days before the first dose of
any study drug

- Active uncontrolled infection or severe infectious disease, such as severe pneumonia,
meningitis, septicemia, or methicillin resistant Staphylococcus aureus infection

- Major surgery within 14 days before the first dose of any study drug or a scheduled
surgery during study period

- Known central nervous system (CNS) involvement

- Known human immunodeficiency virus (HIV) seropositive

- Known hepatitis B surface antigen seropositive or known or suspected active hepatitis
C infection; Note: Patients who have isolated positive hepatitis B core antibody (ie,
in the setting of negative hepatitis B surface antigen and negative hepatitis B
surface antibody) must have an undetectable hepatitis B viral load; patients who have
positive hepatitic C antibody may be included if they have an undetectable hepatitis C
viral load

- Known hepatic cirrhosis or severe pre-existing hepatic impairment

- Systemic antineoplastic therapy or radiotherapy for other malignant conditions within
14 days before the first dose of any study drug, except for hydroxyurea

- White blood cell (WBC) > 50,000/mcL

- Treatment with clinically significant metabolic enzyme inducers within 14 days before
the first dose of the study drug. Clinically significant metabolic enzyme inducers are
not permitted during this study (CYP3A4/5 inducers)

- Female patients who intend to donate eggs (ova) during the course of this study or 4
months after receiving their last dose of study drug(s)

- Male patients who intend to donate sperm during the course of this study or 4 months
after receiving their last dose of study drug(s)

- Subjects, who in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study